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   key: cord-284245-y8q0cjbk authors: Vallis, Michael; Tang, Tricia; Klein, Gerri title: Mental Health in Diabetes: Never a Better Time date: 2020-08-10 journal: Can J Diabetes DOI: 10.1016/j.jcjd.2020.06.004 sha: doc_id: 284245 cord_uid: y8q0cjbk nan Mental Health in Diabetes: Never a Better Time We present this special issue of the Canadian Journal of Diabetes at a very unusual time in all of our lives. Not only has the COVID-19 pandemic had an impact on populations worldwide, the mortality and health-related consequences of this disease have been magnified in some communities over others, specifically for individuals with diabetes. Clearly, we are living through a global crisis that not only affects our health and mental health, but also has disrupted the economy, education and employment. As difficult as it is for us all, living with diabetes during this time of uncertainly caused by the COVID-19 pandemic heightens the already daunting task of diabetes self-management. Routines are disrupted, finances may be challenged and in this era of self-isolation, social supports are not as available. As diabetes care providers, the more we can help patients cope with the mental health impact of the pandemic, the better equipped they will be to perform all the behaviours necessary to keep their blood glucose levels in target. It is in this context that we offer this special issue on mental health and diabetes. Planning this special issue started prior to the pandemic and was based on the beliefs that diabetes has an impact on the mental health of the person living with the condition, and that mental health affects a person's ability to perform diabetes-related selfcare. As stress increases, self-care decreases. So, we have organized this issue to highlight this bidirectional relationship. In providing diabetes care on a day-to-day basis, we see the effect diabetes exerts on emotional health. Patients do not have the luxury of taking a break from diabetes. Not a day goes by without having to be reminded of this demanding condition that requires constant, ongoing self-care decisions. Ironically, the more invested in diabetes self-management our patients are (which is our explicit goal), the larger the psychological impact it will have. Yared et al (1) present a paper describing how a multidisciplinary type 1 clinic has incorporated the assessment and management of diabetes distress into their practice. Hendrieckx et al (2) performed an audit in Australia examining how persons with diabetes want to connect to their diabetes providers to address diabetes distress. Lafontaine (3) examines spousal support and relationship happiness in those with type 2 diabetes. Morgan et al (4) offer a paper on selfcompassion, adaptive reactions and health behaviours that adds to our understanding of living well with diabetes. Morrissey et al (5) present a paper on the role of diabetes distress in adolescents and young adults living with type 1 diabetes. deMolitor et al (6) present a public health perspective on the concept of diabetes distress. Additionally, there are contributions examining the potential for negative mental health impacts in the form of bereavement and grief reactions in those with type 1 diabetes (Fraser [7] ) and an important perspective paper on self-injury and suicide in those with diabetes (Barnard-Kelly et al [8] ). With regard to psychological stressors in economically disadvantaged populations, Kalra et al (9) report on a scoping review of the rates of depression and diabetes distress in South Asians from low-and moderate-income countries. This issue also offers a number of papers on mental health issues as they relate to diabetes. Cimo et al (10) present the outcomes of a diabetes education intervention in those living with diabetes and mental health disorders. Wong and Mehta (11) examine the efficacy integration of psychiatric care into diabetes education clinics for patients with comorbidities of depression and diabetes. Stenov et al (12) offer the diabetes support needs of those living with serious mental health disorders. Alessi et al (13) examine alcohol use and clinical outcomes in youth and adults with type 1 diabetes, and Mehta and Hirji (14) review the outcome of structured education for patients living with type 2 diabetes and substance abuse. Benson et al (15) examine depression in girls with type 2 diabetes, obesity and polycystic ovary syndrome. Finally, Riggin explores the relationship between gestational diabetes and perinatal mental health (16) . We hope that the papers in this issue inform and empower the Canadian diabetes professional community to continue to broaden our ability to address the important quality of life issues that are a central part of living with diabetes. Stay safe. Addressing a care gap in type 1 diabetes management: Using the Diabetes Distress Scale in a community care setting to address diabetes-related treatment challenges Adults with diabetes distress often want to talk with their health professionals about it: Findings from an audit of 4 Australian specialist diabetes clinics Spousal support and relationship happiness in adults with type 2 diabetes and their spouses Self-compassion, adaptive reactions and health behaviours among adults with prediabetes and type 1, type 2 and gestational diabetes: A scoping review Diabetes distress in adolescents and young adults living with type 1 diabetes Diabetes distress in adults living with type 1 and type 2 diabetes: A public health issue Bereavement, grief and adult type 1 diabetes: Living with diabetes today An intolerable burden: Suicide, intended self-injury and diabetes Depression and diabetes distress in South Asian adults living in low-and middle-income countries: A scoping review Exploring the outcomes of a pilot education program tailored for adults with type 2 diabetes and mental illness in a community mental health care setting Efficacy of depression management in an integrated psychiatric-diabetes education clinic for comorbid depression and diabetes mellitus types 1 and 2 Mental health professionals have never mentioned my diabetes, they don't get into that": A qualitative study of support needs in adults with type 1 and type 2 diabetes and severe mental illness Alcohol use and clinical outcomes in adults in the type 1 diabetes exchange The outcome of structured education in patients with type 2 diabetes mellitus and substance use disorder: A literature review Depression in girls with obesity and polycystic ovary syndrome and/or type 2 diabetes Association between gestational diabetes and mental illness Note From the Editors / Can 


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   key: cord-287362-dhl7ynrc authors: Unnikrishnan, Ranjit; Misra, Anoop title: Infections and diabetes: Risks and mitigation with reference to India date: 2020-09-22 journal: Diabetes Metab Syndr DOI: 10.1016/j.dsx.2020.09.022 sha: doc_id: 287362 cord_uid: dhl7ynrc BACKGROUND AND AIMS: The link between diabetes and increased risk of infectious disease has long been recognized, but has re-entered sharp focus following the COVID-19 pandemic. METHODS: A literature search was conducted in PubMed for articles in English on diabetes and infection. RESULTS: Diabetes predisposes to infections through alterations in innate and acquired immune defenses. Outcomes of infection are worse in people with uncontrolled diabetes, and infection can worsen hyperglycemia in hitherto well controlled diabetes (bidirectional relationship). Diabetes does not increase the risk of infection with COVID-19 per se, but predisposes to severe disease and poor outcomes. COVID-19 has also been linked to deterioration of glycemic control as well as new-onset diabetes. CONCLUSIONS: Clinicians caring for people with diabetes should be aware of the increased risk of infections in this population, as well as the possibility of worsening hyperglycemia. A holistic approach with frequent monitoring of blood glucose levels and appropriate titration of medications, along with close attention to nutritional status, is essential to ensure the best possible outcomes. Infectious disease is an important, yet oft-neglected corollary of uncontrolled diabetes mellitus. In the pre-insulin era, most deaths among individuals with type 2 diabetes and many among type 1 diabetes occurred as a result of uncontrolled infection. It is a matter of concern that even today, infections continue to cause significant morbidity and mortality in patients with diabetes, notwithstanding the recent advances in antihyperglycemic and antimicrobial therapeutic options. In this short review, we will review the mechanisms underlying increased susceptibility to infection in diabetes and briefly discuss the clinically relevant infections found in patients with diabetes, with particular reference to the ongoing COVID-19 pandemic. Indian situation has been highlighted whenever data are available. We searched PubMed for original and review articles in English published, using the following keywords: diabetes and infection, hyperglycemia COVID-19, tuberculosis, vaccination, infections, and diabetes in India, from 2000 till September, 2020. The relationship between diabetes and infection has been known for long and has been traditionally considered as bidirectional ( Fig.1) (1). Uncontrolled diabetes affects almost all components of immunity: 1. Dysregulated innate immunity including defective neutrophil and macrophage function (2) 2. Abnormal complement function, which may be related in part to defects in neutrophil function and cytokine responses (3) 3. Defects in T-cell responses (4) 4. Defective humoral (antibody-mediated) immunity (5) In addition, the widespread vasculopathy typical of longstanding uncontrolled diabetes interferes with the body's ability to combat infection by limiting the ingress of immune cells as well as antimicrobial factors, and by promoting tissue necrosis and gangrene. Certain features of the hyperglycemic milieu contribute to the growth of specific micro-organisms (e.g. ketosis promoting the growth of fungi causing mucormycosis). The infections met with in diabetes patients can be broadly classified into two categories. 1. Infections that are common in the non-diabetic population, that also affect people with diabetes, often with more severe clinical presentation and worse outcomes. 2. Infections that are peculiar to individuals with diabetes and virtually unknown in the normal population. These include respiratory infections, genitourinary tract infections and skin and soft tissue infections (Table 1 ). In a series of 380 patients with diabetes and infections attending a tertiary care centre in North India, the most commonly encountered infections were those of the soft tissues (42.8%), respiratory tract (30.2%) and genitourinary tract (28.4%). Infection of more than one site was present in 5.3% of patients (6) . Diabetes has been shown to increase the risk of lower, but not upper respiratory tract infections (7) . Tuberculosis (TB) is a common comorbidity of diabetes, particularly in developing countries. India faces a double burden with the highest number of TB patients, and the second highest number of individuals with diabetes, living within its borders. The relationship between TB and diabetes is bidirectional; individuals with diabetes are more likely to contract TB, and individuals with diabetes are more likely to have diabetes compared to the general population (8) . The greater risk of contracting TB in diabetes, as well as reactivation of latent TB, is postulated to be due to a combination of susceptibility to infection with oxidative stress and J o u r n a l P r e -p r o o f increased tissue inflammation (8) . A recent systematic review on the co-prevalence of TB and diabetes in low and middle-income countries found that diabetes was found in 1.8 to 45% of individuals diagnosed with TB, and that 0.1 to 6% of individuals with diabetes had TB (9) . TB in diabetes has certain peculiar characteristics that make diagnosis and management difficult (see Box 1) (10). Genitourinary infections found in patients with diabetes include urethritis, vaginitis, cystitis, and prostatitis. Common causative organisms are Gram negative bacteria such as E. coli and Klebsiella and fungi such as Candida. In Indian patients with diabetes and UTI, the most common organisms isolated were E. coli (64.6%), Klebsiella (12.1%) and Enterococcus (9.9%) (11) . Infection with extended spectrum beta-lactamase producing E. coli was found to be more frequent in individuals with diabetes. Also, nearly 30% of individuals with positive urine culture were found to be asymptomatic. However, current guidelines state that asymptomatic bacteriuria need not be treated, even among patients with diabetes (12) . Use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for management of hyperglycemia has been associated with increased risk of genital mycotic infections (13); cystitis and upper urinary tract infections are less common but can occasionally occur (14) . Skin and soft tissue infections found in patients with diabetes include furuncles, carbuncles, and cellulitis. In India, more than 60% of all skin and soft tissue infections have been shown to be associated with Staphylococci (6) . Infection is also an important component of the Diabetic Foot Syndrome. Most cases of diabetic foot infection have been shown to be polymicrobial in nature, with predominance of Gram-negative organisms (15, 16, 17) . Prevalence of antimicrobial drug resistance was also found to be higher among patients with diabetes, which could be attributed, at least partially, to the production of biofilms by the causative organisms (18) . The antimicrobial management of these conditions does not differ significantly from that in the population without diabetes. Achievement and maintenance of tight glycemic control, most often requiring the use of intensive insulin therapy, is key to improving outcomes. COVID-19 is an acute, predominantly respiratory viral illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2). From studies conducted in China, Europe, and the U.S., it appears that individuals with diabetes are not at higher risk of infection with SARS-CoV2 compared to the general population (19,20) (Box 2). However, it is clear that they do tend to have worse outcomes, with respect to development of more severe illness and mortality risk, than individuals without diabetes (21) . While mortality due to COVID-19 has been lower in south Asian countries such as India, the sheer number of individuals with diabetes in this region represents a huge population at high risk of adverse outcomes due to this infection (22, 23) . As individuals with diabetes tend to be older and to have higher burden of cardiometabolic risk factors such as obesity and hypertension (as well as cardiovascular disease per se), it is likely that their increased risk of adverse outcomes is mediated, to a large extent, through these comorbidities than by diabetes per se (24) . Recently, there have been reports of new-onset diabetes following infection with SARS-COV2, mainly from the U.S. (25) , but increasingly from elsewhere in the world as well. New-onset hyperglycemia during COVID infection can have multiple causes-weight gain following disordered diet and exercise during lockdown, mental stress, and unwarranted use of dexamethasone for mild to moderate cases of COVID (26) . It is also likely that the novel SARS coronavirus has a direct diabetogenic potential by way of its effects on the pancreas. The angiotensin converting enzyme 2 (ACE2) receptor, by means of which SARS-CoV2 enters target cells, is also present on the pancreatic beta-cell (27) . Infection of the beta cell may lead to acute impairment of insulin secretion or even destruction of the beta cell, as has been reported for human herpesvirus infection in Africa (28). In individuals with pre-existing diabetes, the current COVID pandemic and the public health/ governmental responses to it are also likely to impact glycemic control in significant ways. Lack of accessibility to testing and care during lockdowns, increased snacking and reduced physical activity are likely to worsen diabetes control, and predispose patients to complications (29) , although such deterioration has not been found in all studies (30) . • A high index of suspicion is required for the diagnosis of most of these conditions. Treatment involves, in addition to specific antimicrobial agents, early and aggressive surgical intervention wherever indicated. The prognosis for many of these conditions is poor, even with prompt treatment. While the deleterious effects of uncontrolled hyperglycemia on infection have been well characterized, there is less information available on whether controlling hyperglycemia can have beneficial effects on infection prevention and control (31) . Analysis of patients with type 1 and type 2 diabetes enrolled in primary care in England have shown a clear increase in long-term risk of infection with increasing HbA1c (32) . In a population-based study from Denmark, individuals with HbA1c of 10.5% and above had J o u r n a l P r e -p r o o f hazards ratio of 1.64 for infections requiring hospitalisation, compared to individuals with HbA1c between 5.50 and 6.49% (33) . B. Hyperglycemia and Morbidity and Mortality due to COVID19: During the ongoing COVID pandemic, attempts have been made to link the severity of disease outcomes in COVID-19 with the levels of background glycemic control, as well as the glucose levels at admission and during the course of hospitalization. Higher HbA1c at hospitalization, indicating poor long-term glycemic control, has been associated with higher risk of inhospital death due to COVID, although this has not been replicated in all studies (34) . Patients with higher blood glucose levels at admission tended to have the most florid lesions on chest imaging and were more likely to require ICU admission and intubation and to die compared to those who had lower blood glucose levels (35) . In-hospital hyperglycemia was associated with worse clinical outcomes among patients with COVID studied in China and the U.S (36, 37) . These findings reinforce the need for ensuring tight glycemic control in patients with diabetes during the current pandemic, and also for the maintenance of euglycemia in patients who are hospitalized for COVID-19. In this context, it should be remembered that some medications used for the treatment of severe COVID (particularly corticosteroids) have the potential to raise blood glucose levels, and that the antidiabetic drug regimen will need to be appropriately titrated in patients receiving these treatments (21) . Even in the absence of these treatments, infection with SARS-COV2 has been associated with extremely high insulin requirements among patients with diabetes, and the development of hyperglycemic crises in some cases (38) . The presence of diabetes is associated with increased risk of treatment failure, relapse, and death in patients with TB (39); similar results have been reported from India as well (40) . The role of tight glycemic control in improving treatment outcomes in TB remains controversial (41) . A study from China showed that treatment outcomes were worse among those with suboptimal glycemic control (42) . Similarly, Mahishale et al (43) showed that optimal glycemic control resulted in 88% reduction of sputum non-conversion at 2 months of treatment compared to poor glycemic control. However, Nandakumar et al (44) found no correlation between diabetes control and TB treatment outcomes in their study conducted in Malappuram district of Kerala. In this context, it is interesting to note that recent studies have shown an association of poorly controlled diabetes with better outcomes in individuals with low body-mass index; this needs confirmation in larger studies (45) . Maintenance of tight glycemic control during the peri-and postoperative period has been found to be associated with a lower incidence of surgical site infections in patients with diabetes (46, 47) . Even though maintenance of tight glycemic control has been long considered one of the cornerstones of diabetic foot management, there is little evidence by way of randomized controlled trials to suggest that foot ulcer outcomes are improved by this approach (48) ; such trials are urgently needed, considering the global magnitude of the problem of diabetic foot. In a retrospective study of more than 7300 patients with COVID-19 from China, well controlled blood glucose (defined as glycemic variability between 3.9 to 10 mmol/l) was associated with significantly lower mortality compared to higher blood glucose variability (>10 mmol/l) (49) . The role of diet has often been overlooked while managing infections in patients with diabetes. Some general points can be summarized from available studies: A. Severe infection is a hypercatabolic state and any diet plan for patients with infection should take this into account, ensuring adequate intake of protein and micronutrients to promote healing. This is particularly relevant in the Indian context, where the baseline protein intake is extremely low. Particularly in patients with diabetes and TB without hepatic or renal insufficiency, it is recommended that proteins should be the major source of energy (50) . B. Supplementation of micronutrients for 6 months has been shown to reduce the incidence of common infections (respiratory, skin, and urogenital) in patients with diabetes (51) . A recent review (52) on the role of micronutrient supplementation in diabetic foot ulcers concluded that while there was some evidence to support the role of Vitamins A, C, D and E, and zinc in ulcer healing, the level of evidence was not strong enough to support any recommendations for routine supplementation with these nutrients. In patients with risk of limb ischemia and/or hypoalbuminemia, supplementation with arginine, glutamine and betahydroxy methyl butyrate has been shown to improve foot ulcer healing (53) . C. Supplementation of vitamin D has been shown to improve the proportion of sputum smear and culture conversion in patients with active pulmonary TB (with or without diabetes) (54). D. Similarly, vitamin D deficiency was associated with an increased risk of testing positive for COVID-19, raising the possibility that supplementation of this vitamin could reduce the risk of COVID infection; however, it should be noted that this study was not restricted to individuals with diabetes (55). Recently, consensus guidelines have been published for balanced nutrition in the time of the COVID pandemic (56) . These can be summarized as follows. A. Individuals not infected with COVID, or those with mild to moderate disease, consume a balanced diet rich in vegetables, fruit, legumes, nuts, and whole grain as well as egg and lean meat wherever applicable. B. Intake of probiotic-rich food is encouraged, and hydration should be maintained particularly when febrile. C. Saturated fat and processed food should be avoided, as should extreme "fad" diets. D. The diet should provide at least 1g of protein per kg body weight per day in older persons and should contain adequate amounts of micronutrients such as Vitamins A, C, and D, zinc, and selenium. E. In severely ill patients, these nutritional requirements should be met by way of oral supplementation wherever possible, with enteral and parenteral supplementation being reserved for the most severely ill individuals who cannot tolerate oral intake. As individuals with diabetes represent a vulnerable subgroup of the population with respect to susceptibility to infection, preventing these infections by means of vaccination assumes J o u r n a l P r e -p r o o f paramount importance. In addition to all routine immunisations recommended for the general population, the American Diabetes Association provides additional recommendations for the use of pneumococcal, influenza and hepatitis B vaccines in individuals with diabetes (57) . Attempts have been made to formulate similar recommendations for India also (58, 59) ( Table 2) . In this context, it should also be noted that the nationwide lockdowns imposed in India and other countries to combat the spread of the COVID-19 pandemic have had an adverse impact on the coverage of infection control and immunization programs directed against other communicable disease; these countries should gear up to face a recrudescence of many of these hitherto controlled infections in the near future (60) . Infectious disease continues to take a heavy toll of the population with diabetes even in the present day. The increased susceptibility of the individual with diabetes to infection has recently returned to sharp focus with the advent of the COVID-19 pandemic, reiterating the need for achieving tight control of hyperglycemia and managing comorbidities appropriately J o u r n a l P r e -p r o o f in this population from the time of diagnosis of diabetes. Also, there are certain unusual infections that appear to be exclusively found in patients with diabetes; the clinician dealing with patients with diabetes should be ever alert to the possibility of these infections, as prompt diagnosis may mean the difference between life and death in many cases. J o u r n a l P r e -p r o o f Magnitude of the problem: • 420 million people with diabetes worldwide (75 million in India) • 28 million infections with COVID worldwide as of September 2020 (4.4 million in India) • Diabetes per se not a risk factor for contracting COVID infection • Severe disease and adverse outcomes more likely in individuals with diabetes • Poor outcomes may be linked to other comorbidities such as older age, obesity and hypertension, more frequent among people with diabetes • Poor long-term (pre-infection) diabetes control, admission hyperglycemia and inpatient hyperglycemia linked with poor outcomes • COVID infection can worsen diabetes control • New onset diabetes has been reported with COVID mention ketoacidosis • Some treatments used for COVID treatment (e.g. steroids) can exacerbate hyperglycemia • Adverse effect of pandemic and consequent lockdowns on routine diabetes care. This is likely to exacerbate diabetes control and also add new patients of diabetes to already high numbers. • Patients unable to exercise regularly, access healthy diet and procure medications promptly. This will increase morbidity and even mortality. J o u r n a l P r e -p r o o f Infections in patients with diabetes mellitus: A review of pathogenesis Common infections in diabetes: pathogenesis, management and relationship to glycaemic control The role of diabetes mellitus in patients with bloodstream infections Immune dysfunction in patients with diabetes mellitus (DM) Type 2 diabeets and its impact on the immune system Pattern of infections in patients with diabetes mellitus--Data from a tertiary care medical center in Indian Subcontinent Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus Diabetes and tuberculosis: an important relationship Coprevalence of type 2 diabetes mellitus and tuberculosis in low-income and middleincome countries: A systematic review Diabetes and tuberculosis: an appraisal Clinical profile of urinary tract infections in diabetics and non-diabetics Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America Genital infections with sodium glucose cotransporter-2 inhibitors: occurrence and management in patients with type 2 diabetes mellitus Case of acute unilateral emphysematous pyelonephritis and bacteraemia on treatment with canagliflozin Epidemiology of diabetic foot infections in a reference tertiary hospital in India Bacterial etiology of diabetic foot infections in South India Microbiological and clinical characteristics of diabetic foot infections in northern India Infections and diabetes Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China Prevalence and impact of diabetes among people infected with SARS-CoV-2 COVID-19 in people with diabetes: understanding the reasons for worse outcomes COVID19 in South Asians/Asian Indians: Heterogeneity of data and implications for pathophysiology and research COVID-19 in people living with diabetes: An international consensus Clinical characteristics and risk factors for mortality of COVID-19 patients with diabetes in Wuhan, China: A two-Center, retrospective study New-onset diabetes in COVID-19 National Diabetes Obesity and Cholesterol Foundation (NDOC), and Diabetes Expert Group, India. Strict glycemic control is needed in times of COVID19 epidemic in India: A Call for action for all physicians Novel therapeutic approaches targeting the renin-angiotensin system and associated peptides in hypertension and heart failure Ketosis-prone type 2 diabetes mellitus and human herpesvirus 8 infection in sub-Saharan Africans Increase in the risk of type 2 diabetes during lockdown for the COVID19 pandemic in India: A cohort analysis Acceptability and utilization of newer technologies and effects on glycemic control in type 2 diabetes: Lessons learnt from lockdown Diabetes and infection: assessing the association with glycaemic control in population-based studies Glycemic control and risk of infections among people with type 1 or type 2 diabetes in a large primary care cohort Study Impact of glycemic control on risk of infections in patients with type 2 diabetes: a population-based cohort study Factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients Admission hyperglycemia and radiological findings of SARS-CoV2 in patients with and without diabetes Clinical characteristics of 28 patients with diabetes and COVID-19 in Wuhan, China Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States Guidance on the management of diabetic ketoacidosis in the exceptional circumstances of the COVID-19 pandemic The impact of diabetes on tuberculosis treatment outcomes: a systematic review Effect of diabetes on treatment outcome of smear-positive pulmonary tuberculosis--a report from South India Effect of glycemic control and type of diabetes treatment on unsuccessful TB treatment outcomes among people with TB-Diabetes: A systematic review The influence of diabetes, glycemic control, and diabetesrelated comorbidities on pulmonary tuberculosis Effect of poor glycemic control in newly diagnosed patients with smear-positive pulmonary tuberculosis and type-2 diabetes mellitus Outcome of tuberculosis treatment in patients with diabetes mellitus treated in the Revised National Tuberculosis Control Programme in Malappuram district Impact of diabetes and low body mass index on tuberculosis treatment outcomes Postoperative tight glycemic control significantly reduces postoperative infection rates in patients undergoing surgery: a meta-analysis Long-term glycemic control and postoperative infectious complications Does improving glycemic control accelerate healing of diabetis foot ulcers? Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes Insights on medical nutrition therapy for type 2 diabetes mellitus: An Indian perspective Micronutrients decrease incidence of common infections in type 2 diabetic outpatients Micronutrients and natural compounds status and their effects on wound healing in the diabetic foot ulcer Effect of oral nutritional supplementation on wound healing in diabetic foot ulcers: a prospective randomized controlled trial Effects of vitamin D supplementation on the outcomes of patients with pulmonary tuberculosis: a systematic review and meta-analysis Association of vitamin d status and other clinical characteristics with COVID-19 test results Balanced nutrition is needed in times of COVID19 epidemic in India: A Call for Action for all nutritionists and physicians Comprehensive medical evaluation and assessment of comorbidities: Standards of medical care in diabetes Suggested use of vaccines in diabetes RSSDI-ESI clinical practice recommendations for the management of type 2 diabetes mellitus COVID-19 pandemic and challenges for socio-economic issues, healthcare and National Health Programs in India J o u r n a l P r e -p r o o f • Diabetes confers increased risk of common and uncommon infections.• Individuals with diabetes have worse outcomes with COVID-19.• There is a bidirectional link between tuberculosis and diabetes.• Good glycemic control improves outcomes in most infections. ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: 


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   key: cord-292344-3bj567gr authors: Zimmet, P. title: The burden of type 2 diabetes: are we doing enough? date: 2003-09-30 journal: Diabetes & Metabolism DOI: 10.1016/s1262-3636(03)72783-9 sha: doc_id: 292344 cord_uid: 3bj567gr Summary Increasing levels of obesity, arising from energy-rich diets and sedentary lifestyles, are driving a global pandemic of type 2 diabetes. The prevalence of type 2 diabetes worldwide is set to increase from its present level of 150 million, to 225 million by the end of the decade and to as many as 300 million by 2025. Shocking as they are, these figures represent only clinically diagnosed diabetes, and many more cases of diabetes remain undiagnosed and untreated. In addition, up to one-quarter of western populations have impaired glucose tolerance or the dysmetabolic syndrome, which are considered to represent pre-diabetic states. Type 2 diabetes is appearing increasingly in children and adolescents, and the frequency of diagnosis of paediatric type 2 diabetes is outstripping that of type 1 diabetes in some areas. The long-term complications associated with type 2 diabetes carries a crushing burden of morbidity and mortality, and most type 2 diabetic patients die prematurely from a cardiovascular event. Diabetic patients are more than twice as costly to manage as non-diabetic patients, due mainly to the high costs associated with management of diabetic complications. Indeed, diabetes care already accounts for about 2-7% of the total national health care budgets of western European countries. Controlling the type 2 diabetes epidemic will require changes to the structure of healthcare delivery. Well-resourced interventions will be required, with effective co-ordination between all levels of government, health care agencies, multidisciplinary health care teams, professional organisations, and patient advocacy groups. Above all, intervention is needed today. Diabetes Metab, 2003,29,6S9-6S18 • www.e2med.com/dm P Zimmet T oday we are seeing a paradox in global public health. In recent decades, we have seen the reemergence of communicable diseases such as tuberculosis, and a new group including HIV/AIDS, Ebola virus and, most recently, the devastating epidemic of severe acute respiratory syndrome (SARS). In addition, there is still a global crisis resulting from widespread malnutrition. However, against this background, we are seeing a dramatic rise in prevalence of chronic non-communicable diseases such as type 2 diabetes, cardiovascular diseases, hypertension and obesity in developed and developing nations. There were already signals that diabetes was to become the epidemic of the 21 st century in the early 1970s. At this time, Bennett and his colleagues discovered an extraordinarily high prevalence of type 2 diabetes in the Pima Indians of the USA [1] , and we reported on the equally high rates of diabetes in the Micronesian population of Nauru and other Pacific island communities [2, 3] . Over subsequent decades, numerous reports have highlighted the high prevalence of type 2 diabetes in a number of other populations including native Americans, Afro-Americans, and Mexican Americans in the USA [4] [5] [6] [7] , native Canadians [8] , Australian Aborigines and Torres Strait islanders [9] , and Polynesians in New Zealand [10, 11] . The prevalence of type 2 diabetes is rising relentlessly around the world (Fig 1) . Current estimates suggest that, globally, the number of persons with diabetes will rise from 151 million in the year 2000, to 221 million by the year 2010, and to 300 million by 2025 [12, 13] . This rise is predicted to occur in virtually every nation, with the greatest increases expected in developing countries. Type 2 diabetes will account for nine patients in every ten of these diagnoses. This explosive increase in the prevalence of type 2 diabetes, and the consequences of its complications and associated disorders, represents the greatest health care challenge facing the world today [14] . The highest rates of type 2 diabetes occur in native Americans and Pacific islanders, followed by Hispanics or Mexican Americans, people originating from the Indian subcontinent, South East Asians and African Americans [12, 13] . In addition, a relatively high prevalence has been reported from some of the Middle East Arab states [15, 16] , and from disadvantaged minorities in the developed countries, including Australia's indigenous population [17, 18] . Type 2 diabetes affects up to 40% of adults in native American and Pacific island populations [1, 2, 19, 20] and the years 1976 to 1988 saw an increase from 11.4% to 14.3% in the prevalence of diabetes among people age 40-74 years in the USA [21] . In China, a prevalence figure of 2.5%, from a 1994 survey of 224,251 subjects aged 25-74 from all parts of the country, was about three-fold higher than prevalence estimates from a decade before [22] . The type 2 diabetes prevalence in an urban south Indian population among individuals aged over 20 years rose from 8.3% in 1989 to 11.6% in 1995 [23] , while in Denmark, a 38% rise in diabetes prevalence has been reported over a 22year period [24] . In our recent national study in Australia, 7.4% of adults were found to have diabetes compared to an estimated 3.4% in 1981 [18] . Our studies in Mauritius have provided a future guide to the magnitude of the global diabetes epidemic [25] . The population of this nation are Asian Indian, Creole (Black) and Chinese, and these three ethnic groups account for over 66% Increasing prevalence of type 2 diabetes by region [12] . of the world's population. Mauritians have a high diabetes prevalence [26] and a 40% secular increase occurred between 1987 and 1992 in Mauritian Asian Indians and Creoles [27, 28] . The Mauritian Chinese share this high prevalence [26] . Data showing that the prevalence of type 2 diabetes doubled between 1984 and 1992 in Singaporean Chinese, together with the high prevalence in Taiwan [29, 30] , provide an alarming indicator of the magnitude of the anticipated epidemic in the People's Republic of China (PRC) [25] . In the PRC, the prevalence of type 2 diabetes was, until recently, less than 1% [31] , but recent studies show a three-fold increase in prevalence in certain areas of China within the last two decades [22] . If China has just 50% of the prevalence of diabetes in Taiwan, the number of individuals with diabetes will increase dramatically from 8 million in 1996 to well over 35 million by 2010. Diabetes prevalence is currently estimated at 6.2% in the developed world, and forecast to rise to 7.6% by 2025 [13] . Developing countries are starting from a lower baseline, at 3.5%, but this is set to increase by more than a third, to 4.9%, in 2025. The lower overall prevalence in developing countries conceals considerable heterogeneity between individual nations. In Latin American countries, the crude prevalence of type 2 diabetes for 2000 ranges from 1.2% in Chile to 8.2% in Argentina [32] and in Africa from 0.7% in Tanzania to 10.0% in the Northern Sudan [33] . In Asia, the overall prevalence is low in some countries, such as Bangladesh (roughly 1-2%), but higher in others, such as Pakistan (4-7%) [12, 13] . The Pacific islands bear an especially heavy burden of diabetes, as described above, with an estimated prevalence of 7% in Kiribati, 8% in the Cook islands, 11% in Fiji, and 24% in Nauru [13] . Increased rates of obesity due to low levels of physical activity and high-energy diets are driving this global epidemic [14] . For example, between 1990 and 1998, the average body weight of men and women in the USA increased by 3.4 kg and 3.9 kg, respectively, while the prevalence of diabetes increased from 4.9% to 6.5% [34] . Obesity, particularly abdominal obesity, promotes the development of insulin resistance and the dysmetabolic syndrome (also known as the "metabolic syndrome", or "syndrome X") and, ultimately, type 2 diabetes [35] [36] [37] [38] . Approximately one quarter of the population of the developed world are already believed to have the dysmetabolic syndrome [36, 39] . Impaired glucose tolerance or impaired fasting glucose develop in response to worsening insulin resistance before the clinical diagnosis of type 2 diabetes is made, and signify an increased risk of developing type 2 diabetes [40] . Between 10% and 25% of western populations may already have IGT [21, 41] . For example, the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) recently surveyed the glycaemic status of a population of 11,247 adults [18] . The overall preva-lence of diabetes was 7.4%, but the combined prevalence of impaired fasting glucose or impaired glucose tolerance was more than twice as high, at 16.4%. These glucose-intolerant, but non-diabetic, individuals represent a reservoir of potential new diabetes cases. Approximately 4-9% of individuals with impaired glucose tolerance go on to develop type 2 diabetes each year [42] . Demographic, social and cultural factors profoundly influence the prevalence of diabetes in a developing nation, as shown by recent studies in India. The overall prevalence of diabetes in that country was estimated at 4.0% in the year 2000 [13] . However, a survey in Madras, an urban area of southern India, showed that the prevalence of diabetes had risen by 40% between 1988-1989 and 1994-1995, and by a further 16% in the year 2000 [25, 43] . Increasing urbanisation and sedentary work was significantly associated with this increased prevalence [44, 45] . Indeed, 12% of urban residents, and only 2% of rural residents were found to have type 2 diabetes in this survey. South Asians who migrate to developed nations face a similar increase in the risk of developing diabetes [46, 47] . A greater tendency to insulin resistance is already evident in children of south Asian descent in the UK, which is associated with a steeply rising incidence of type 2 diabetes [48, 49] . The impact of urbanisation on diabetes prevalence in India is consistent with experience from other cultures, such as Australian Aborigines, Pacific islanders and native Americans [17, 50] . Global estimates predict that the ratio of people with diabetes in urban and rural areas in the developing world will rise from 1.5-fold, at present, to more than 3-fold in 2025 [13] . Other socio-economic factors, particularly poverty, also increase the risk of type 2 diabetes [51] . Patients with a diagnosis of diabetes represent the tip of the iceberg, and a large number of patients with undiagnosed diabetes may also be at risk of adverse clinical outcomes. In the AusDiab study, there was one undiagnosed case for every known case of diabetes [18] . An observational study carried out in an apparently healthy, elderly (70-79 years) population in the US revealed that 8% of the 3,075 participants had undiagnosed diabetes. Higher estimates have been observed in patients with a previous MI (12%; [52] ) or awaiting coronary angioplasty (17.9%; [53] ). A study in the UK, which surveyed 553 subjects without known diabetes in an impoverished urban area, illustrates how genetic and socioeconomic factors combine to amplify the problem of undiagnosed diabetes [54] . The age-adjusted prevalence of diabetes in this population was high in subjects of south Asian or African-Caribbean descent (33% and 22%, respectively), as would be expected from earlier studies. However, the age-adjusted prevalence of type 2 diabetes was unexpectedly high (20%) in subjects of European descent. Similarly, data from the Third US National Health and Nutrition Examination Survey suggested that the adult prevalence of undiagnosed type 2 diabetes nationwide was 2.7%, though this concealed wide vari-6S12 Diabetes Metab, 2003,29,6S9-6S18 • www.e2med.com/dm P Zimmet ations between men and women and between ethnic groups [21] . For example, the prevalence of undiagnosed diabetes among middle-aged (50-59 years) Mexican-American men and women was 12.9% and 7.5%, respectively, compared with 3.3% and 5.8%, respectively, for the general population within this age range. There is compelling evidence that undiagnosed diabetes is associated with cardiovascular risk factors characteristic of insulin resistance or the dysmetabolic syndrome, including hypertension and abdominal obesity [53] [54] [55] . The additional increases in metabolic dysfunction associated with westernisation and urbanisation of the developing world, as described above, can only exacerbate this problem in the future. Type 2 diabetes mellitus in children, teenagers and adolescents is a serious new aspect of the type 2 diabetes epidemic and is an emerging public health problem of significant proportions [14] . While, globally, type 1 diabetes is still numerically the major form in children, it is likely that type 2 diabetes is set to be the predominant form within 10 years in many ethnic groups and potentially in Europid groups. Type 2 diabetes has already been reported in children from Japan, the United States, Pacific islands, Hong Kong, Australia and the United Kingdom [14] . The prevalence of type 2 diabetes in the general population of the USA has been estimated at 4.1/1000 12-19 year olds [56] . Dabelea et al. have studied Pima Indian children since the late 1960s, and have demonstrated rising rates of glucose intolerance with time and age, as well as a female preponderance [57] . From 1967-76 to 1987-96, the prevalence of type 2 diabetes has markedly increased from 2.4% in males and 2.7% in females to 3.8% in males and 5.3% in females. Diagnoses of type 2 diabetes now outnumber diagnoses of type 1 diabetes by 4:1 in children in parts of Japan and China, compared with a ratio of about 1:3 of total diagnoses of diabetes in urban USA centres [58, 59] . Obesity and insulin resistance are driving this explosion of paediatric diabetes, as in adults [60] . A diagnosis of diabetes has a profound impact on life expectancy, and a patient diagnosed with type 2 diabetes in middle age (40-49 years) stands to lose as much as 10 years of life expectancy [61] . Given the close association between type 2 diabetes and the cardiovascular risk factors constituting the dysmetabolic syndrome, it is not surprising that most type 2 diabetic patients ultimately die from a cardiovascular cause [62] . Indeed, type 2 diabetes confers the same degree of risk of premature death as a previous myocardial infarction in a non-diabetic subject [63] . A substantial proportion of type 2 diabetic patients already have diabetic complications at the time of diagnosis of diabetes. For example, retinopathy, peripheral neuropathy and proteinuria were present in 35%, 12% and 2%, respectively, of the newly-diagnosed patients in the UK Prospective Diabetes Study (UKPDS) at baseline [64] . The Cost of Diabetes in Europe -Type 2 (CODE-2) study has investigated the prevalence of diabetic complications in a randomly selected cohort of type 2 diabetic patients. Less than half (41%) of the German cohort of 2,701 patients (mean age 67 years) did not have diabetic complications, while 23% had at least two, and 3% had at least three complications [65] . Cardiovascular complications were present in 43% of patients, cerebrovascular complications in 12%, and neuropathy or diabetic foot syndrome, retinopathy and nephropathy were present in 23%, 11% and 6% of patients, respectively. The CODE-2 data are consistent with previous estimates of the prevalence of coronary heart disease and other complications in type 2 diabetic patients in various countries (Fig 2) . The prognosis of type 2 diabetes in patients who already have diabetic complications is extremely poor. A retrospective review of 126 patients referred to a combined diabetesrenal clinic showed that their median survival was only 61 months [66] . Similarly, odds ratios for all-cause and cardiovascular mortality in 104 Finnish type 2 diabetes patients with diabetic retinopathy were 5.1 and 5.6, respectively, compared with non-diabetic control subjects [67] . Diabetes is expensive to manage, and the per capita costs of managing a diabetic patient are 2-4-fold higher than for a non-diabetic patient [68] . However, the additional cost burden associated with type 2 diabetes begins long before diabetes is diagnosed. Analysis of data from a managed care organisation in the USA showed that the cumulative costs associated with inpatient, outpatient and pharmacy provision for patients with type 2 diabetes were higher, on average, than those incurred by control subjects matched for gender and age for each of the 8 years preceding diagnosis of diabetes [69] . By the time of diagnosis, the total cost of treatment was $9,643 higher for a diabetic patient, compared with a control subject (Fig 3) . Costs for the 8 years following diagnosis were higher in diabetic subjects, as would be expected, with a total difference in average total costs of $18,057 between a type 2 diabetic patient and a matched control subject (Fig 3) [70] . Most of the cost of managing type 2 diabetes is associated with the management of diabetes-related complications, especially where hospital treatment is required. The UKPDS performed separate health economic evaluations, based on the main cohort, who were managed with conventional dietbased treatment or intensive glycaemic management with a sulphonylurea or insulin [71] , and on overweight patients, who were managed with diet or with intensive metforminbased treatment [72] . The total costs incurred during 11 years of follow-up are shown in Table I . Managing complications accounted for about two-thirds of the total costs in the diettreated group of the main cohort, and about three quarters of the costs in diet-treated overweight patients. Complications accounted for more than half of the total costs during follow-up even after intensive glycaemic management with a sulphonylurea or insulin (main cohort) or metformin (overweight cohort), which significantly reduced the incidence of microvascular and macrovascular complications, respectively [64, 73] . Comparing the health economic costs between countries is difficult, because of variations in the costs of services and standard clinical practice, and variations in how data are presented. However, in general terms, the cost of managing complications drives the overall treatment costs in most countries. Fig 4 compares the average annual costs of managing a type 2 diabetic patient across Europe: in most countries, costs arising from hospital treatment (mainly associated with the management of complications) were markedly greater than out-of- Columns show the average of estimates of the prevalence of individual complications for adults with type 2 diabetes presented by Amos et al. [12] . Numbers beneath columns show the number of estimates used in each case. CHD: coronary heart disease; PVD: peripheral vascular disease. Cumulative costs of managing a type 2 diabetic patient and an age-and gender-matched control subject in a managed care organisation over a period of 8 years before (A and B) or after (C and D) the diagnosis of diabetes [69, 70] . hospital (ambulatory) costs [51] . Data from the USA, from a model based on the interventions used in the UKPDS, show that the annual costs of managing complications in patients receiving diet-based therapy ($37,602) accounted for 78% of total direct costs of care ($48,343) [74] . A retrospective analysis of 11,768 patients within a managed care organisation in the USA compared the costs of diabetes management in type 2 diabetic patients with no evidence of significant cardiovascular or renal disease ("no complications"), in patients under treatment or investigation for risk factors for cardiovascular or renal conditions ("pre-event"), and in patients with a history of cardiovascular events or clinically significant renal dysfunction ("post-event") [75] . Direct costs were lowest in the "no complications" group (Fig 5) , and increased in the "preevent" group for men and women. However, the greatest differences in costs were between the "pre-event" and "postevent" groups, with a greater than doubling of costs for patients who developed cardiovascular complications. Data are from separate analyses, from the perspective of a healthcare purchaser. All costs are undiscounted direct costs and are in UK £ (1997 values). Additional costs for specialist care were for eye or renal care in lean patients and eye care in overweight patients. The analysis in lean patients presented individual costs from the clinical trial setting and adjusted the total for the routine community care setting; the analysis in obese patients presented all costs after adjustment for the routine care setting, hence NA (= not available) for trial costs for overweight patients. The percentage of costs due to complications was calculated using trial costs for lean patients and standard practice costs for overweight patients, for the same reason. Total costs (in UK £) associated with type 2 diabetes and its management during 11 years of follow-up in the UK Prospective Diabetes Study [71, 72] . Direct medical costs per type 2 diabetic patient in some European countries in 1998 [51] . Additional treatment costs arising from the development of cardiovascular or renal diabetic complications [75] . Costs are in 1993 prices from the perspective of a health care purchaser. Patients were stratified as follows. No complication: patients in the analysis either had no history of cardiovascular or renal disease or treatment; pre-event: patients were under treatment with an antihypertensive drug, had made at least two visits to a cardiologist, or had had at least one positive test for microalbuminuria; post-event: patients had suffered at least one major cardiovascular event (e.g. myocardial infarction, stroke, revascularisation, or hospitalisation for congestive heart failure) or had documented clinical renal dysfunction indicated by high serum creatinine measurements. The high prevalence of type 2 diabetes means that the overall costs of managing the disease, including costs arising from managing diabetic complications, are high enough to place a substantial burden on national economies. The total direct healthcare expenditure on the management of diabetes in the USA in 1997 was $44 billion. Of this amount, only $7 billion was required for glycaemic management, with $36 billion required for the management of complications and other problems related to diabetes [76] . The total costs of managing type 2 diabetes in Europe already range between roughly 2% and 8% of national healthcare budgets in Europe (Fig 4) . The burden on some other economies is even higher. For example, diabetes care in Mexico accounts for 15% of the total healthcare budget, which equates to 0.8% of gross domestic product [77] . Moreover, the burden grows heavier as the global epidemic of type 2 diabetes evolves. Projections based on the UK diabetic population suggest that the total costs of managing type 2 diabetes will increase from £1.8 billion in 2000 to £2.2 billion by 2040, an increase of 24% [78] (Fig 6) . National governments have either failed to recognise the future socioeconomic burden of type 2 diabetes or are ignoring it. The global epidemic of type 2 diabetes is already threatening healthcare budgets, and the burden will continue to increase. We should not forget that these prevalence figures relate to people with a clinical diagnosis of type 2 dia-betes. Many more people have undiagnosed diabetes, and there is a vast reservoir of people with IGT, most of whom will develop diabetes eventually, and who are already at substantial risk of developing cardiovascular disease [40] . Increasing rates of obesity will place ever more people at risk of developing the dysmetabolic syndrome, type 2 diabetes, and cardiovascular disease. The increasing prevalence of type 2 diabetes in children and adolescents underlines the urgency of taking action. The Diabetes Prevention Program has shown us that preventing type 2 diabetes with lifestyle interventions or with pharmacologic therapy is cost-effective in either the European or American settings [79, 80] . However, extending these benefits beyond the tightly-controlled structure of a randomised clinical trial will require an unprecedented degree of public health intervention. Educating the public on the dangers of obesity and glucose intolerance will certainly be important. Some steps in this direction have been made. For example, efforts are underway to improve the lifestyles of school-age children in Japan [81] , and health workers in Philadelphia in the USA patrol the streets armed with weighing machines to spread the message of the dangers of obesity [82] . In Finland, a simple questionnaire is being used as a screening tool to identify citizens at risk of type 2 diabetes, who may benefit from further follow-up and intervention [83] . Mounting a successful challenge to the diabetes epidemic, however, will require major alterations to the structure of society. For example, the intervention in Finland is being mounted in collaboration with a broad range of governmental agencies and healthcare advocacy groups, as part of a broader strategy dating back several decades [84] . Support from the highest level of governments is also needed, as resources to mount diabetes prevention efforts must be made available, and changes to taxation and reimbursement structures relating to resources for people to improve their lifestyles would also certainly help in the longer term. The rising tide of type 2 diabetes and its complications will place an increasingly heavy burden of morbidity and mortality on patients and their families for decades to come. Moreover, the expenditure required to manage these patients will stretch the healthcare systems even of the richest countries. 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   key: cord-294966-3jolt83r authors: Joensen, L. E.; Madsen, K. P.; Holm, L.; Nielsen, K. A.; Rod, M. H.; Petersen, A. A.; Rod, N. H.; Willaing, I. title: Diabetes and COVID‐19: psychosocial consequences of the COVID‐19 pandemic in people with diabetes in Denmark—what characterizes people with high levels of COVID‐19‐related worries? date: 2020-05-29 journal: Diabet Med DOI: 10.1111/dme.14319 sha: doc_id: 294966 cord_uid: 3jolt83r AIM: To map COVID‐19‐specific worries and overall psychosocial health among people with diabetes in the initial phase of the COVID‐19 pandemic in Denmark, and to explore characteristics of people with diabetes and high levels of worries related to the COVID‐19 pandemic. METHODS: A cross‐sectional survey was conducted by distributing online questionnaires to 2430 adult members (> 18 years) of two user panels consisting of people with diabetes who have volunteered to share information about their life with diabetes. The questionnaire included items on COVID‐19‐specific worries as well as such worries related to diabetes, sociodemographic and health status, social relations, diabetes‐specific social support, diabetes distress and changes in diabetes‐specific behaviours. Responses were analysed with descriptive statistics and logistic regressions. RESULTS: People with diabetes have COVID‐19‐specific worries related to their diabetes. More than half were worried about being overly affected due to diabetes if infected with COVID‐19, about one‐third about being characterized as a risk group due to diabetes and not being able to manage diabetes if infected. Logistic regressions showed that being female, having type 1 diabetes, diabetes complications and diabetes distress, feeling isolated and lonely, and having changed diabetes behaviours were associated with being more worried about COVID‐19 and diabetes. CONCLUSION: People with diabetes have COVID‐19‐specific worries related to their diabetes which is associated with poorer psychosocial health. These worries should be addressed through support targeting specific questions and needs of individuals with diabetes as well as frequent updates on new knowledge regarding COVID‐19 and diabetes. Spread of coronavirus disease 2019 (COVID- 19) was declared a global pandemic by the World Health Organization (WHO) on 11 March 2020 [1] . For most people, COVID-19 will cause only mild symptoms similar to a common cold, but it can also cause severe respiratory infections and multi-organ failure [2] . The COVID-19 outbreak started in in the Hubei Province, China in December 2019. Since then, the virus has spread rapidly to multiple countries across the globe within a very short space of time. In Denmark, all schools and childcare services were closed on 12 March, employees in the public sector with non-critical roles were sent home and a ban on gatherings of more than 10 people was issued. Care services were adapted to handle the COVID-19 pandemic not only by increasing capacity to treat people with COVID-19, but also by avoiding spread of the virus between healthcare professionals and patients [3] . The COVID-19 outbreak and associated mass media coverage about the course of the pandemic worldwide and the frightening mortality levels in some countries are expected to increase the prevalence and change the character of psychological problems, including anxiety, depression and stress among citizens in affected countries [4] [5] [6] . Previous studies have highlighted the psychological impact of quarantine, which can cause post-traumatic stress symptoms, confusion and anger [6, 7] . Stressors related to quarantine include fear of infection, frustration, boredom, inadequate supplies, inadequate information, financial loss and stigma [7] . During the COVID-19 outbreak in China, a survey of 1210 respondents found that half rated the psychological impact of the outbreak as moderate or severe; 17% reported moderate to severe depressive symptoms; 29% reported moderate to severe anxiety symptoms; and 8% reported moderate to severe stress levels [8, 9] . The study showed that people with chronic illness experienced greater stress, anxiety and depression compared with people without chronic illness [9] . An increase in generalized fear has also been documented during other outbreaks such as SARS in 2003 and spread of the Ebola virus in 2014 [10] . The psychological responses were particularly high among high-risk persons [10] . It is well-established that diabetes under 'normal' conditions can have a significant and negative effect on quality of life. Around 40% of people with diabetes experience diabetes distress as well as an increased prevalence of a range of psychosocial problems, including depression, anxiety, eating disorders and general stress compared with the general population [11, 12] . The psychosocial consequences of the COVID-19 pandemic may add to the burden of psychosocial problems of people with diabetes. The aim of this paper is: (1) to map overall psychosocial health and COVID-19-specific worries among people with diabetes in the initial phase of the COVID-19 pandemic in Denmark; and (2) to explore characteristics of people with high levels of worries related to the COVID-19 pandemic. A cross-sectional survey was conducted by distributing online questionnaires to 2430 adult (> 18 years) members of two user panels at Steno Diabetes Center Copenhagen and The Danish Diabetes Association, respectively. The user panels consist of people with diabetes, who have volunteered to share information about their lives with diabetes. Panels comprise people from all parts of Denmark with type 1 and type 2 diabetes, latent autoimmune diabetes of adulthood (LADA), gestational diabetes (GDM) and other rarer types of diabetes. Thus, the panels represent people with diabetes who are treated in different primary and/or secondary care settings across Denmark. Invitations containing a link to the online questionnaire and written informed consent were sent to all members of the user panels via e-mail. The questionnaire was open for response seven days from the distribution date and a reminder was sent out if a response had not been recorded within the first three days. The study was approved by the Danish Data Protection Agency (P-2020-271). The questionnaire was developed in close collaboration with a person with diabetes and professional communication people working with patient involvement in diabetes care. This was done to ensure appropriate wording of normative items in the questionnaire to avoid inducing unnecessary worry or anxiety in the surveyed population. Alongside with items on COVID-19-specific worries, the questionnaire included items on sociodemographic and health status, social relations, diabetes-specific social support, diabetes distress as well as changes in diabetes-specific behaviours. The generic mental health questions were developed as part of a larger Danish data collection initiative 'Standing together-at a distance: How Danes are living with the Corona Crisis' (https://coronaminds.ku.dk/). The specific questions used in this study are listed in Table S1 . Items on COVID-19-specific worries included one question measuring general worries due to the COVID-19 pandemic :'How worried are you about the Corona-crisis on a scale from 1 to 10?', and a yes/no list of ten potential diabetesrelated worries due to the COVID-19 pandemic. Sociodemographic and health status items included age, gender, type of diabetes, complication status and latest HbA 1c measurement as well as questions about whether the respondent had other chronic or mental illnesses. Items regarding whether relatives or respondents themselves had experienced COVID-19 symptoms or been diagnosed with COVID-19 with or without hospitalization were also included. Measures of social relations included general and diabetesspecific loneliness and diabetes-specific social support. General loneliness was measured with the three-item UCLA Loneliness Scale [13, 14] with response categories 'never/rarely', 'sometimes' What's new? • Little is known about how worldwide pandemics affect the psychosocial health of people with diabetes. • This study showed a high prevalence of diabetesspecific worries related to COVID-19, especially fear of being overly affected by the virus, labelling of people with diabetes as a high-risk group, and inability to manage diabetes if infected. • Female gender, type 1 diabetes, diabetes complications, isolation, loneliness, high diabetes distress and behaviour changes were associated with being more worried about COVID-19 and diabetes. • When providing information and support to people with diabetes in time of crisis, attention should be payed to crisis-specific worries in specific groups. and 'often', providing a total score from 0 to 9. Diabetes-related loneliness was measured with two questions developed for a previous qualitative pilot study [15] and took the same format as the UCLA Loneliness Scale. The questions measured: (1) if the respondents missed someone to talk to about diabetes; and (2) whether they felt alone with diabetes. The questions on loneliness were accompanied by a 1-to 10-point scale about the degree of feelings of isolation. Diabetes-related social support from family, friends, people at work, healthcare professionals, other people in the community and people on social media was measured with questions inspired by the Diabetes Attitudes, Wishes and Needs (DAWN) Support for Diabetes Self-Management Profile [16] . The original scale measures how supportive potential support providers are, with the response categories 'not supportive', 'somewhat supportive' and 'very supportive'. We also included social media as potential support which is not included in the original scale. The social support questions were analysed separately as single items in this study and not as a total score. Diabetes distress was measured by the brief two-item diabetes distress scale (DDS2) [17] : 'Feeling overwhelmed by the demands of living with diabetes' and 'Feeling that I am often failing with my diabetes routine'. Possible scores on each item range from 1 (not a problem) to 6 (a very serious problem). The DDS2 score is derived as the average of the two items. A score > 2 indicates moderate to high diabetes distress. Changes in diabetes-related behaviours as a result of the COVID-19 pandemic were measured with a yes/no list of potential behaviour changes related to diet, physical activity, medication taking and measurement of blood glucose. Multivariate logistic regression models were used to examine the likelihood of experiencing: (1) diabetes-related worries related to the COVID-19 pandemic by sociodemographic factors and health status; and (2) diabetes-related worries related to the COVID-19 pandemic by sociodemographic factors, health status and psychosocial and behavioural factors. For each diabetes-related worry, the same base model consisting of age, gender, education, diabetes type and number of diabetes complications was used. In each regression, a specific explanatory psychosocial variable of interest was included. All coefficients were estimated using maximum likelihood and all coefficients are reported as odds ratios (or) with 95% confidence intervals (CI) and standard errors (SE). P-values ≤ 0.05 were considered statistically significant. All analyses were performed in Stata 15.1 (StataCorp, College Station, TX, USA) Table 1 shows sociodemographic and health status characteristics of the study population. Half of the participants were women; age ranged from 18 to 99 years with a mean of 62 years; almost half of the population had medium to higher tertiary education; 36% were employed; around one-third had type 1 diabetes; 27% had diabetes complications; over COVID-19-specific diabetes worries Figure 1 shows that participants were most frequently worried about 'being overly affected due to diabetes if infected with COVID-19' (56%), about 'people with diabetes being characterized as a risk group' (39%) and 'not being able to manage diabetes if infected with COVID-19 (28%). In all, 24% were worried about 'possible lack of diabetes medications' and 14-17% were worried about 'possible lack of diabetes equipment', 'reduced quality of professional health care during the COVID-19 crisis' and 'insufficient access to health care professionals if needed'. In the later analyses, we focus on the three most prevalent worries. Psychosocial health Table 2 presents levels of different psychosocial factors. Mean rating of overall COVID-19-specific worries was 5.9 and mean rating of feeling socially isolated was 5.5. One-quarter of participants had moderate to high diabetes distress (DDS2 score > 2). Around 57%, 29% and 61% often or sometimes felt lonely, isolated from others and starved for company, respectively. The average loneliness score was 4.8. Roughly 33% often or sometimes felt alone with their diabetes, while 23% felt that they often or sometimes missed someone to talk to about diabetes. Regarding diabetesspecific social support, most respondents (80%) received moderate to high levels of support from family, friends and people close to them. Moderate to high support from people at work or school, diabetes care team, other people in the community and other people with diabetes, and people on social media ranged from~35% (people at work or school) to 50% (diabetes care team). Characteristics of people with worries related to the COVID- Sociodemographic and health status were also more likely to be worried than those participants who did not experience diabetes loneliness. Feelings of isolation also predicted being worried. Participants who felt a stronger sense of isolation were more likely to experience worries (OR 1.1 to 1.1, 95% CI 1.0 to 1.2). Changes in diabetes management due to the COVID-19pandemic Participants who were more likely to have diabetes-related worries about the COVID-19 pandemic were more likely to check blood glucose more often (OR 1.6 to 1.7, 95% CI 1.0 to 2.6), were more aware of medication taking (OR 2.3 to 3.0, 95% CI 1.3 to 4.9) and exercised more than usual (OR 1.3 to 1.7, 95% CI 1.0 to 2.2) ( Table 4) . Eating more or less than usual were both associated with being worried about people with diabetes being characterized as a risk group compared with people eating as usual (OR 1.4, 95% CI 1.1 to 1.9 and 2.1, 1.4 to 3.2). This study of 1396 people with diabetes showed that worries related to the COVID-19 pandemic were highly prevalent. Participants most frequently worried about 'being overly affected due to diabetes if infected with COVID-19' (56%), that 'people with diabetes are characterized as a risk group' (39%) and 'not being able to manage diabetes if infected with COVID-19' (28%). People with diabetes have been informed of the necessity to be acutely aware of the advice and restrictions imposed by the health authorities [12] because they are expected to be at higher risk of being infected and to experience more severe symptoms of COVID-19 if infected. The information from, for example, the Danish health authorities varied in the initial phase of the pandemic: At first, people with diabetes were said to be at [18] . The high morbidity and mortality in people with diabetes was made clear as well as the lack of knowledge about reasons for this. This information may potentially increase worries among people with diabetes and is likely to create a demand for more information. The question regarding worries about being labelled as a risk group was intended to measure experiences of stigma associated with this labelling. However, respondents may have interpreted this as being worried about the actual risk associated with diabetes. Living with diabetes and managing the condition on a dayto-day basis are associated with heightened levels of anxiety and distress [11, 12] . Likewise, a range of different factors, such as sex, diabetes type and presence of complications, moderate the levels at which distress and anxiety are experienced [12, 19] . In our population, 25% experienced diabetes distress at the beginning of the COVID pandemic, which corresponds to what is found under normal circumstances [20] [21] [22] . Our findings also showed that experiencing high diabetes distress and feeling lonely were related to experiencing COVID-19specific worries. Women, people with type 1 diabetes and people with diabetes complications were more likely to express COVID-19 worries than men, people with type 2 diabetes and people without complications, respectively. This corresponds to previous findings of predictors for diabetes distress. [14, 16] . We did not find an association between level of social support and COVID-19-specific worries, although previous studies have shown that a lack of social network and social support was associated with higher diabetes distress [23, 24] . Thus 'corona worries' seem to have resemblances to as well as differences from worries under normal circumstances. In 2016, a survey of~1000 members of the Danish Diabetes Association showed that loneliness is more frequent among people with diabetes and their relatives compared with the general Danish population [25] . In this population, 28% often or sometimes felt left out, 39% often or sometimes felt isolated from others, and 40% often or sometimes felt starved for company [25] . In our study, the corresponding figures were, respectively, 57%, 29% and 61%. This indicates that a larger proportion of people with diabetes feel left out and starved for company during the COVID-19 pandemic than during normal circumstances, but the proportion of people feeling isolated does not differ. People with diabetes are supposedly even more alone at home than the general population, which may lead to feelings of being left out and starved for company. The feeling of being left out may refer to not being able to, for example, take up what is allowed for the general population such as gathering up to 10 people, which might not seem appropriate for people with diabetes, either by themselves or their friends and relatives. People feeling alone with or having no one to talk to about their diabetes were more than twice as likely to worry about COVID-19. Qualitative studies show that people with diabetes under usual conditions experience a burden of feeling lonely with their diabetes [26] . The present study showed that 33% often or sometimes felt alone with their diabetes, while 23% felt that they often or sometimes missed someone to talk to about diabetes. These are high numbers per se, and although we have not found valid information about usual conditions related to feeling lonely with diabetes, the frequency is expected to be higher under the COVID-19 pandemic and the related isolation. Our study indicates that people who report being more worried are more likely to check their blood glucose levels, are more aware of taking their medication and exercise more. This appears to be an upside and may be an adaptive response to the current situation. This behaviour may even relieve feelings of worry as exercise is associated with lower levels of, for example, stress, anxiety and depression [27] . Our results emphasize the need to communicate all new information regarding diabetes and COVID-19, as well as to provide support and guidance associated with specific and individual worries related to diabetes and COVID-19. More knowledge about how to provide this support systematically is needed. Even under normal circumstances, it is often not possible for people with diabetes to get access to emotional support, but in the case of the COVID-19 pandemic this might be even more important [28] . Peer support, social media and telephone support may be part of the solution [26, 29, 30] . Strengths of our study include the timeliness of the survey, which was initiated very shortly after substantial lockdown in Denmark due to the COVID-19 pandemic. The response rate of > 50% is considered relatively large under the circumstances, with a relatively short response time and only one reminder. Also, the study included both people with type 1 diabetes (35%) and type 2 diabetes (62%). Limitations include the convenience sample of participants, who may generally be healthier than the average person with diabetes. This is evinced by the relatively low prevalence of diabetes complications, for example retinopathy, with 7% in our study population reporting retinopathy compared with 18% in the Danish Diabetes Registry [31] . However, one could argue that our estimates are conservative given the fact that psychosocial issues are less pronounced in healthier individuals with diabetes, further emphasizing the gravity of the situation. Furthermore, more than half of the population has at least one comorbid condition. All measures are selfreported, which may introduce uncertainties about prevalence of diabetes complications, comorbidity and glycaemic levels. Validation of the questionnaire was somewhat compromised by time constraints imposed by the need to administer the survey as and when concerns about COVID-19 were emerging. However, relevant actors from the Danish Diabetes Association, the user-involvement programme at Steno Diabetes Center Copenhagen and a person with type 1 diabetes contributed to and piloted the questionnaire through several iterations. Very few respondents commented negatively about the questionnaire. This study highlights a high prevalence of worry among people with diabetes during the COVID-19 pandemic related to being part of a high-risk group, as well as several other significant worries due to diabetes. Further studies are needed to explore if and how COVID-19 worries change during the pandemic. Our study will be continued, and the future longitudinal study will contribute to this understanding. Our findings are expected to be relevant in settings other than the Danish, depending on the local course of the COVID-19 pandemic and local restrictions. Thus, our findings could be helpful in the effort to improve support for people with diabetes to manage their anxieties, particularly for those at greater risk of worries. Providing peer support and support help lines may be helpful in mediating feelings of loneliness. None. None declared. WHO declares COVID-19 a pandemic The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak Diagnosis and clinical management of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection: an operational recommendation of Peking Union Medical College Hospital (V2.0) 2019-nCoV epidemic: address mental health care to empower society The emotional impact of Coronavirus 2019-nCoV (new Coronavirus disease) The novel coronavirus (COVID-2019) outbreak: amplification of public health consequences by media exposure The psychological impact of quarantine and how to reduce it: rapid review of the evidence Mental health strategies to combat the psychological impact of COVID-19 beyond paranoia and panic Immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (COVID-19) epidemic among the general population in China Public mental health crisis during COVID-19 pandemic Diabetes distress in adults with type 1 diabetes: prevalence, incidence and change over time Psychosocial care for people with diabetes: a position statement of the American Diabetes Association A short scale for measuring loneliness in large surveys: results from two population-based studies Reliability and validity of the Danish version of the UCLA Loneliness Scale The effect of peer support in adults with insulin pump-treated type 1 diabetes: a pilot study of a flexible and participatory intervention Diabetes Attitudes, Wishes and Needs second study (DAWN2): cross-national benchmarking of diabetes-related psychosocial outcomes for people with diabetes Development of a brief diabetes distress screening instrument Sundhedsstyrelsen: Alle med diabetes er i risikogruppen [Danish Health Authority: All People with Diabetes are at Risk Addressing diabetes distress in clinical care: a practical guide The prevalence of diabetes-specific emotional distress in people with type 2 diabetes: a systematic review and meta-analysis The detection and management of diabetes distress in people with type 1 diabetes Diabetes distress in type 1 diabetes-a new measurement fit for purpose Understanding the sources of diabetes distress in adults with type 1 diabetes Social support and self-management behaviour among patients with type 2 diabetes En undersøgelse om ensomhed -ensomhed blandt mennesker med diabetes og p arørende til mennesker med diabetes [An investigation of loneliness -loneliness among people with diabetes and relatives to people with diabetes Patient perspectives on peer support for adults with type 1 diabetes: a need for diabetes-specific social capital Diabetes Prevention Program Research Group. Psychological predictors of physical activity in the diabetes prevention program If it does not significantly change HbA 1c levels why should we waste time on it? A plea for the prioritization of psychological well-being in people with diabetes Out-of-office hours nurse-driven acute telephone counselling service in a large diabetes outpatient clinic: a mixed methods evaluation The tinkering m-patient: co-constructing knowledge on how to live with type 1 diabetes through Facebook searching and sharing and offline tinkering with self-care Dansk Diabetes Database We extend our sincere gratitude to the participants of this study for their invaluable responses to our questionnaire in a time of crisis, and to PhD student Astrid Andrea Schultz, Dr Tanja Thybo and Dr Bryan Cleal for valuable input to this study and paper. We would also like to acknowledge the entire 'Standing togetherat a distance' team of researchers at the University of Copenhagen for their cooperation in the conception of this study. Additional supporting information may be found online in the Supporting Information section at the end of the article. Table S1 . Questionnaire content Doc. S1. English translation of the online article 'Sundhedsstyrelsen: Alle med diabetes er i risikogruppen' published on the website of the Danish Diabetes Association, 7 April 2020. 


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   key: cord-299637-6qarauys authors: Assaloni, Roberta; Carnevale Pellino, Vittoria; Puci, Mariangela V.; Ferraro, Ottavia E.; Lovecchio, Nicola; Girelli, Angela; Vandoni, Matteo title: Coronavirus disease (Covid-19): how does the exercise practice in active people with Type 1 Diabetes change? A preliminary survey date: 2020-07-03 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108297 sha: doc_id: 299637 cord_uid: 6qarauys Abstract Aims Coronavirus disease (Covid-19) could lead persons with pre-existing medical conditions to severe respiratory infections. The Italian Government introduced quarantine to limit viral transmission. This measure could lead people with type 1 diabetes (PWT1D) to disrupt daily care routine including PA practice with difficulties in glycemia management. This study aims to explore PA level in PWT1D before and during quarantine and to describe variation in glycemia values. Methods An online survey investigating medical factors and the perceived and PA level in pre-established period before and after the introduction of quarantine was developed. Comparison between pre and post quarantine was assessed by Wilcoxon Signed Ranks test for continuous variables. Results A total of 154 subjects satisfied the eligibility criteria (54.5% males, 44.8±12.5 years). We found a decrease of PA level (Godin Scale Score 25±1.7vs38.6±1.7 points), steps number and minutes of exercise (respectively 12.606±5026vs4.760±3.145 and 66±4vs38±3) and an increase of glycemia values (142.1± 25.4 mg/dLvs150.8±29.4 mg/dL) Conclusions PWT1D reported a decrease in exercise and worst glycemia. Although PWT1D tried to remain active, their PA level was inadequate to prevent glycemia rising. The difficult to maintain a glycemic control could expose patients to diabetes complications and to an higher risk to counteract infections. The on-going Coronavirus disease , an acute infectious respiratory that could lead to a severe pneumonia till to death, has become the world's leading health headline causing public concerns [1, 2] . On January 30, 2020, the World Health Organization (WHO) declared that the new coronavirus outbreak is a public health emergency [3] . Further, on February 22, 2020, the Covid-19 expanded in Italy causing the largest and deadly epidemic in the Country [4] . WHO warned that the most at-risk populations are older and people with pre-existing medical conditions such as high blood pressure, heart disease, lung disease, cancer and diabetes [5] . In particular, people with type 1 (PWT1D) and poor glucose control, in particular high glycated hemoglobin (HbA1c) or/and insulin resistance, showed higher risk to counteract infections due to the impaired body immune response, this also holds true with Covid-19 [6, 7] . For this reason, PWT1D should manage blood glucose levels with frequent glycemia controls and subsequent insulin delivery adaptations and improving their life style to prevent serious illness [8] . Moreover, it seems that the routine care of diabetes that included also diet and physical activity (PA) were disrupted during the current pandemic, these may contribute to worsening outcomes [9] [10] [11] . In accordance to Istituto Superiore della Sanità (ISS), the Italian Government implemented extraordinary measures to limit viral transmission throughout people and the territory, imposed national quarantine, reduced social interaction and travelling and "stay at home" as a basic means of limiting people's exposure to the virus [12] . Unfortunately, the mandated restrictions on travel and on participating in outdoor activities, including regular PA and exercise, inevitably disrupted the daily routine activities of millions of people [13, 14] . Although containing the virus spread remains a priority, it is also necessary to act on multiple aspects of public health. Unfortunately, few public health guidelines for the public in terms of maintaining daily exercise or PA routines were developed [15] . PWT1D have been advised to follow general guidance on risk reduction, including social distancing and were emphasized the importance of good glycemic control. The major strategies to control glycaemia levels and reduce the risk of hyper or hypoglycemia are: more frequent blood glucose monitoring, diet and maintain the regular practice of PA [11, [16] [17] [18] [19] . We hypothesize that quarantine reduced social and environmental exposure and consequently PA practices (gym and outdoor activities) with possible health impairment. In particular, in PWT1D, even in active people, the reduction of PA could have altered euglycemia maintenance. Regular and safe exercise practice should preserve good psycho-physical wellbeing and the protective effects of it. Despite the closure of green areas, gyms and swimming facilities, we assume that an increased use of technology, such as specific training channels, applications and resources posted on social media could help people to train at home. The aim of this study is to explore the PA level in Italian people with type 1 diabetes before and after the national quarantine introduced to contrast Covid-19 disease and describe variation in glycemia values. We conducted an observational study. PWT1D were recruited through an online survey developed by Sport scientists and Diabetologists through SurveyMonkey software (SurveyMonkey inc 2020, California, Usa) in Italy. The inclusion criteria for PWT1D were age> 18 years, HbA1c < 86 mmol/mol (< 10%) and the capacity to understand Italian language. The exclusion criteria were uncontrolled diabetes, comorbidities that do not allow exercise practice, ongoing Covid-19 infection and cognitive impairments. Participants were asked to fill out a survey consisting of multiple features referred to two periods: before the outbroken of Covid-19 disease and after the introduction of national quarantine. All the participants were asked to completed the written informed consent to the threat of data before to be enrolled in the study: "We guarantee the confidentiality of the information Anthropometric characteristics such as body weight (kg) and height (m), socio-demographical outcomes and medical factors such as the duration of disease (yrs) and the self-reported values of the last (mmol/mol;%) HbA1c were collected by online survey to describe the sample. PA level was investigated into pre-established days before the outbreak of Covid-19 disease and after the introduction of national quarantine . The perceived PA level was explored through the Godin-Leisure Time Exercise questionnaire [20] . The Godin-Leisure Time Exercise questionnaire is a self-reported questionnaire that investigated leisure activity during a 7day period of different intensity exercise (strenuous, moderate and light). The Weekly Leisure Activity Score was previously described by Godin et al (2011) . To obtain PA level, we ask to report the number of steps and minutes of exercise of subjects with an activity tracker (AT). Patients reported their glycaemia values (mg/dl) through the mean values (7 days) showed by system connected to continuous glucose monitoring in the two periods of the study: two weeks before and two weeks after quarantine beginning. Then, the modifications of subjective perception of metabolic compensation (optimal, good or low) before quarantine while glycemia trend (ameliorated, stable, worsted with glycemia rising and/or glycemia fluctuation) and changes in insulin delivery (stable, increase or decrease) during quarantine were investigated. Quantitative variables were expressed by mean ± standard deviation (SD) and qualitative variables by frequencies or percentage as appropriate. The assumption of normality of data was tested by Shapiro-Wilk test. Comparison between pre and during quarantine was assessed by a Paired t-test and Wilcoxon Signed Ranks test for continuous variables. A p-value of less than 0.05 was considered statistically significant. All analyses were performed using STATA 13 software. A total of 188 PWT1D answered to the survey. The quality control of data was made in order to evaluate discrepant responses, missing data and ineligibility criteria. A total of 154 subjects satisfied the eligibility criteria ( Figure 1 ). The 54.5% of sample was males, the mean age was 44.8 ±12.5 years. The mean height and weight were 1.70±0.1 m and 70.7±13.5 and the mean BMI was 24±3.7 Kg/m 2 (Table 1 ). In the period before the quarantine 90.9% practiced exercise in different modalities (36.4% in autonomy), during the quarantine 82.5% maintained exercise in autonomy. Godin Scale Score showed an active PA level (score >23 points) both in pre and during quarantine, but during quarantine we observed a significant decrease (respectively 25±1.7 points vs 38.6±1.7 points; p<0.001).We observed, also, a significant increase in the mean values of glycemia during the quarantine (pre quarantine 142.1± 25.4 mg/dL vs during quarantine 150.8±29.4 mg/dL; p<.001) (Table 3) . Further, we investigated the variation of perceived metabolic compensation and the insulin delivery finding that during the quarantine the 41.9% of PWT1D perceived worst metabolic compensation due to increased glycemia mean values and glycemic variability; 63.9% of PWT1D had to modify the insulin delivery and, in particular 32% of them, had to modify both the basal and rapid dosage. (Data not shown). The sub-sample of 100 subject with AT confirmed a low PA level during national quarantine, in fact, we found a decrease in steps number and in minutes of exercise (respectively 12.606±5026 vs 4.760±3.145 steps number; 66±42 vs 38±31 minutes of exercise; p<.001). Also glycemia and GSS follow the same trend of whole sample (Table 4 ). The Covid-19 pandemic is considered the worst public health concern in the last decades that resulted the largest and severest measures to contrast the diffusion of the disease [2] . People of all ages risk to counteract this virus but the most at-risk populations are older and people with pre-existing medical conditions such as diabetes [5] . People with uncontrolled type 1 diabetes showed higher risk to get infections so they should manage blood glucose levels as close as possible to their goal to prevent serious complications related to the disease such as onset and progression of microvascular (neuropathy, nephropathy and retinopathy) and macrovascular complications [6] . The movement limitations imposed by Italian Government created difficulties to patients in maintaining routine care with limitation of option of PA and more complex management of diabetes [8, 15] . In our study, PWT1D reported a significant decrease both perceived and measured PA level and an increase of glycemia values during the national quarantine. In particular, more than 42% of patients reported a worst perceived of metabolic compensation and more than 62% of patients underlined a worst glycemia management and the necessity to modified insulin delivery. Many researches supported the role of PA practice to maintain the euglycemia state and to reduce the glycemic rebound helping patients to better manage diabetes [11, 17, 19, 21, 22] . The increased difficult to maintain good glycemic control could expose patients to general diabetes complications and, in particular, to higher risk to counteract infections. Diabetologists had to advise patients to ameliorate diabetes control and suggested the strategies to pursue this aim. However, in this period, the entire health system was overloaded and PWT1D have less possibilities to interact with clinicians with a possible repercussion on disease and therapy management. An encouraging aspect that emerge from our data is that PWT1D tried to remain active in the quarantine period but, nevertheless their PA level was adequate, it seems that it was not sufficient to totally prevent glycemia rising. The main training methods used by PWT1D trough application or video in internet and an implementation of this "tele-exercise" provided by Sport Specialist could help patients to remain active in a totally safe way. Training is usually seen as a protective factor but, in this situation, it was almost halved and PWT1D, to control adverse glycemic events, had to modify therapy increasing both rapid both basal insulin deliveries. In particular, when lifestyle decrease from active to sedentary, clinicians suggest PWT1D to improve basal and bolus insulin delivery from 20 to 40% and to adequate doses after 2-4 days. Mean glycemia level increased according to PWT1D perceptions of increased glycemic variability. Rise of glycaemia and glycemic variability are indicators of poor glycemic control that usually restore in a long period. [23, 24] . We are conscious of some limitations of this study. Primary, due to the impossibility to recruit people in the quarantine, people responded on a voluntary base to the survey. This caused a bias to the sample, in fact, the majority of responders were active people. However, this aspect, enforce the validity of the results because, also in a sample of trained people, we found alterations in glycemia trend and difficulties in therapy management. Furthermore, PA assessment could be affected by some bias due to self-reported questionnaires (wrong perception of actual PA) and accuracy of smartwatches. Nevertheless, the values of both self-reported and objectively measured PA data showed the same trend of reduction of exercise. In conclusion, training level and performance are destined to decreased during the quarantine so it is conceivable that, also when usual training routine will be resumed, health benefits will be less substantial. For this reason, guidelines for PWT1D on exercise during quarantine should be established. In our opinion and in accordance with previous studies, to face the less possibilities to exercise, aerobic exercise of moderate to vigorous should be performed with an accurate control of heart rate and circuit or resistance training should be preferred to classical body weight exercise [24] [25] [26] [27] . 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   key: cord-304240-rqlfnywm authors: Bloomgarden, Zachary title: Does glycemic control affect outcome of COVID‐19? date: 2020-10-03 journal: J Diabetes DOI: 10.1111/1753-0407.13116 sha: doc_id: 304240 cord_uid: rqlfnywm nan Diabetes is associated with adverse outcome of coronavirus disease 2019 . In a whole-population study of a UK data set of >60 million persons, approximately 5% had diabetes, but of 23 698 in-hospital COVID-19-related deaths in this population, 33.2% were of people with diabetes, with mortality rates among persons those with type 1 and type 2 diabetes approximately 5-fold and 10-fold greater than that in the nondiabetic population; with adjustment for age and other risk factors, type 1 and type 2 diabetes were associated with near tripling and doubling of mortality rates, respectively. 1 We define diabetes by the presence of hyperglycemia, but we also know that, even among persons not known to have diabetes, the development of hyperglycemia in the setting of infection, trauma, surgery, or a cardiovascular event is associated with adverse outcome. It is then logical to ask whether the adverse outcome of COVID-19 among persons with diabetes is related to the degree of hyperglycemia and, if so, whether this represents a causal relationship or rather shows that the severity of illness in a given individual with diabetes leads to both higher blood glucose concentration and greater likelihood of mortality. So far, reports from different data sets are somewhat contradictory. The same whole-population UK data set reported that, compared with those having glycated hemoglobin (HbA1c) 48-53 mmol/mol (6Á5-7Á0%), COVID-19-related mortality with HbA1c of 86 mmol/mol (10Á0%) or more was 2.23 fold greater among persons with type 1 diabetes, and among those with type 2 diabetes, mortality with HbA1c 59-74 (7.6%-8.9%), 75-85 (9.0-9.9), and ≥86 (10.0%) was increased 1.22, 1.36, and 1.61-fold, respectively. 2 A different UK data set of >17 million adult National Health Service patients gave an adjusted mortality hazard ratios of 1.31 and 1.95 among those with diabetes having HbA1c <7.5% and ≥7.5%, respectively. 3 Specific hospitalized patient data sets, however, do not show that prior glycemic control, as reflected in HbA1c, are associated with different likelihood of adverse outcome among persons with diabetes. In an Iranian hospital, 24 persons with HbA1c 6.5-7 had a similar mortality rate (21%) to that of 93 persons (23%) with HbA1c 8%-11.2%. 4 In analysis of 1317 persons with diabetes hospitalized for COVID-19 in France, the outcome of tracheal intubation or death by day 7 was not associated with HbA1c level on admission, although there was a linear correlation with admission plasma glucose, as well as with body mass index. 5 Another study, of 1279 persons with diabetes hospitalized for COVID-19 in New York, showed no association of mortality with HbA1c on admission, whereas obesity, as well as increasing age and male sex and increasing complexity of outpatient diabetes treatment, were again associated with greater likelihood of adverse outcome. 6 What can we conclude from the discrepancy between the population and hospital data sets? Conceptually, several sets of mediators of adverse COVID-19 outcome may exist among persons with diabetes (Box 1). There may be a direct risk associated with hyperglycemia. Hyperglycemia may, however, be a marker of stress of illness. The risk seen among persons with diabetes may be because of insulin resistance, inflammation, hypercoagulation, or underlying obesity. And diabetes is associated with cardiovascular disease, chronic kidney disease, dyslipidemia, Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study Risk factors for COVID-19-related mortality in people with type 1 and type 2 diabetes in England: a population-based cohort study Factors associated with COVID-19-related death using OpenSAFELY Wellcontrolled vs poorly-controlled diabetes in patients with COVID-19: are there any differences in outcomes and imaging findings? Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study Preadmission diabetes-specific risk factors for mortality in hospitalized patients with diabetes and coronavirus disease 2019 NATIONAL INPATIENT DIABETES COVID-19 RESPONSE TEAM. COncise adVice on Inpatient Diabetes (COVID:Diabetes): FRONT DOOR GUIDANCE. Downloaded 


id: cord-305405-me4gebvm
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   key: cord-305405-me4gebvm authors: Conway, J.; Gould, A.; Westley, R.; Raju, S.; Oklopcic, A.; Broadbent, A.; Abdelhafiz, AH.; Sinclair, AJ. title: Characteristics of patients with diabetes hospitalised for COVID-19 infection-a brief case series report date: 2020-09-21 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108460 sha: doc_id: 305405 cord_uid: me4gebvm Objectives Diabetes has been shown to be a risk factor for corona virus disease-2019 (COVID-19) infection. The characteristics of patients with diabetes vulnerable to this infection are less specified. We aim to present the characteristics of patients with diabetes admitted to hospital with COVID-19. Design: A retrospective case series. Setting: A single clinical centre in the UK. Methods We have retrospectively collected the demographics, medical characteristics and outcome of all patients with diabetes admitted to hospital over two-week period with COVID-19 infection. All cases were diagnosed by a reverse transcription polymerase chain reaction (RT-PCR) of pharyngeal and nasal swabs. Results A total of 71 COVID-19 patients were admitted during the study period of whom 16 (22.5%) patients had diabetes and were included in this case series. There was no significant difference between patients with compared to those without diabetes regarding age, gender or clinical presentation. However, comorbidities were more common in patients with diabetes specially hypertension {75% v 36.4%, a difference of 38.6%, 95% confidence interval (CI) 6.5 to 58.3} and chronic kidney disease (37.5 v 5.5, a difference of 32% (1.6 to 51.6). Patients with diabetes were significantly more obese than those without diabetes (56.2% v 21.8% a difference of 34.4%, 95% CI 7.7 to 61.1). About one third (31.3%) of patients with diabetes were frail. Mean {standard deviation (SD)} duration of diabetes was 10 (2.8) years and mean (SD) HbA1c was 60.3 (15.6) mmol/mol. The use of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and non-steroidal anti-inflammatory drugs (NSAIDs) was common (37.5%, 25% and 18.8% respectively). There was no significant difference in the outcomes between patients with compared to those without diabetes. Conclusion Patients with diabetes hospitalised for COVID-19 were significantly more obese and had high prevalence of comorbidities than those without diabetes. Other features of patients with diabetes and COVID-19 infection included long duration of diabetes, less tight glycaemic control and common use of ACE inhibitors, ARBs and NSAIDs. In December 2019, a pneumonia like illness was first reported in Wuhan-China caused by a new coronavirus named corona virus disease-2019 (COVID-19) which then spread to cause a global pandemic. 1 In the Chinese cohorts, diabetes mellitus appeared to be a risk factor for COVID-19 infection. A meta-analysis of 8 Chinese studies to assess the prevalence of comorbidities in 46,248 infected patients with COVID-19, median age 46.0 years (51.6%) men, diabetes mellitus was the second most prevalent comorbidity (8%) after hypertension (17%) and higher than cardiovascular (5%) and respiratory diseases (2%). 2 Also diabetes appeared to be detrimental in predicting worse outcomes. Patients infected with COVID-19 who required intensive care unit (ICU) treatment were more likely to have diabetes (22.2% V 5.9%) compared to those who did not require ICU admission. 3 Presence of diabetes increased mortality from COVID-19 compared to patients without comorbidities (7.3% V 0.9%). 4 In addition to the Chinese studies, subsequent international studies have demonstrated that diabetes was a frequent comorbidity and a risk factor for adverse outcomes of COVID-19 infection such as higher rates of ICU admissions and refractoriness to anti-viral and anti-inflammatory therapies. [5] [6] [7] [8] The high risk of COVID-19 infection in patients with combined hypertension and diabetes has been now highlighted in the literature which may be related to the fact that the severe acute respiratory syndrome corona virus-2 (SARS-CoV-2) is a cause of endothelial dysfunction and endothelial dysfunction could represent a common link between hypertension, diabetes and COVID-19. 9 The criteria of patients with diabetes infected with the COVID-19 virus are less specified. In this brief analysis, we report the characteristics of 16 patients with diabetes admitted to hospital in the UK with COVID-19 infection. A retrospective single-centre case report enrolling consecutive patients with diabetes admitted to a District General Hospital in the UK with COVID-19 infection from the period of 23 rd of March to 4 th of April 2020. Identification of cases with diabetes was verified by the confirmed diagnosis in medical records or by the use of hypoglycaemic medications. Identification of COVID-19 status was undertaken in line with Public Health England (PHE) which recommends screening of cases if they present with clinical or radiological evidence of pneumonia, acute respiratory distress syndrome or influenza like illness associated with fever and additional respiratory symptom of persistent cough, hoarseness of voice, nasal discharge, shortness of breath, sore throat, wheezing and sneezing. 10 Patients meeting the above criteria then had nasopharyngeal and oropharyngeal swabs sent to our local laboratory for identification of 2019-nCoV nucleic acid by reverse transcription polymerase chain reaction (RT-PCR). Patients who tested negative by RT-PCR but still have a high index of clinical suspicion were re-tested with a further swab for RT-PCR. Medical records were reviewed and patients' demographic, medical and social history was collected. Laboratory and radiological information were available in the electronic records. We used a standardised data collection sheet which was used by the authors to capture all the relevant information for each patient. To assess frailty, we used the clinical frailty score (CFS) which classifies patients in a range of very fit (score 1) to terminally ill (score 9). 11 As the study was retrospective, only available data in medical records were collected but other relevant tests, which are not routinely done in our practice, such as IL-6 and cardiac enzymes were not available and this was a limitation of this study. We used descriptive statistics and calculated 95% confidence interval for comparison between proportions. Patients outcomes such as discharged alive from hospital, died or required ICU admission were extracted from electronic medical records. Study was approved by our local research and development department. A total of 71 consecutive patients with COVID-19 infection were admitted to hospital during data collection over two-week period, of whom 16 (22.5) patients had diabetes mellitus. Demographics of patients with diabetes are displayed in Table 1 . All patients were White British, had type 2 diabetes, mean (SD) age 70.5 (16.6) years, majority (12 patients, 75%) were ≥65 years old and predominantly men (9, 56.3%). Source of infection was not very clear in most patients, but no patient reported animal contact, which may suggest that all infections were due to human to human transmission. Two patients reported recent travel to Spain and to a Mediterranean cruise respectively. Pre-existing comorbidities were present in 100% of patients with diabetes with a mean (SD) of 4.4 (1.8). All patients with diabetes were either overweight (7, 43.7%) or obese (9, 56.3%). About one third of patients (5, 31.3%) scored ≥5 in CFS indicating frailty. Mean (SD) duration of diabetes was 10 (2.8) years and about one third of patients (5, 31.3%) were on insulin treatment in addition to oral hypoglycaemic therapy. The use of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and non-steroidal anti-inflammatory drugs (NSAIDs) was common {6 (37.5%), 4 (25%) and 3 (18.8%) respectively}. Diabetes tended to be uncontrolled with a mean (SD) HbA1c of 60.3 (15.6) mmol/mol and 10 (63%) patients had HbA1c >58.5 mmol/mol. Common presenting symptoms were fever (11 patients, 68.8%), general fatigue (10, 62.5%), cough (9, 56.3%), shortness of breath (8, 50%), gastrointestinal symptoms (7, 43.7%) and acute confusion (3, 18.8%). One patient presented with diabetic ketoacidosis. In comparison to those without diabetes, patients with diabetes had significantly higher prevalence of hypertension (75% v 36.4%, a difference of 38.6%, 95% CI 6.5 to 58.3) and chronic kidney disease (37.5 v 5.5, a difference of 32% (1.6 to 51.6). Patients with diabetes were significantly more obese than those without diabetes (56.2% v 21.8% a difference of 34.4%, 95% CI 7.7 to 61.1). Majority of patients had abnormal opacifications in the chest X-ray and abnormal systemic laboratory results. Comparison of patients with to those without diabetes is summarised in Table 2 . All patients with diabetes were treated in acute medical wards and no patients were escalated to ICU. Supportive care was the only therapy given and no specific antiviral treatment was tried in this cohort. Most patients (12, 75%) had recovered fully and discharged home but 4 (25%) patients have died. The patients who died were not considered for ICU admission or escalation plans due to the severity of illness and their comorbidity burden. We present 16 case series with type 2 diabetes admitted to hospital with COVID-19 infection. In the Chinese COVID-19 affected patients, diabetes was found to be a risk factor for infection but the characteristics of patients with diabetes vulnerable to this infection have not been specified. Our cohort represented 22.5% of all COVID-19 patients admitted during study period. Diabetes prevalence has been shown to be 16% in one study and 12% in another. 12, 13 We aimed to collect clinical data on these patients including their clinical presentations, laboratory findings, metabolic profile and their progression. Our cohort had a mean age of 70.5 years and 75% of patients were ≥65 years, which appears to be older than the Chinses cases that have a median age of 46.0 years and only 44.1% of them were above the age of 60 years. 4 About half of our patients presented with respiratory symptoms (fever 68.8%, cough 56.3 % and shortness of breath 50%). Most prominent was the general nonspecific symptoms of being generally unwell or fatigued (62.5%) and gastrointestinal symptoms (43.7%). Of note, gastrointestinal symptoms were not common in the Chinese population for example only 3.8% had diarrhoea. 12 Although in another Chinese study by Wang et al, 10% of patients initially presented with nausea and diarrhoea 1-2 days before the onset of fever and dyspnoea. 3 Metabolic profile showed that our patients had uncontrolled and long duration of diabetes. Poor glycaemic control may be associated with impairment of the immune response to viral infections and may predispose to potential secondary bacterial infections. 14 The most striking feature was that all patients were either overweight or obese. Obesity is a risk factor for severe infection. 15 It has been shown that obesity is associated with the severity and the longer duration of viral infections. 16 Central obesity, which is the predominant type in persons with diabetes, is particularly associated with higher risk. The increased secretion of cytokines characterises a chronic low-grade inflammation in central obesity and may induce an impaired immune response. 15 Other factors may be related to the fact that obesity may mechanically impair ventilation with reduced aeration of the lung bases that leads to accumulation of secretions and increased risk of infections. 17 Similar to our case series, a study from New Jersey has demonstrated that COVID-19 infection is associated with hyperglycaemia and obesity. 18 Also, in a small study of 49 outpatients with diabetes and COVID-19, the reported median BMI was 33.9 and a range that reaches as high as 63.9 Kg/m 2 . 19 The prevalence of hypertension was a common finding in our cohort (12 patients, 75%) and most patients used either ACE inhibitors or ARBs. Hypertension was also the most common (17%) comorbidity found in the Chinese population infected with COVID-19. 2 Although less prevalent than in our cohort, but this is likely to be due to the fact that all our patients are diabetic and diabetes usually coexists with other cardiovascular diseases especially hypertension which has been shown to be associated with worse outcomes in COVID-19. [20] [21] [22] [23] Is not clear whether hypertension itself increases the risk of infection or it is due to the fact that many hypertensive patients are using ACE inhibitors or ARBs. The COVID-19 virus gains entry to the pulmonary cells through binding to membrane ACE2 receptors. The ACE inhibitors and ARBs appear to increase ACE2 receptors expression and may increase COVID-19 infectivity and illness severity. 24 The concentration of glycated SARS-CoV-2 viral particles and glycated ACE2 in the lung epithelium may explain the severity of COVID-19 infection. Binding of ACE2 by SARS-CoV-2 in COVID-19 also suggests that prolonged uncontrolled hyperglycaemia, and not just a history of diabetes mellitus, may be important in the pathogenesis of the disease. 25 On the contrary to this, these medications may reduce the pulmonary and systemic inflammatory response by decreasing cytokines and therefore may be beneficial. 26 Recent data from a small Italian study of 62 patients with COVID-19 has demonstrated that anti-hypertensive therapy of ACE inhibitors, ARBs or calcium channel blockers did not affect the outcome. Therefore, this issue remains needing further exploration in future larger studies. 27 We did not demonstrate higher mortality in our diabetes cohort compared to those without diabetes. This could be due to the small study sample. Also our cohort, although had overall less tightly controlled diabetes, their admission random blood glucose was not grossly elevated. Data from the US showed that mortality rate was higher for patients with uncontrolled hyperglycaemia compared to those without hyperglycaemia. Also, hyperglycaemia related mortality was 41.7% compared to 14.8% for patients with diabetes but no hyperglycaemia suggesting that hyperglycaemia itself, rather than diabetes, played a crucial role in adverse outcome. 28 Also, a recent study has shown that insulin infusion to tighten blood glucose control in the immediate post-admission period was associated with a significant reduction of inflammatory cytokines and pro-coagulant state which may reduce the risk of disease progression. 6 About one third of our cohort was frail. Frailty is a syndrome that is characterised by multisystem dysregulation that leads to reduced physiologic reserve and increased risk of adverse health outcomes. Dysregulation in the innate and adaptive immunity also leads to chronic inflammation, increase in inflammatory markers and increased susceptibility to sever infections. 29 In a recent multicentre European cohort study, frailty, assessed by CFS, proportionately predicted mortality. 30 A limitations of this study is the small number of population included which may limit its generalisability. Also, no patients in our cohort was admitted to ICU, which may be just a reflection of the small study sample. Also of note, the cause of death in patients who died in this cohort was severe sepsis and these patients were not considered for further escalation to ICU treatment due to the perceived poor prognosis of their high comorbidity burden. Patients with diabetes hospitalised for COVID-19 were significantly more obese and had higher prevalence of comorbidities, in particular hypertension and chronic kidney disease, than those without diabetes. Other features of patients with diabetes and COVID-19 infection include long duration of diabetes, less tight glycaemic control and the common use of ACE inhibitors, ARBs and NSAIDs. Preventative measures should continue to develop to improve the metabolic profile of people with diabetes to reduce their risk of infection. Overweight and obesity appeared to be a striking feature affecting all patients in this cohort. It is not yet clear whether the new weight reducing hypoglycaemic therapy will have an effect in reducing risk of infections in people with diabetes. Although a specific anti-viral drug is urgently required, a multi-target agent is also required to help regulate the dysregulated neuro-endocrine-immune system that is common in metabolic diseases including diabetes, cardiovascular disease, atherosclerosis, insulin resistance, hypertension, dyslipidaemia and obesity. Research is urgently required to develop protective vaccination. Due to vulnerability of the characterised group in our cohort these criteria should be considered in future vaccination programmes. The viral entry into the cell membrane through the ACE2 receptors needs further exploration and future trials are needed to investigate the role of the current blockers of angiotensin aldosterone pathway in viral infections. The role of hypoglycaemic medications such as dipeptidyl peptidase-4 (DPP-4) inhibitors, which may act as receptor for COVID-19 and the glucagon-like peptide-1 receptor agonist (GLP-1 RA), that may reduce inflammation, will need further investigation. 31, 32 Key points  Patients with diabetes hospitalised for COVID-19 are significantly more obese and had higher prevalence of comorbidities, in particular hypertension and chronic kidney disease, compared to those without diabetes. CI=Confidence interval, COPD=Chronic obstructive pulmonary disease, CVD=Cardiovascular disease, CKD=Chronic kidney disease, CLD=Chronic liver disease, CFS=Clinical frailty score, BMI=Body mass index, AKI=Acute kidney injury, CRP=C-reactive protein, CXR=Chest X-ray, ICU=Intensive care unit. *Significant difference. The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health -The latest 2019 novel coronavirus outbreak in Wuhan, China Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan The novel coronavirus pneumonia emergency response epidemiology team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) -China Impact of diabetes mellitus on clinical outcomes in patients affected by Covid-19 Outcomes in Patients With Hyperglycemia Affected by COVID-19: Can We Do More on Glycemic Control? Hyperglycaemia on admission to hospital and COVID-19 Negative impact of hyperglycaemia on tocilizumab therapy in Covid-19 patients Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence Guidance COVID-19: investigation and initial clinical management of possible cases A global clinical measure of fitness and frailty in elderly people Clinical characteristics of coronavirus disease 2019 in China Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China Glycemic control and risk of infections among people with type 1 or type 2 diabetes in a large primary care cohort study Obesity and the risk and outcome of infection Impact of obesity on influenza a virus pathogenesis, immune response, and evolution The effect of obesity on lung function Impaired glucose metabolism in patients with diabetes, prediabetes, and obesity is associated with severe COVID-19 Positive Patients with Diabetes Managed as Outpatients Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study Can angiotensin receptor-blocking drugs perhaps be harmful in the COVID-19 pandemic? Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics Could Anti-Hypertensive Drug Therapy Affect the Clinical Prognosis of Hypertensive Patients With COVID-19 Infection? Data From Centers of Southern Italy Glycemic Characteristics and Clinical Outcomes of COVID-19 Patients Hospitalized in the United States Clinical Features Predicting Mortality Risk in Patients With Viral Pneumonia: The MuLBSTA Score The effect of frailty on survival in patients with COVID-19 (COPE): a multicentre, European, observational cohort study Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection Coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications 


id: cord-306670-c2jm0g88
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   key: cord-306670-c2jm0g88 authors: Zhang, Yan; Cui, Yanhui; Shen, Minxue; Zhang, Jianchu; Liu, Ben; Dai, Minhui; Chen, Lingli; Han, Duoduo; Fan, Yifei; Zeng, Yanjun; Li, Wen; Lin, Fengyu; Li, Sha; Chen, Xiang; Pan, Pinhua title: Association of Diabetes Mellitus with Disease Severity and Prognosis in COVID-19: A Retrospective Cohort Study date: 2020-05-22 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108227 sha: doc_id: 306670 cord_uid: c2jm0g88 Abstract The 2019 novel coronavirus disease (COVID-19) emerged in Wuhan, China, and was characterized as a pandemic by the World Health Organization. Diabetes is an established risk associated with poor clinical outcomes, but the association of diabetes with COVID-19 has not been reported yet. Methods In this cohort study, we retrospectively reviewed 258 consecutive hospitalized COVID-19 patients with or without diabetes at the West Court of Union Hospital in Wuhan, China, recruited from January 29 to February 12, 2020. The clinical features, treatment strategies and prognosis data were collected and analyzed. Prognosis was followed up until March 12, 2020. Results Of the 258 hospitalized patients (63 with diabetes) with COVID-19, the median age was 64 years (range 23-91), and 138 (53.5%) were male. Common symptoms included fever (82.2%), dry cough (67.1%), polypnea (48.1%), and fatigue (38%). Patients with diabetes had significantly higher leucocyte and neutrophil counts, and higher levels of fasting blood glucose, serum creatinine, urea nitrogen and creatine kinase isoenzyme MB at admission compared with those without diabetes. COVID-19 patients with diabetes were more likely to develop severe or critical disease conditions with more complications, and had higher incidence rates of antibiotic therapy, non-invasive and invasive mechanical ventilation, and death (11.1% vs. 4.1%). Cox proportional hazard model showed that diabetes (adjusted hazard ratio [aHR]=3.64; 95% confidence interval [CI]: 1.09, 12.21) and fasting blood glucose (aHR=1.19; 95% CI: 1.08, 1.31) were associated with the fatality due to COVID-19, adjusting for potential confounders. Conclusions Diabetes mellitus is associated with increased disease severity and a higher risk of mortality in patients with COVID-19. Since December 2019, China has been experiencing an outbreak of pneumonia with a novel coronavirus [1] , which was officially named as Severe Acute Respiratory WHO characterized COVID-19 as a pandemic, as it has spread rapidly throughout China and more than 100 countries in the following months after the outbreak, causing more than 150,000 confirmed cases and thousands of deaths by March 15, 2020 . SARS-CoV-2 belongs to the subgenus Sarbecovirus (β-CoV lineage B), and shares 79% of sequence with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), but only 50% homology with Middle East Respiratory Syndrome Coronavirus (MERS-CoV) [2, 3] . China has had a climbing prevalence rate of diabetes in recent decades. According to the latest nationally representative cross-sectional survey among 170287 participants in 2013 in mainland China, the overall prevalence of diabetes was 10.9% in adults and 20.2% in the elderly [4] . Patients with diabetes are more susceptible to be infected by bacteria, viruses, and fungus than individuals without diabetes owing to relatively lower immune function [5, 6] . As a result, these patients might be at an increased risk of SARS-CoV-2 infection and consequently poor prognosis. Although many studies have described the clinical characteristics of COVID-19, so far [1, 7, 8, 9] , information with respect to diabetes among these patients, has not been well characterized yet. In the current study, we retrospectively reviewed the clinical data of 258 patients with laboratory-confirmed COVID-19, and compared the differences in clinical characteristics, laboratory markers, treatment strategies, and short-term prognosis including death between patients with and without diabetes. We hope that these findings will provide new insights into the risk stratification, disease management, and therapeutic strategies for COVID-19 patients with diabetes. This was a retrospective cohort study among patients with COVID- 19 Demographic, clinical features, laboratory and radiological findings, treatment strategy, and short-term prognosis data of the patients were obtained from their medical records. Clinical outcomes were followed up to March 12, 2020. All the data was checked by two senior physicians (P.P and J.Z). All the patients enrolled in this study were laboratory-confirmed COVID-19 patients, and the diagnostic criteria of COVID-19 was based on the positive detection of viral nucleic acids. The severity of COVID-19 was defined based on the diagnostic and treatment guidelines (Version 5-7) by the National Health Committee of China. Severe subtype was defined if a patient met one of the following criteria: 1) Respiratory distress with respiratory frequency ≥ 30/min; 2) Pulse oximeter oxygen saturation ≤ 93% at rest; 3) Oxygenation index (artery partial pressure of oxygen/inspired oxygen fraction, PaO2/FiO2) ≤ 300 mmHg. Critically ill subtype followed the criteria mentioned above, and met one of the following criteria: 1) Needs mechanical ventilation due to respiratory failure; 2) shock; 3) combined with multiple organ failure requiring transfer to intensive care unit (ICU). Pharyngeal swab specimens were collected from each patient for viral nucleic acid detection of SARS-CoV-2 using a real-time reverse-transcriptase polymerase-chainreaction (RT-PCR) assay as previously described [11] . The viral nucleic acid testing All data was reviewed and transferred to the standardized forms from the electronic medical records in the hospital, including case report forms, nursing records, laboratory and radiological findings. Two senior physicians (P.P and J.Z) independently reviewed the data. Information on demographic data, symptoms, preexisting chronic comorbidities, computed tomographic images of chest, laboratory results were collected. All treatment strategies were recorded during the hospitalization, such as antiviral therapy, antibiotic therapy, use of corticosteroid, and respiratory support. The time from the onset of the illness to the hospital admission was also recorded. Patients with diabetes were identified based on the patient's documented medical history and guidelines for the prevention and control of T2D in China [12] . Cardiovascular disease including coronary artery disease, congestive heart failure, or a history of myocardial infarction were included; reports of isolated hypertension were not included. Chronic pulmonary disease, chronic obstructive pulmonary disease (COPD), allergic airway disease or the use of supplemental oxygen at home was included. The presence of ARDS was designated by The berlin definition [13] . Cardiac injury was identified when the serum level of hypersensitive cardiac troponin I (hsTNI) was above the upper limit of the normal range or new abnormalities were shown in electrocardiography and echocardiography [14] . Acute kidney injury (AKI) was classified on the basis of the highest serum creatinine level or urine output criteria based on KDIGO clinical practice guideline for AKI [15] . Prognosis was defined based on the patient being discharged from hospital, not discharged yet, or death during hospitalization. The follow-up observation was conducted before March 12, 2020. Continuous variables were shown as median and interquartile range (IQR), and compared by the Mann-Whitney test since most laboratory data was with skewed distribution. Categorical variables were presented as counts and proportions, and compared by Chi-square test or Fisher's exact test. The Cox proportional hazard model was used to determine the associations of diabetes and FBG with fatality of COVID-19, and adjusted for potential confounders. Adjusted hazard ratio (aHR) with 95% confidence interval (CI) was presented as the effect size. All statistical analyses and graphs were generated and plotted using the GraphPad Prism version 7.00 software (GraphPad Software Inc) or SPSS version 25.0 (IBM, United States). A P value <0.05 was considered statistically significant. A total of 258 consecutive laboratory-confirmed patients with SARS-CoV-2 infection were included and analyzed in the study, and 24% of them had diabetes. Demographic and clinical characteristics of the patients on admission were summarized by diabetes in The laboratory and radiological findings on admission of the COVID-19 patients with or without diabetes were presented in Interestingly, decreased eosinophil count was also common in these patients (43%), but no significant difference in eosinophil count and the ratio of patients with decreased eosinophil count was found in patients with or without DM. Besides, a positive correlation between eosinophil and lymphocytes numbers on admission was observed (Data not shown), which was consistent with previous study [16] . Other laboratory findings showed no significant differences between the two groups of patients with respect to serum levels of CRP, PCT, and LDH, but COVID-19 patients Next, we compared the severity, treatment, and short-term prognosis of the COVID-19 patients with and without diabetes in Table 3 . Compared with non-diabetes subjects, patients with diabetes were more likely to develop severely or critically ill subtypes (P=0.028) with more complications including acute respiratory distress (38.1% vs. 19.5%, P=0.001), acute cardiac injury (14.5% vs. 5.1%, P=0.016), and had more antibiotic therapy (74.6% vs. 59.0%, P=0.026), non-invasive and invasive mechanical ventilation (P=0.037). As of March 12, 2020, only 33.7% patients were discharged from the hospital. Patients with diabetes had a higher fatality rate than those without diabetes (11.1% vs. 4.1%, P=0.039). Table 3 . Analysis of severity, treatment and prognosis of COVID-19 patients. To further assess the association of diabetes and FBG with the fatality of COVID-19, Cox proportional hazard model was carried out, and the results ( In this retrospective cohort study, we characterized 258 COVID-19 patients with respect to demographics, clinical features, preexisting chronic comorbidities, treatment, and short-term prognosis. We found that COVID-19 patients had a relatively high proportion (24%) of diabetes, and demonstrated that diabetes was associated with alterations in laboratory markers, more severe clinical subtypes at the time of presentation, and worse prognosis compared to those without diabetes, after To the best of our knowledge, this study was the first to investigate the clinical characteristics and prognosis of COVID-19 patients with diabetes. The prevalence of diabetes mellitus is sharply climbing in China in the last few decades. According to the latest nationally representative cross-sectional survey in mainland China in 2013, the estimated prevalence of diabetes in elderly participants (≥60 years old) was 20.2% [4] . Previous studies reported 9% to 14% prevalence of diabetes in COVID-19 patients [1, 8, 14, 16] . Here, we reported a higher prevalence rate of diabetes in these patients, which might be due to the larger proportion of geriatric patients infected by SARS-CoV-2 in our study. The median age of all the participants was 64 years old, which was older than the data previously reported [1, 7, 8 ]. In the current study, 53.5% of the patients were male, and the percentage is similar to that reported by Wang et al [8] and Zhang et al [16] . Besides diabetes mellitus, hypertension (38.0%) and cardiovascular diseases (15.1%) were also common underlying chronic illness, and COVID-19 patients with diabetes seemed to have more comorbidities of cardiovascular diseases and chronic kidney diseases in the current study. The laboratory findings on admission showed that leucocytes and neutrophils count and the proportion of increased leucocytes were higher in COVID-19 patients with diabetes than those without, which might be explained by the fact that patients with diabetes were more susceptible to pathogens after a viral infection due to lower immune function. During hospitalization, patients with diabetes were more likely to receive antibiotic therapy as well. Decreased lymphocytes count and eosinophil count were also common in these patients; this was consistent with the results of previous studies [16] . However, no significant differences were found in the cell counts and percentage lymphocytes and eosinophil count between COVID-19 patients with or without diabetes. The data revealed that COVID-19 patients with diabetes had a higher NLR, which was recently reported as a predictor of severity of COVID-19 in the early stage [17] . We found that COVID-19 patients with diabetes were more likely to develop severely or critically ill subtypes, including more complications with ARDS, acute cardiac injury, resulting in receiving more antibiotic therapy and mechanical ventilation. Cox regression model indicated that both diabetes and FBG level on admission were independent predictors for the fatality of COVID, after adjusting for potential confounders. Based on these findings, we diligently concluded that diabetes was associated with deteriorating disease severity and worsening prognosis in patients with COVID-19. This is the first report to demonstrate that diabetes was associated with aggravating disease severity and poorer prognosis in COVID-19 patients. An increasing number of studies have shown that patients with diabetes have had higher mortality and morbidity of severe medical illness, such as myocardial infarction. High FBG plays an independent predictive role in hospitalized critically ill patients than those without diabetes as well [18, 19, 20] . Diabetes has also been identified as a significant risk factor for severe disease following respiratory tract infections [21] . Several studies demonstrated that diabetes was associated with increased risks of severity and mortality after SARS-CoV and MERS-CoV infection [22, 23, 24, 25] , and FBG level was an independent predictor for fatality in patients with SARS [22] . A very recent study indicated that well-controlled glycemia was associated with markedly improved outcomes of COVID-19 patients combined with pre-existing T2D [26] . Additionally, we found that COVID-19 patients with diabetes also had preexisting cardiovascular disease, and were more susceptible to having acute cardiac injury during hospitalization, which might increase the possibility of short-term poor prognosis in patients with diabetes after SARS-CoV-2 infection. Previous studies reported that patients with diabetes who received intensive glycemic control had lower risk of cardiovascular events [27] . Nevertheless, we could conclude that diabetes and FBG were independent predictive risks for poor outcomes in COVID-19 patients after adjusting those confounders and mediators. Diabetes results in a proinflammatory homeostatic immune response skewed toward helper T cell 1 (Th1) and T17 cells and a decrease in regulatory T cells (Treg) [28] . Immune dysfunction of diabetes alone or following infection has been reported for a wide variety of immune cells, not just macrophages, monocytes and CD4 + T cells [28] . A recent study reported the number of total T cells, CD4 + and CD8 + T cell subsets were substantially reduced and functionally exhausted in COVID-19 patients, especially among geriatric and critically ill patients who required ICU admission [29] . Kulcsar KA et al showed that diabetic mice presented a prolonged phase of severe disease and delayed recovery after MERS-CoV infection, which was attributed to dysregulated immune response with lower inflammatory monocytes/macrophages and CD4 + T cells [30] . Thus, optimal management of diabetes and intensive glycemic control may help prevent the occurrence of life-threatening infections and complications associated with diabetes mellitus, as well as to combat the increased susceptibility of infections due to impaired cellular and humoral immunity. Our study was subject to a few limitations that should not go unnoticed. Firstly, this study was a retrospective study, so we included a very small proportion of patients with laboratory-confirmed SARS-CoV-2 infection in Wuhan. Berkson bias might be introduced since asymptomatic patients and those with mild symptoms were less likely to be enrolled. Secondly, due to the massive number of patients and the lack of medical resources, the interval from the onset of the illness to hospital admission was more than 10 days for most patients, which could further complicate and deteriorate their condition. Nevertheless, patients with diabetes had a similar interval from onset of illness to hospital admission compared with those without diabetes. Thirdly, at the time of the study submission, most of the patients were not discharged yet, and the final survival outcome could not have been determined, and the long-term prognosis was not observed. Fourthly, other diabetes-associated parameters, including glycated hemoglobin, "peak levels" or "postprandial levels" of plasma glucose could better reflect the association of plasma glucose control and mortality in patients with COVID-19 if that data was available. In the current study, we demonstrated that diabetes mellitus is associated with greater disease severity and poorer short-term outcomes including death. Stronger personal prophylactic strategies are advised for patients with diabetes, and more intensive surveillance and treatment should be considered when they are infected with SARS-CoV-2, especially for geriatric patients or those with preexisting comorbidities. The authors declare no conflict of interests. <0.0 01 AHR, adjusted hazard ratio; CI: confidence interval. DM: diabetes mellitus; FBG: fasting blood glucose. a Adjusted for age. b Additionally adjusted for preexisting cardiovascular disease and chronic kidney disease. c Additionally adjusted for inflammatory biomarkers (leucocytes, neutrophils, lymphocyte, eosinophil, NLR, neutrophil-to-lymphocyte ratio; C-reactive protein, procalcitonin). Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding WHO. Middle East respiratory syndrome coronavirus Prevalence and Ethnic Pattern of Diabetes and Prediabetes in China in 2013 Role of T lymphocytes in type 2 diabetes and diabetesassociated inflammation Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Clinical characteristics of 2019 novel coronavirus infection in China Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance Clinical features and progression of acute respiratory 1 distress syndrome in coronavirus disease Guidelines for the prevention and control of type 2 diabetes in China Acute respiratory distress syndrome: the Berlin Definition Association of Cardiac Injury With Mortality in Hospitalized Patients With COVID-19 in Wuhan, China Kidney disease: improving global outcomes (KDIGO) acute kidney injury work group. KDIGO clinical practice guideline for acute kidney injury Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Neutrophil-to-Lymphocyte Ratio Predicts Severe Illness Patients with 2019 Novel Coronavirus in the Early Stage Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes Intensive insulin therapy in the critically ill patients Outcome benefit of intensive insulin therapy in the critically ill: insulin dose versus glycemic control The etiology of lower respiratory tract infections in people with diabetes Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS Clinical Presentation and Outcomes of Middle East Respiratory Syndrome in the Republic of Korea Risk factors for severity and mortality in patients with MERS-CoV: Analysis of publicly available data from Saudi Arabia Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes Intensive Glucose Control in Patients with Type 2 Diabetes -15-Year Follow-up Reduction and Functional Exhaustion of T Cells in Patients with Coronavirus Disease Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection PT (sec), median (IQR) DM, diabetes mellitus; IQR, interquartile range; WBC, white blood cell; NLR, neutrophil-to-lymphocyte ratio; CRP, C-reactive protein LDH, lactate dehydrogenase; FBG, fasting blood glucose CREA, serum creatine; BUN, blood Urea nitrogen; CK-MB, creatine kinase isoenzyme MB We thank all the patients involved in the study. We thank all the medical staff who are fighting against this public crisis. We also thank Dr. Abira Afzal Choudhry for proofreading this paper. 


id: cord-309474-9h9w46eq
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   key: cord-309474-9h9w46eq authors: Schiaffini, Riccardo; Barbetti, Fabrizio; Rapini, Novella; Inzaghi, Elena; Deodati, Annalisa; Patera, Ippolita P; Matteoli, Maria C; Ciampalini, Paolo; Carducci, Chiara; Lorubbio, Antonella; Schiaffini, Gabriele; Cianfarani, Stefano title: School and pre-school children with type 1 diabetes during covid-19 quarantine: the synergic effect of parental care and technology date: 2020-07-03 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108302 sha: doc_id: 309474 cord_uid: 9h9w46eq Abstract Introduction Management of Type 1 Diabetes (T1D) poses numerous challenges, especially for young children and their families. Parental care positively influencesthe outcomesofchildren with T1D, while there are often criticisms in school environment. The COVID-19 pandemic has forced children and parents to spend many hours at home and diabetes care has returned mainly in the hands of parents. Aim of the study To evaluate the effectiveness of exclusive return to parental care in pre-school and school children with T1D treated with Tandem Basal IQ system during the COVID-19 pandemic. Patients and methods 22 children (M:F = 14:8) with T1D have been evaluated. We compared insulin and CGM data (TIR, TBR and TAR) of two periods: PRE-COV and IN-COV, in which children have transitioned from normal school attendance to the exclusive care of their parents. Results During the IN-COV period a significantly (p < 0.001) higher median value of TIR (66,41%) was observed as compared to PRE-COV period (61,45%). Patients also showed a statistically significant difference (p < 0.002) between the IN-COV period and the PRE-COV period as concerning the TAR metric: respectively 29,86 ± 10,6 % vs 34,73 ± 12,8 %. The difference between the bolus insulin doses was statistically significant (PRE-COV 5,3 IU/day, IN-COV 7,9 IU/day – p<0.05). Conclusion Our observational real-life study confirms the positive effect of parental care in T1D very young children and demonstrates that during the COVID-19 pandemic it was possible to obtain a good glycometabolic compensation despite the significant change in lifestyle. Type 1 diabetes (T1D) is one of the most common chronic diseases in infancy 1 and the most frequent endocrinopathy in childhood. It is estimated that about 20000 children are affected by T1D in Italy 2. Correct management of T1D involves frequent blood glucose monitoring, insulin therapy, dietary indications and structured physical activity, representing a high burden on young children and their families. Because of these daily challenges, effective diabetes treatment requires -in principlecomplete parental dedication and involvement 3. Moreover, parents and teachers of kindergarteners and of children in primary school usually experience the additional challenges of a critical management in school hours, due in particular to the fear of hypoglycemia, the extreme glycemic variability of this age group and the difficulties in correcting the hyperglycemic peaks. Parents of kids diagnosed with T1D early in life tend to be proactive in the care of diabetes of their children during school and pre-school periods with a strong parental involvement in disease management and a positive influence on the metabolic and psychosocial outcomes 4-5. Conversely, parents of patients diagnosed in late childhood or in adolescence are less involved in care, and usually this is associated with less than optimal glycemic control 6. Nevertheless, parental care remains important throughout childhood into young adulthood and a progressive sharing of responsibilities is considered an important step towards a therapeutic approach well balanced between self-monitoring and quality of life 7. The gap between family and school care capacities can be bridged by the use of technologies in the treatment of diabetes in children. In the last two decades, new tools for the management of children with T1D have been proven to be safe and useful. Continuous Subcutaneous Insulin Infusion (CSII), Continuous Glucose Monitoring (CGM) and remote monitoring in case of Multiple Daily Injections (MDI) seem to be valid options to manage children with diabetes. In particular, CGM systems and remote control access have improved the treatment and management of diabetes during school hours. Parents of kindergartner (pre-school) and school children reported that the use of remote monitoring and CGM was effective in control glucose excursions 8. In particular, the use of technologies capable of reducing hypoglycemic risk, such as the Tandem Basal IQ system, have proven to be helpful in reducing parental burden. This system is able to prevent/reduce hypoglycemia thanks to CGM real-time data and was introduced in Italy about 6 months ago. COVID-19 pandemic has forced children and parents to spend many hours together at home, reducing structured physical activity while bringing back diabetes care in the hands of parents. We aimed at investigating whether this unusual situation lead to an improvement or a worsening of the glucose control. This is a real-life, retrospective, observational study aimed at evaluating how constant parental care compared to spending time outside home affected glycemic control in pre-school and school children with T1D utilizing Tandem Basal IQ system before and during the quarantine period due to pandemic COVID-19 infection. The Diabetes Unit of the Bambino Gesù Children's Hospital -Rome, Italy, regularly follows 980 Type 1 Diabetes pediatric patients (age 0-18 years); of these patients, 90 use the Tandem Basal IQ Technology (considered as an inclusion criteria) and 29 are in the school-preschool age range; finally 22 pre-school and school children (M:F = 14:8) with T1D have been retrospectively evaluated (7 patients/parents resulted not reachable during the lockdown period). The mean age was 8,7 ± 1,9 years (range 3,5-10,5 years) and the diabetes duration was at least of 1 year. Enrolled patients were all being intensively insulin treated with the Tandem Basal IQ technology for at least six months. Tandem basal IQ technology consists of an insulin pump integrated with a Dexcom G6 glucose sensor capable of previously suspending insulin delivery in case of hypoglycemia prediction. A multidisciplinary team (diabetologist, nurse, dietitian and psychologist) dispensed a standardized protocol of education to all patients enrolled and their parents at the time of diabetes diagnosis and at 6 months intervals. All the patients and their families were educated in carbo-counting procedures and were instructed to follow a balanced nutritional program consisting in 55% of carbohydrates, 20% of proteins and 25% of lipids. The study was conducted according to the Declaration of Helsinki. Participants and their parents provided informed consent to have their CGM data downloaded at regular intervals, as part of routine clinical control and the study was ethically approved. Potential conflict of interest do not exist. Beginning March 9, 2020, the start of the lockdown in Italy, all patients and families were asked to stay at home due to the COVID-19 pandemic emergency. During the pandemic, the children maintained the same diet with a similar distribution between the different macronutrients and they were unable to carry out any structured physical activity, as often happens also in routine life, considering the young age of the group. We compared CGM data of the last two weeks of "normal life" (normal school attendance) (PRE-COV period) with the first two weeks of confinement at home (IN-COV period) . The following CGM metrics were evaluated: time in range (TIR -percent of time in the ideal range of glucose between 70 and 180 mg/dl), time above range (TAR -percent of time above 180 mg/dl), time below range (TBR -percent of time below 70 mg/dl). We also compared the insulin requirement in the 2 different periods, in terms of total insulin (IU/day), basal insulin delivery and insulin administered as boluses. All data were extracted from the Dexcom Clarity and Diasend platforms. Results are reported as the mean ± SD. Normal distribution was assessed by Shapiro-Wilk test. Mean variations of distributions were evaluated using the Student's t test for paired data. The entire analyses were performed using SPSS 25.0 (SPSS Inc., Chicago, Ill, United States) with p < 0.05 considered significant. Data from 22 children (mean age 8,7 ± 1,9 years) (M:F 14:8) with T1D and disease duration longer than 1 year were analyzed. The percentage of time of CGM wearing was 98%. No significant differences between the two evaluated periods (IN-COV vs PRE-COV) were found in TBR (hypoglycemia): respectively 3,73 ± 3,04 % vs 3,95 ± 4,4 % (Tab. 1). In contrast, during the IN-COV period a significantly (p <0.001) higher median value of TIR (66,41%) was observed as compared to PRE-COV period (61,45%) (Tab 1 and Fig.1 ). Conversely, patients showed a lower TAR during IN-COV period than PRE-COV period 29,86 ± 10,6 % vs 34,73 ± 12,8 %, p < 0.002). Interestingly, no differences between IN-COV and PRE-COV periods were observed regarding the total insulin dose (20,7 vs 18,2 IU/day) and the basal insulin delivery (13,3 vs 11,9 IU/day), while a statistically significant difference (p<0.05) was found between the mean bolus doses (7,9 vs 5,3 IU/day) and the daily number of correction boluses (3,1 vs 1,9 IU/day). In this group of pre-school and school T1D children using CGM and semi-automated insulin delivery systems (TANDEM BASAL IQ), the forced and exclusive return to parental care due to the "stay at home" rule decided by the Italian government was associated with a better metabolic performance with higher percentage values of TIR and lower mean values of TAR. This result seems to be due to a greater use of correction boluses; in fact, our evaluation shows a significant increase in insulin boluses during the IN-COV period as compared to PRE-COV one. We speculate that similar results will be hardly seen in adolescents and middle school teens, because the management of the disease in these age groups remains in the hands of the patients even during confinement the and physical activity has no significant impact in younger children. Nonetheless, we think that it would be worthwhile to investigate older age groups in Countries where the lockdown is still in force, though we recognize that other variables -say good or bad interaction with parents-are probably at work in adolescents with T1D. We predict that a better outcome in terms of TBR could be likely in this group because of increased regularity of meals' content and stringent control on alcohol consumption 9. The study has some limitations: first, patients selection limited only to preschool/school children who used Tandem Basal IQ technology can represent a selection bias; secondly, the small size of the sample may not make the results obtained generalizable. Our observational real-life study confirms the positive effect of parental care in T1D very young children and that, though new technologies can potentially improve diabetes outcomes also in this sub-population, maintenance of a good glucose control remains largely dependent on family competence and education 10. Usually the majority of young people with T1D spend many hours at school. Trained school-staff is therefore essential to provide a safe environment for children with diabetes. Teachers, along with the school's auxiliary staff, play a key role in reducing strong glycemic oscillations typical of younger children 11. Our study shows also a no significant differences in TBR, despite the shift to predominant parental care. This can be explained by the fact that all the evaluated children were already using a technology (Tandem Basal IQ System) that effectively reduces the risk of hypoglycemia and therefore for this specific metric it can be assumed that parental intervention does not change the outcomes. In the past 2 decades, technological innovations have revolutionized the treatment of T1D and the real-world data highlighted that patients using insulin pump therapy have a better short and long-term glycemic control relative to the matched injection therapy groups 12. However, despite the use of technology, parental intervention still seems to be more effective and probably the difference in the near future could be made by the spread of Hybrid Closed Loop (HCL) systems. In the real-world experiences HCL use is associated with improved glycemic control and no change in psychosocial outcomes 13. Why children with T1D attending school are often not adequately managed? Recent studies showed that a limited availability of glucagon kits, the shortage of trained personnel able to manage daily diabetes-specific emergencies and a reduced ability to perform an adequate carbohydrate counting, considered an effective means to provide good glycemic control, are the main causes 14-15. Consequently, family-based interventions for youth with T1D are believed to be effective at improving diabetes outcomes 16. Since young patients with T1D spend most of daytime at school, teachers and assisting personnel should receive appropriate training in order to provide a safe environment. However, it is likely that teachers of kindergartens, preschools and primary schools have not enough knowledge to appropriately assist children with T1D 17-18. This may negatively reverberate on trust in school personnel of parents of very young children with T1D, whose perception of the burden of care is very strong. Thus, health care providers, parents, teachers, and school assistants of youngsters with T1D should team up to improve, by specific educational programs 19-20, the skills to handle the disease and guarantee a safe attendance at school. Type 1 diabetes Evaluating Parents' Self-Efficacy for Diabetes Management in Pediatric Type 1 Diabetes Collaborative involvement of primary and secondary caregivers: associations with youths' diabetes outcomes The Impact of Managing School-Aged Children's Diabetes: The Role of Child Behavior Problems and Parental Discipline Strategies Caregiving for children with type 1 diabetes and clinical outcomes in central India: The IDREAM study Shared responsibility for Type 1 Diabetes care is associated with glycemic variability and risk of glycemic excursions in youth Use of remote monitoring with continuous glucose monitoring in young children with Type 1 Diabetes: the parents' perspective Social Consumption of Alcohol in Adolescents With Type 1 Diabetes Is Associated With Increased Glucose Lability, but Not Hypoglycaemia The Impact of Technology on Current Diabetes Management Diabetes care in the school setting: a position statement of the American Diabetes Association Real-world outcomes of insulin pump compared to injection therapy in a population-based sample of children with type 1 diabetes Six months of hybrid closed loop in the real-world: An evaluation of children and young adults using the 670G system Are children and adolescents with type 1 diabetes in Saudi Arabia safe at school? Effects of carbohydrate counting method on metabolic control in children with Type 1 Diabetes Mellitus Family-Based Interventions Targeting Improvements in Health and Family Outcomes of Children and Adolescents with Type 1 Diabetes: a Systematic Review Level of knowledge and evaluation of perceptions regarding pediatric diabetes among Greek teachers Special needs of children with type 1 diabetes at primary school: perceptions from parents, children, and teachers I'm essentially his pancreas": Parent perceptions of diabetes burden and opportunities to reduce burden in the care of children <8 years old with type 1 diabetes ISPAD Clinical Practice Consensus Guidelines 2018: Management and Support of Children and Adolescents With Type 1 Diabetes in School The authors declare no conflict of interest. The authors received no funding from an external source. 


id: cord-309795-2kozsv4z
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   key: cord-309795-2kozsv4z authors: Dewidar, Bedair; Kahl, Sabine; Pafili, Kalliopi; Roden, Michael title: Metabolic liver disease in diabetes – from mechanisms to clinical trials date: 2020-06-20 journal: Metabolism DOI: 10.1016/j.metabol.2020.154299 sha: doc_id: 309795 cord_uid: 2kozsv4z Abstract Non-alcoholic fatty liver disease (NAFLD) comprises fatty liver (steatosis), non-alcoholic steatohepatitis (NASH) and fibrosis/cirrhosis and may lead to end-stage liver failure or hepatocellular carcinoma. NAFLD is tightly associated with the most frequent metabolic disorders, such as obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). Both multisystem diseases share several common mechanisms. Alterations of tissue communications include excessive lipid and later cytokine release by dysfunctional adipose tissue, intestinal dysbiosis and ectopic fat deposition in skeletal muscle. On the hepatocellular level, this leads to insulin resistance due to abnormal lipid handling and mitochondrial function. Over time, cellular oxidative stress and activation of inflammatory pathways, again supported by multiorgan crosstalk, determine NAFLD progression. Recent studies show that particularly the severe insulin resistant diabetes (SIRD) subgroup (cluster) associates with NAFLD and its accelerated progression and increases the risk of diabetes-related cardiovascular and kidney diseases, underpinning the critical role of insulin resistance. Consequently, lifestyle modification and certain drug classes used to treat T2DM have demonstrated effectiveness for treating NAFLD, but also some novel therapeutic concepts may be beneficial for both NAFLD and T2DM. This review addresses the bidirectional relationship between mechanisms underlying T2DM and NAFLD, the relevance of novel biomarkers for improving the diagnostic modalities and the identification of subgroups at specific risk of disease progression. Also, the role of metabolism-related drugs in NAFLD is discussed in light of the recent clinical trials. Finally, this review highlights some challenges to be addressed by future studies on NAFLD in the context of T2DM. Nonalcoholic fatty liver diseases (NAFLD) is currently defined by lipid deposition that exceeds more than 5% of hepatocytes, as assessed from liver biopsy, and/or by more than 5 .6% hepatocellular fat content per liver weight, as assessed from magnetic resonance (MR) methods, in the absence of significant alcohol consumption and other causes of fatty liver [1, 2] . NAFLD, which affects about 25% of the population [3] , comprises a broad range of abnormalities ranging from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH), characterized by inflammation, necrosis, and hepatocellular ballooning, and progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) [2] . Some gene variants promote risk of NAFLD by altering lipid droplet formation and de novo lipogenesis (DNL), such as variants of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and glucokinase regulatory protein [4] , or by decreasing very-low-density lipoproteins (VLDL) export as shown for a missense mutation (E167K) in transmembrane 6 superfamily member 2 (TM6SF2) [5] . Nevertheless, NAFLD is tightly associated with common acquired metabolic diseases such as obesity and type 2 diabetes (T2DM). The mutual relationship between both diseases is illustrated by several epidemiological data. The prevalence of steatosis and NASH has been estimated to be 50 and 56%, respectively, in T2DM [6] . The age-adjusted relative risk of NAFLD is about 5.36fold higher in T2DM compared to healthy humans [7] . T2DM is also an emerging risk factor for NASH progression to advanced fibrosis, cirrhosis and HCC [8, 9] . Diabetes was even a better predictor for HCC development in people with NASH and cirrhosis compared to other metabolic risk factors such as hyperlipidemia, body mass index (BMI) and hypertension [10] . Recently, a consensus panel has proposed to rename NAFLD a metabolic-dysfunction-associated fatty liver disease (MAFLD) based on the presence of overweight/obesity, T2DM and evidence of so-called "metabolic dysregulation" [11] . Future will tell, if this will help to better understand the multiple relationships between NAFLD and T2DM. In this context, NAFLD per se associates with more than double risk of incident diabetes pointing to specific liver-related mechanisms [12, 13] . Moreover, multicenter studies in Skandinavia and Germany have recently found that diabetes can be stratified into subtypes J o u r n a l P r e -p r o o f the circulation. On the contrary, a recent study demonstrated that obesity-induced insulin resistance preceded inflammation in adipose tissues of mice [29] . Indeed, adipose tissue inflammation might be a protective feedback mechanism as its local inhibition in mice induced ectopic lipid accumulation in liver, glucose intolerance, and systemic inflammation [30] . Besides released inflammatory cytokines and FFA, adipose tissue could still communicate with the liver and muscle through secretion of different adipokines such as adiponectin and leptin. Persons with NASH have lower serum adiponectin compared to those with NAFLD with or without normal liver enzymes [31] . By contrast, the circulating levels of leptin were higher in people with NAFLD and T2DM, probably due to increased leptin resistance, and were associated with disease severity [32] . Increased FFA influx to skeletal muscle promotes accumulation of intramyocellular lipid (IMCL). Reduced mitochondrial oxidation contributes as well to IMCL as shown in aging and insulin-resistant humans [33] . Consequently, skeletal muscle exhibits insulin resistance, which often precedes the onset of T2DM and insulin resistance in the liver [34] . Lipid intermediate metabolites, in particular sn 1,2 diacylglycerols (DAG), link IMCL to skeletal muscle insulin resistance through activation of protein kinase C-theta (PKCθ) resulting in its translocation from cytoplasm to the plasma membrane [35] . Muscles of insulin resistant humans with obesity and T2DM showed increased DAG content and PKCθ activity as compared to healthy humans [35] . Mutation studies highlighted serine amino acid residue (Ser1101) of IRS1 to be a substrate for activated PKCθ [36] . As a consequence of skeletal muscle insulin resistance, postprandial energy storage shifts from glycogen synthesis in the muscle into triacylglycerol (TAG) in the liver, promoting NAFLD development [25] . Gut microbiome is increasingly recognized as a modulator of liver pathogenesis through what is called the "gut-liver axis" [37] . Distinctive alterations of gut microbiome were reported in humans having NASH and T2DM [38] . The intestinal microbiome alters host metabolism by modulating the production of short-chain fatty acids (SCFA) e.g. butyrate, acetate, and propionate, which have beneficial effects on insulin sensitivity, lipid and glucose metabolism [38] . Also, intestinal dysbiosis could associate with increased intestinal permeability permitting translocation of bacterial lipopolysaccharide (LPS) into the systemic circulation, J o u r n a l P r e -p r o o f 6 which could induce fat deposition in the liver, NASH progression, weight gain, and diabetes [39] . Moreover, intestinal microbiome could suppress the expression of fasting-induced adipocyte factor (FIAF) in intestinal epithelium, which functions as an inhibitor of circulating lipoprotein lipase, resulting in increased TAG storage in the peripheral tissues [22] . Also, ethanol-producing microbiome could increase blood alcohol concentration in NASH, which is metabolized in the liver generating high levels of reactive oxygen species (ROS). The last mechanism could explain the histological similarity between NASH and alcoholic steatohepatitis [22] . Furthermore, microbiota metabolize liver-derived primary bile acids into secondary bile acids. The latter are reabsorbed into bloodstream and may act as signaling molecules via a variety of receptors including farnesoid X receptor (FXR), which regulates the transcription of different metabolic genes involved in bile acid synthesis, transport, lipogenesis, and glucose homeostasis [40] . Insulin resistance in both skeletal muscle and adipose tissues initiates liver steatosis by providing precursors and substrates for DNL and mitochondrial β-oxidation e.g. glucose, FFA and glycerol [25] . Although reesterification of FFA derived from diet and adipose tissue is the dominant contributor to TAG pool in the liver (59%), it did not increase in people with NAFLD. On the other side, DNL-derived FFA contribute by about 26%, which is severalfold higher as compared to individuals without NAFLD (10%) [41] . Later, insulin resistance of the liver develops, resulting in increased gluconeogenesis and elevation of endogenous glucose production (EGP) from the liver, which contributes to fasting hyperglycemia in individuals with T2DM [25] . Insulin signaling inhibits typically hepatic gluconeogenesis through Akt-induced phosphorylation of forkhead box (FOXO1) and induces lipogenesis through activation of sterol regulatory element-binding proteins (SREBP1C) and mammalian target of rapamycin complex (mTORC1) pathways. During hepatic insulin resistance, insulin does not suppress gluconeogenesis efficiently, while DNL is preserved or even increased. To explain this discrepancy, pathway-selective hepatic insulin resistance was postulated, which means that only one arm of insulin signaling is defective i.e. Akt/FOXO1 leading to reduced insulin-mediated suppression of gluconeogenesis, whereas insulin-activated SREBP-1C/mTORC1 pathway remains intact and activates lipogenesis [28] . Actually, DNL was reduced after induction of hepatic insulin resistance by feeding mice with J o u r n a l P r e -p r o o f 7 a high-fat diet (HFD) [42] , which challenges the concept of selective hepatic insulin resistance and suggest the existence of alternate mechanisms that contribute to increased DNL and gluconeogenesis in insulin-resistant liver, for example, hyperinsulinemia, insulinindependent re-esterification of adipose tissue-derived FFA, and increased acetyl CoA generation from β-oxidation of FFA, which allosterically activates pyruvate carboxylase enzyme, leading to enhanced gluconeogenesis [25] . In addition, increased blood glucose level can activate carbohydrate response element-binding protein (ChREBP) signaling pathway, thereby stimulating expression of several glycolytic genes, which provide additional metabolic precursors for DNL [43] . In line, ChREBP overexpression induced stearoyl-CoA desaturase 1 (Scd1) expression, an enzyme responsible for the biosynthesis of monounsaturated fatty acids (MUFA), resulting in increased liver fat content [44] . PKC epsilon (PKCε) is crucial in mediating hepatic insulin resistance and once activated by DAG, it translocates to the cell membrane, and phosphorylates specific threonine residue (Thr1160 in human and Thr1150 in mouse) on insulin receptor leading to destabilization of the active configuration of insulin receptor kinase and inhibition of its tyrosine kinase activity [45] (Figure 2 ). In general, both hyperglycemia and toxic lipids such as ceramides, DAG, FFA, and cholesterol can induce deleterious effects on liver cells (glucolipotoxicity), which might initiate NAFLD progression from simple steatosis to NASH and fibrosis via various mechanisms, including cell death, oxidative stress, endoplasmic reticulum (ER) stress and mitochondrial disorders [46] . Alterations in the activity and abundance of oxidative phosphorylation (OXPHOS) proteins and antioxidant enzymes were described in various animal models of NAFLD [47] . Impaired hepatic mitochondrial function was evident as well in T2DM and NASH [48, 49] . In a mouse model of choline-deficient diet-induced NAFLD, mitochondrial OXPHOS was increased at 12 weeks but lost at a later time point [50] . Also, the higher maximal respiration rate of liver mitochondria was severalfold higher in insulin-resistant obese individuals with fatty liver as compared to lean individuals [51] . These studies highlight the flexibility of mitochondria to adapt to increased metabolic inputs to keep energy homeostasis and to protect against the harmful effects of increased FFA and TAG in the liver. In NASH, mitochondrial flexibility was lost, which was associated with increased ROS production and exhaustion of protective antioxidant enzymes [51] (Figure 2 ). Whether loss of mitochondrial flexibility is a cause or consequence for NAFLD progression remains obscure. Depletion of ATP due to J o u r n a l P r e -p r o o f mitochondrial disorders, together with hyperglycemia and lipid overload could be inducers for another signaling pathway, termed unfolded protein response "UPR", which is adaptive response to resolve unfolded or misfolded proteins and to restore ER homeostasis [52, 53] . Prolonged UPR stress can activate JNK and NF-kB signaling pathways, which are involved in insulin resistance, liver steatosis, and inflammation [52] . Furthermore, ER stress could increase insulin resistance through induction of lipin-2 expression, which is a phosphatase enzyme that catalyzes biosynthesis of DAG leading to activation of DAG/PKCε axis [54] . Interestingly, UPR could also increase liver steatosis through activation of SREBP-1c signaling pathway [53] . Elevated ROS and UPR are well-identified pathways that could induce hepatocytes death in NASH. Hepatocytes apoptosis and necroptosis are the main forms of cell death in human steatohepatitis and diet-induced mouse models of NASH [55] . The key fibrogenic liver cells, hepatic stellate cells (HSCs), usually exist in a quiescent state and get activated by engulfment of apoptotic bodies, the inflammatory milieu, or damage-associated molecular patterns (DAMPs) released from stressed and dying hepatocytes [56] . Interestingly, FFA-mediated lipotoxic effects stimulate hepatocytes to release extracellular vesicles (EVs) with distinctive microRNAs (miRNA) profile that increase the expression of fibrogenic genes in the surrounding HSCs [57] (Figure 3 ). Free cholesterol could directly sensitize HSCs to the action of tumor growth factor (TGF)-β, a potent fibrogenic cytokine [58] . Treatment of human and rat immortalized HSCs cell lines with saturated fatty acid increased the expression of various profibrogenic genes [59] . Macrophages aggregate as well around dead hepatocytes forming a crown-like structure, a phenomenon that exists only in persons with NASH but not in those with simple steatosis [60] . Recruitment of more inflammatory cells from systemic circulation is facilitated by "Find me" signals that are released from dead cells [61] . Inhibition of inflammatory monocytes recruitment via inhibition of C-C chemokine receptors type 2 and type 5 (CCR2/CCR5) suppressed fibrogenesis and steatohepatitis in murine NASH [62] . Macrophages can modulate also hepatic insulin resistance and favor TAG accumulation in hepatocytes through secretion of IL-1β that downregulates peroxisome proliferator-activated receptor (PPAR) α, a key transcriptional pathway involved in fatty acid oxidation [63] . Liver sinusoidal cells (LSECs) are fenestrated cells that exist in close vicinity to hepatocytes, J o u r n a l P r e -p r o o f macrophages and HSCs, which, under physiological conditions, regulate lipid transport, maintain the quiescence of Kupffer cells, resident liver macrophages, and HSCs [64] . At early stage of NAFLD, LSECs lose their fenestrae, a process termed capillarization, which could favor liver steatosis and initiate HSCs activation [64] (Figure 3 ). During NASH, LSECs display a pro-inflammatory phenotype that promotes steatohepatitis [64] . Autophagy is a self-degradative process which is used by the cells to remove misfolded proteins and damaged organelles [65] . Singh et al. showed that the cells can use autophagic process as lipolytic mechanism to mobilize lipids from intracellular lipid store, which is termed in this case "macrolipophagy" [66] . Various in vitro and in vivo studies showed that autophagy was decreased in fatty hepatocytes [67] . Impairment of autophagy by palmitic acid in macrophages induces inflammatory IL-1β production [68] . On the other side, selective loss of autophagic activity reduced liver fibrogenesis in cultured HSCs [69] and protected against diet-induced insulin resistance [70] . The results highlight that the net effect of autophagy on NAFLD might depend on the tissue or type of the cells that show autophagic dysfunction and the stage of NAFLD. The liver biopsy is considered the gold standard for NAFLD diagnosis, especially for distinguishing steatosis from inflammation and fibrosis [2] . Nevertheless, this technique has several limitations not only resulting from the invasive procedure and rare post-interventional complications, but also due to the small tissue volume, which might not be representative for the whole liver and may not take into account inhomogeneous distribution of NAFLDassociated alterations. Novel imaging modalities such as ultrasound-or MR-based techniques are of increasing value, as recently reviewed [71] , but are still not generally available, so that there is an urgent need for noninvasive screening tools. Non-invasive detection of NASH and fibrosis remains challenging today. Biomarker-based panels such as aspartate aminotransferase (AST)/platelets count ratio index, fibrosis-4 (FIB-4) index, FibroTest, FibroSpect II, and NAFLD fibrosis score (NFS) offer variable diagnostic efficacy for assessing different stages of liver fibrosis [73, 74] . Although combination of these panels could enhance their predictive values [73] , they still suffer from limited accuracy even compared to the alanine aminotransferase (ALT) and AST, particularly in T2DM [75] . In this regard, transient elastography looks like a promising alternative in diabetes clinics for detection of liver fibrosis in NAFLD [74] . Numerous biomarkers have been developed to specifically track features of NASH progression and fibrosis. Cytokeratin (CK) 18, an intermediate filament protein that is cleaved during cell death to CK18 M30 and CK18 M65, has been intensively investigated as a surrogate of NASH-associated liver cell damage, but a recent meta-analysis of 25 studies reported a maximum sensitivity of 0.75 for NASH diagnosis [76] and suboptimal diagnostic value was shown in T2DM [75] . The ECM turnover marker, type III procollagen, can offer a diagnostic efficacy of 0.81 and 0.88 to detect moderate and advanced liver fibrosis in T2DM, respectively [77] . In 2016, the European Associations for the Study of the Liver, Obesity and Diabetes (EASL-EASO-EASD) jointly released recommendations for diagnosis and monitoring of disease severity in persons with suspected NAFLD and metabolic risk factors [78] . People with metabolic risk factors, such as T2DM, should undergo assessment by abdominal ultrasound, serum transaminases and fibrosis markers (e. g. FIB-4, NFS). Elevated transaminases or steatosis plus abnormal fibrosis test shall require referral to a specialist. This strategy has raised the question of a possible overreferral when adhering to these guidelines [79] . However, recent analyses show that a refined strategy of specific combining indices such as FLI and FIB-4 could reduce the number of people with T2DM for further diagnostic work up to a reasonable size [80] . This retrospective analysis also found that certain non-invasive biomarkers are consistently associated with different patterns of diabetes-related complications. Analyses of the plasma metabolomic of insulin-resistant individuals with NAFLD suggested that bile salts, e. g. glycocholate, taurocholate, and glycochenodeoxycholate allow to detect NASH in one study [81] , while another study reported an association with insulin resistance J o u r n a l P r e -p r o o f but not with liver necroinflammation [82] . Also amino acids, specifically a glutamate-serineglycine index, was associated with hepatic insulin resistance and transaminases and discriminated individuals with fibrosis grade 3-4 from those with grade 0-2 independently of BMI [83] . The diagnostic performance of a serum-based lipidomic analysis was substantially lower for NAFLD detection in T2DM compared to healthy individuals [84] . Nevertheless, certain sphingolipid species were recently found to be increased in insulin-resistant NASH and to correlate with hepatic oxidative stress and inflammation [85] . One circulating small noncoding RNA, miRNA-122, was found to be more than 5.7fold in steatosis and further doubled in NASH [86] . This miRNA was also higher in T2DM with NAFLD than in those without NAFLD and provided better prediction of NAFLD when combined with LDL and waist-to-hip ratio [87] . Moreover, extracellular vesicles (EV), which among other cargo also transport miRNA, may be promising biomarkers for NAFLD as shown by higher serum levels in people with NAFLD, obesity and diabetes [107] . Recently, metagenomics data derived from gut microbiota alterations allowed to detect advanced fibrosis in 86 NAFLD patients, of whom 23% had T2DM, with a robust diagnostic accuracy (AUROC: 0.936) [88] . The current guidelines recommend only lifestyle modification and -for certain groupsbariatric or metabolic surgery to treat NAFLD [1, 2] . Although the numerous activities in this field, no pharmacological treatment is currently approved or expecting approval for the use in NAFLD with or without concomitant T2DM (Table 1 and 2), except for obeticholic acid (OCA). Marketing authorization application for OCA has been submitted to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), awaiting FDA decision by June 2020 [89] . Against this background, current guidelines and recommendations primarily advise lifestyle modification (healthy nutrition and exercise) and weight loss in overweight/obese persons. The EASL-EASO-EASD guidelines recommend to consider pharmacological treatment in people with NASH when combined with fibrosis and in those with less severe disease, but high risk conditions for disease progression such as T2DM [78] . The American Association for the Study of Liver Diseases (AASLD) recommends to limit pharmacological treatment to those with biopsy-proven NASH and fibrosis [1] . J o u r n a l P r e -p r o o f Weight management and physical exercise are key to the treatment of both NAFLD and T2DM. A proof-of-concept study showed that a hypocaloric diet with weight loss of ~8 kg within 12 weeks not only normalized fasting EGP and thereby hyperglycemia, but decreased hepatic TAG content down to normal concentrations in obese T2DM humans with NAFLD [90] . Subsequent studies in larger cohorts extended these results by demonstrating that a very low-caloric diet with weight loss of about 15% rapidly normalized liver fat content in 90 in dividuals with T2DM, which persisted for one year if weight loss was maintained [91] . Interestingly, Mediterranean, low-saturated fat and high plant-based protein diets also improve steatosis in NAFLD combined with T2DM despite minor or no relevant weight loss [92, 93] . In addition, physical activity and exercise training interventions can also decrease liver fat content, which may not be exclusively depending on concomitant weight loss [94] . Although the beneficial effects of structured behavioral treatment to improve histological endpoints, likely extend beyond reduction of hepatic fat content to ameliorating the grade and stage of inflammation and fibrosis [95] , only a minority of the people manages to adhere to dietary weight loss and exercise programs, which raises the issue of other therapeutic approaches [94] . Weight-loss inducing drugs could be an attractive option for persons with NAFLD with a BMI > 30 kg/m 2 or >27 kg/m 2 in the presence of at least one metabolic comorbidity, as an adjunct treatment to lifestyle modifications [96, 97] . Currently, the most-popular weight-loss inducing medications associated with at least 5% body weight decrease in one year as compared to placebo are orlistat, the fixed combination of phentermine and topiramate or naltrexone and bupropion, and the glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1ra), liraglutide [97] . Of these drugs, orlistat treatment failed to improve liver histology when compared to placebo [98] , while no reports are available for topiramate, naltrexone, bupropion and phentermine regarding hepatic endpoints in humans with NAFLD [99] . Only Bariatric or metabolic surgery is a therapeutic option to induce sustained weight loss partricularly in people with combined NAFLD and T2DM. In obese humans, bariatric surgery resulted in 85% resolution of NASH within one year [101] and in 77% complete remission of T2DM [102] . Surgical weight loss improves glucose metabolism and insulin sensitivity by different mechanisms such as increased GLP-1 secretion [103] and epigenetic modification [104, 105] . Several antihyperglycemic drug classes were or are currently being investigated in clinical trials and preclinical models to evaluate their efficacy for people with NAFLD and with or without T2DM. Metformin reduces body weight, hepatic gluconeogenesis -by yet unclear mechanisms [106] , and the risk of macrovascular complications, which is still controversially discussed due to lack of optimally designed clinical trials [116] . Despite its action on hepatic metabolism, former small-scale studies reported conflicting results [109, 110] (Table 1 ) and recent metaanalysis failed to demonstrate any effect of metformin on liver histology [111] . Nevertheless, epidemiological, observational and preclinical studies suggest that metformin may reduce the risk of HCC and also in T2DM, possibly by promoting apoptosis, but controlled clinical trials are not available [112] . DPP4 degrades incretins such as GLP-1 so that DPP-4i treatment increases the postprandial levels of endogenous GLP-1, which leads to lower glucose peaks after meals [113, 114] . In individuals with NAFLD with prediabetes or recent onset diabetes, sitagliptin did not improve liver steatosis or liver fibrosis compared to placebo as assessed by MR-based techniques [115] . In line, another recent trial reported no benefits for sitagliptin versus placebo on liver fibrosis or steatohepatitis in T2DM [116] (Table 1) . In contrast, a moderate reduction in liver fat content was observed with vildagliptin in individuals with T2DM [117] . J o u r n a l P r e -p r o o f 14 The actions of endogenous GLP-1 are mimicked by GLP-1 receptor agonists (GLP-1ra), which effectively reduce blood glucose levels and also reduce the risk for CVD in T2DM [118] . In individuals with NAFLD and T2DM, liraglutide in combination with metformin reduced liver, subcutaneous, and visceral fat [119] . Also, liraglutide improved hepatic steatosis measured by MR-based methods as well as resolved biopsy-proven NASH without worsening of fibrosis [100, 120] (Table 1) . However, a recent subanalysis did not detect an effect of liraglutide on liver fat content quantified by 1 H-MRS [121] (Table 1) . Respective trials with semaglutide and dulaglutide are still waiting for results (NCT02970942, NCT03648554). In an animal model of T2DM, exenatide also counteracted HCC development by suppression of STAT3-regulated genes [122] . Glucose-dependent insulinotropic polypeptide (GIP) represents the second important incretin with proposed beneficial effects on peripheral energy metabolism [123] . Tirzepatide, a novel dual agonist for GIP and GLP-1 receptors with probably greater efficacy than GLP-1ra [124] , decreased transaminases and surrogate markers of liver injury paralleled by increased circulating adiponectin levels in people with T2DM [125] . A clinical trial on NASH resolution is currently ongoing in persons with NASH with or without T2DM (NCT04166773). SGLT2i inhibit reabsorption of glucose in the proximal renal tubule resulting in glucosuria and calory loss, thus effectively reducing blood glucose level and body weight in T2DM. Moreover, SGLT2is show beneficial effects on cardiovascular risk and progression of nephropathy [118, 126] . Most, but not all recent randomized controlled trials (RCTs) showed that SGLT2i treatment resulted in reduction in liver fat content compared to placebo [127] [128] [129] [130] [131] (Table 1) . In an open-label pilot study in liver-biopsy proven cohort of NASH with T2DM, treatment with empagliflozin for 6 months reduced liver steatosis, ballooning and fibrosis and induced NASH resolution in approximately half of those persons [132] . Animal models further suggested anti-inflammatory, anti-oxidant and pro-apoptotic actions of SGLT2i with cardio-protective effects as well as inhibition of NASH progression and tumor growth of HCC [133, 134] . The dual SGLT1/2i, licogliflozin, is expected to block both intestinal and renal glucose (re)absorption [135] and currently investigated to evaluate its efficacy on resolution of NASH as monotherapy and as combination therapy with the FXR agonist, tropifexor, in people with NASH and fibrosis (NCT04065841). First results hint at improvement of transaminases and reduction of steatosis by licogliflozin in NASH [136] . PPARs is a family of nuclear receptors composed of multiple isoforms with wide tissue distribution [137] . The PPAR-γ agonist pioglitazone had convincing efficacy on NASH resolution in individuals with and without T2DM, but with conflicting results on fibrosis [138] [139] [140] (Table 1) . Of note, pioglitazone has been withdrawn in many European countries because of its disadvantageous safety profile [231] . However, pioglitazone exerts beneficial effects on cardiovascular outcomes in persons with T2DM and a history of CVD [141] . It has been proposed that non-PPAR-γ dependent mechanisms, as the inhibition of the mitochondrial pyruvate carrier (MPC), might mediate the beneficial effects of pioglitazone on NAFLD [142] . However, a novel drug with PPAR-γ sparing effects and MPC binding activity did not improve histological components of NASH in individuals with T2DM compared to placebo [143] . Elafibranor is a dual agonist for PPAR-α and PPAR-δ without PPAR-γ stimulation [144] . Based on a post-hoc analysis, NASH was resolved without worsening of fibrosis in a higher percentage of people with and without T2DM in the elafibranor group as compared to the placebo [145] and a follow-up study on these findings has been initiated ( Table 2) . Recent announcements on an interim analysis state that elafibranor treatment failed to resolve NASH and improve fibrosis when compared to placebo [146] . Saroglitazar is another dual PPAR-α/γ agonist with higher affinity for PPAR-α. In a mouse model of NASH, saroglitazar reduced liver steatosis, inflammation and prevented fibrosis development and a respective clinical trial is ongoing [147] ( Table 2) . Lanifibranor is a pan-PPAR agonist for PPAR-α, β, and γ receptors focused on treatment of liver fibrosis and NASH (NCT03008070). In an animal model of liver fibrosis, lanifibranor decreased hepatic collagen deposition [148] . Several other strategies for pharmacological targeting of NASH have emerged over the last few years; however, these strategies are not specifically designed for T2DM, but for the whole NAFLD collective. They comprise antiinflammatory drugs, but also modulators of other pathways, which are briefly summarized in the following sections. J o u r n a l P r e -p r o o f FXR can be activated by bile acids in a negative feedback mechanism to suppress bile acid synthesis [40] . OCA is a potent semisynthetic and selective FXR agonist approved for treatment of primary biliary cholangitis [149] . OCA treatment resulted in histologic improvement of NASH in people with and without T2DM compared to placebo [150, 151] ; however, concerns were raised about OCA-induced changes in plasma lipoprotein profile [152] . Tropifexor, another potent FXR agonist [153] , is currently being tested in combinatorial approaches of NASH treatment (cenicriviroc and licogliflozin; NCT03517540). Oltipraz is a synthetic dithiolethione with antisteatotic effects by inhibiting the activity of LXR-α. It activates adenosine monophosphate activated protein kinase (AMPK) and inactivates S6K1, affecting LXR-α thus reducing lipogenesis and increasing lipid oxidation [154] . A recent 24-week phase 2 clinical trial found decreased steatosis measured by 1 H-MRS with oltipraz compared to placebo treatment [154] and a respective phase 3 clinical trial is ongoing ( Table 2 ). Chemokine receptors type 2 (CCR2) and type 5 (CCR5) are expressed on various inflammatory and fibrogenic cells [155] . Cenicriviroc is a CCR2/CRR5 dual antagonist that reduced insulin resistance, liver inflammation and fibrosis in diet-induced models of NASH [62] . In recent RCTs in a NASH cohort with fibrosis, cenicriviroc treatment did not improve NAS but may reduce liver fibrosis [156, 157] . Currently, there is an ongoing clinical trial to evaluate the effects of cenicriviroc on fibrosis in NASH ( Table 2) . Both people with obesity, metabolic syndrome or T2DM as well as those with NAFLD are at increased risk for dyslipidemia. Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are generally safe and have unmet efficacy to decreased serum LDL and prevent cardiovascular outcomes, despite slightly increasing the risk of T2DM [2] . Use of statins associated with a 46% lower relative risk of hepatic decompensation and mortality in cirrhosis and a trend towards lower fibrosis progression in non-cirrhotic liver diseases [158] . However, the data on liver histology ist limited [159] so that statins are not currently recommended for the management of NAFLD [2] . The inhibitor of intestinal J o u r n a l P r e -p r o o f cholesterol absorption, ezetimibe, decreased the histological NAS, but not consistently liver fat content in an analysis of the few available studies [160] . Fenofibrate, a PPAR-α agonist, does not affect or even increase liver fat content or volume [161, 162] . Nevertheless, the combination of statins with certain anti-NASH drugs, such as OCA, could be beneficial to counteract drug-related increases in LDL during long-term treatment. Inhibition of DNL in NAFLD may be achieved by inhibition of ACC as this enzyme catalyzes the conversion of acetyl CoA into malonyl CoA, which acts as a substrate for fatty acid synthesis and inhibitor for fatty acid β-oxidation [163] . In a recent clinical trial in individuals with NASH with and without T2DM, treatment with the dual ACC1 and ACC2 inhibitor GS-0976 decreased liver steatosis without improvement of fibrosis [164] . The major concern of this strategy is that decreased DNL in NAFLD might channel lipids towards other harmful directions, e.g. increased blood lipids [163] . SCD1 is a key enzyme for hepatic lipogenesis that catalyzes the conversion of saturated fatty acids to MUFA and its downregulation protected mice from high carbohydrate-induced liver steatosis [165] . A clinical trial with aramchol, an inhibitor of SCD1, showed a reduction in liver fat content, resolution of NASH and improvement of liver fibrosis in persons with NAFLD with prediabetes or T2DM [166] . These results paved the way for a respective phase 3 clinical trial ( Table 2) . Mitochondrial uncoupling describes any process that uncouples the electron transport from ATP synthesis in mitochondria [167] . 2,4-dinitrophenol (DNP) was widely used for the treatment of obesity before its discontinuation due to life-threatening serious adverse events [168] . To overcome the side effects of DNP, improved formulas of DNP were recently developed to decrease the toxic to effective dose ratio (DNP-methyl ether (DNPME) and controlled-release mitochondrial protonophore (CRMP)) [169, 170] . Oral CRMP targets mainly the liver due to the first-pass effect and decreased hepatic insulin resistance, hepatic steatosis and liver fibrosis in a methionine-choline deficient rat model of NASH [170] . CRMP was also effective in nonhuman primates with diet-induced NAFLD for reduction of hepatic steatosis and EGP [171] . Thyroid hormone deficiency has been associated with NAFLD development [172] . Thyroid hormone analogues decreased liver fat, liver transaminases, and inflammatory and fibrosis markers in animal models of NASH [172] . Resmetirom is a liver-targeted highly selective THR-β agonist which showed efficacy in reducing liver fat content in NASH with and without T2DM [173] . Currently, there is ongoing clinical trial for evaluation of long-term outcomes of resmetirom and its efficacy on NASH resolution ( Table 2 ). Vitamin E is a potent antioxidant [174] . In NASH without T2DM, vitamin E improved NAS without worsening of fibrosis [139] . Despite concerns regarding adverse effects of long term vitamin E usage, treatment with vitamin E for ≥2 years reduced the risk of liver failure in a NASH cohort with advanced fibrosis and with or without T2DM [175] . Therapeutic manipulation of intestinal microbiome is still in its infancy. Rodent data showed efficacy for fecal microbiota transplantation in improving NAFLD in a diet-induced NASH model [176] . Also, modulation of the intestinal microbiota by antibiotic treatment reduced liver transaminases in NAFLD [177] . The use of prebiotics and probiotics in obese NAFLD/NASH is currently not supported by high-quality clinical studies with MR-or biopsy-based endpoints [178]. The evidence for shared pathophysiological mechanisms between T2DM and NAFLD will help to develop strategies for detecting and treating both diseases and preventing their leading complication, CVD. Altered lipid and energy metabolism, insulin resistance, low-grade inflammation and intestinal dysbiosis represent key targets. In addition to weight loss by lifestyle modification or bariatric surgery, GLP-1ra and SGLT2i are promising antihyperglycemic concepts with beneficial effects on NAFLD and CVD. In addition, many J o u r n a l P r e -p r o o f metabolism-based drugs are currently studied comprising PPAR agonists, endocrine dual coagonists to modulators of hepatic metabolism or microbiota. Nevertheless, several roadblocks need to be overcome to reduce the burden of NAFLD in T2DM. First, there is still lack of preclinical animal models that encapsulate essential features of human NASH and diabetes. Second, available biomarkers lack diagnostic efficacy to identify NAFLD progression. Innovative strategies such as cluster analysis already enabled detection of a diabetes subtype (SIRD) with high risk of NAFLD [14] . Combination with computational integration of multiomics data shall identify specific disease signatures and pave the way to precision medicine and targeted management of T2DM and NAFLD. Finally, studies on so-called endpoints are scarce, which may be due to the need of long-term studies to evaluate liver-related mortality, to the current neglect to accept CVD morbidity and mortality as NAFLD outcome and to ongoing discussions on the relevance of surrogate markers. The research of the authors is supported in part by grants from the German Federal Ministry Phase III registered interventional trials on "clinicaltrials.gov" for NAFLD as accessed on 10 th April 2020. BL, baseline; CCR2/5, C-C chemokine receptors type 2 and type 5; FXR, farnesoid X receptor; HbA 1c , glycated haemoglobin; LXR, Liver X receptor; MPC, mitochondrial pyruvate carrier; NA, data not available; NAFLD, non-alcoholic fatty liver disease; NFS, NAFLD fibrosis score; PPAR, peroxisome proliferator-activated receptor; NASH, non-alcoholic steatohepatitis; SCD, stearoyl-CoA desaturase; SGLT, sodium-glucose cotransporter; THR, thyroid hormone receptor; T2DM, type 2 diabetes. *Only placebo-controlled, randomized clinical trials are listed, except for saroglitazar, a 4-arm active-controlled study. 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diabetes Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial) Empagliflozin for the Treatment of Nonalcoholic Steatohepatitis in Patients with Type 2 Diabetes Mellitus The SGLT2 Inhibitor Canagliflozin Prevents Carcinogenesis in a Mouse Model of Diabetes and Non-Alcoholic Steatohepatitis-Related Hepatocarcinogenesis: Association with SGLT2 Expression in Hepatocellular Carcinoma Empagliflozin Ameliorates Obesity-Related Cardiac Dysfunction by Regulating Sestrin2-Mediated AMPK-mTOR Signaling and Redox Homeostasis in High-Fat Induced Obese Mice SGLT1 inhibition: Pros and cons LIK066 (licogliflozin), an SGLT1/2 inhibitor, robustly decreases ALT and improves markers of hepatic and metabolic health in patients with 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Discovery and Development Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening Announces-Results-from-Interim-Analysis-of-RESOLVE-IT-Phase-3-Trial-of-Elafibranor-in-Adultswith-NASH-and-Fibrosis.html Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models Synthesis , and Evaluation of a Novel Series of Indole Sulfonamide Peroxisome Proliferator Activated Receptor (PPAR) α/γ/δ Triple Activators: Discovery of Lanifibranor, a New Antifibrotic Clinical Candidate Targeting FXR in Cholestasis Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial Impact of obeticholic acid on the 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decreased nonalcoholic fatty liver disease activity score but not hepatic steatosis Effect of fenofibrate and niacin on intrahepatic triglyceride content, ve ry low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease Effects of free omega-3 carboxylic acids and fenofibrate on liver fat content in patients with hypertriglyceridemia and non-alcoholic fatty liver disease: A double-blind, randomized, placebo-controlled study Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation Acetyl -CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis One-year results of the Global Phase 2b randomized placebo-controlled ARREST Trial of Aramchol, a Stearoyl CoA Desaturasemodulator in NASH patients n Mitochondrial uncoupling and lifespan Emerging Pharmacological Targets for the Treatment of Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Type 2 Diabetes Reversal of Hypertriglyceridemia, Fatty Liver Disease and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats Controlledrelease mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates Nonalcoholic Fatty Liver Disease and Hypercholesterolemia: Roles of Thyroid Hormones, Metabolites, and Agonists MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial Nonalcoholic Fatty Liver Disease and Diabetes: Part II: Treatment Vitamin E Improves Transplant-Free Survival and Hepatic Decompensation Among Patients With Nonalcoholic Steatohepatitis and Advanced Fibrosis Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease 


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   key: cord-309799-fhkbcp7z authors: Hwang, Yerin; Khasag, Altaisaikhan; Jia, Weiping; Jenkins, Alicia; Huang, Chien-Ning; Yabe, Daisuke; Kim, Doo-Man; Kadowaki, Takashi; Lee, Moon-Kyu title: Diabetes and COVID-19: IDF perspective in the Western Pacific Region date: 2020-06-25 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108278 sha: doc_id: 309799 cord_uid: fhkbcp7z Abstract The World Health Organization (WHO) declared a pandemic, the highest risk level in the infectious disease alert phase, on 11 March 2020. In the Western Pacific Region (WPR), 192,016 confirmed cases with 7,125 deaths had been reported as of 8 June 2020. In people with diabetes COVID-19 can be more difficult to treat due to the wide fluctuations in blood glucose levels or presence of comorbidities such as diabetes complications, including cardiovascular disease and renal damage, which are recognized risks for adverse outcomes. National diabetes associations and governments have established guidelines for subjects with diabetes in relation to COVID-19, and are trying to supply emergency and their regularly required medical products for them. The WPR is so large and composed of such diverse countries and COVID-19 situations, no one conclusion or program applies. Instead we could see a diverse COVID-19 pandemic profile in the WPR, and several creative diagnostic and therapeutic measures undertaken. This includes drive-through screening facilities, high-speed RT-PCR technologies, convalescent patients’ plasma therapy, which potentially had some positive contributions in combatting COVID-19 in the WPR as well as globally. Although the numbers of confirmed cases are currently decreasing in the region, the COVID-19 pandemic is not over, and many experts are recommending to prepare measures for potential second or third waves of COVID-19. In January 2020, a novel coronavirus (2019-nCoV, COVID-19) from a cluster of pneumonia cases of unknown etiology was discovered in Wuhan, China 1 In people with diabetes COVID-19 can be more difficult to treat due to wide fluctuations in blood glucose levels or presence of comorbidities such as acute and chronic diabetes complications, including CVD and renal disease, which even in the general population with COVID-19 are recognized risk factors for poor outcomes, including death 2,3,4,5 . To mitigate COVID-19 infection and poor outcomes many national diabetes associations and governments have established COVID-19 guidelines for subjects with diabetes, and are trying to supply the emergency and routinely required medical products for them. The following is a summary of the current situation of each country in the Western Pacific Region related to COVID-19. Western Pacific Region (WPR) 1) Australia -In Australia, as at June 9 2020, there have been 7,265 positive cases and 102 5 deaths. The first COVID-19 positive case in Australia was confirmed on January 25 th 2020 in a person returning from Wuhan China. This was followed by a lag phase with a doubling of positive cases approximately every 7-10 days. However, by March 21 st 2020, when COVID-19 positive cases in Australia exceeded 1,000 with 7 deaths, Australia was clearly on the exponential part of the curve 6 . With introduced measures the number of new cases has substantially reduced since mid-April. Since early May, 2020 daily testing nationally has ranged between 23,015 and 36,867 tests. Details regarding diabetes status are not yet available. Health personnel availability and support 8 -Reconfiguring wards-expanding or establishing new ICUs, with separate facilities for those with and without COVID-19: At no stage has there been a lack of ventilator facilities. -Setting up separate inpatient COVID-19 screening "hot" wards that were separate from "cold" wards -Setting up special "fever" clinics, initially attached to a hospital but separate from other services, particularly emergency departments -Novel screening pathways with initially more than less restrictive criteria for screening: an on-line self-registration and self-screening tool, drive-through screening and rapid throughput screening, to allow hospital workers with mild symptoms to be screened and get back to work in 24 hours -Securing adequate personal protective equipment (PPE), including from pre-existing national medical resources stockpiles and providing training on specialized techniques for urgent/safe gowning up -Suspension of non-urgent surgery and procedures in both public and private hospitals with graded reintroduction -Arrangements between State governments and private hospitals for the latter to take COVID and non-COVID patients, if and when required -Upskilling and education of appropriate staff in best practice in procedures such as intubation to minimize risk to health professionals -Call-up of, and short-term registration of, recently retired healthcare professionals and senior medical students -Limitation or suspension of face-face non-urgent medical ambulatory or outpatient services (including outpatient adult and pediatric endocrinology/diabetes services), with a provision of telehealth services that would prevent emergency department presentations/admissions. Newly diagnosed Type 1 diabetes patients were often still seen. -Contact tracing those exposed to a person diagnosed with COVID-19, and planning, and subsequently implementing the COVIDSafe contact tracing app -Fast-tracking of approval and implementation of COVID-19 related research studies, with additional specific funding being made available by our national research funding agencies -Implementing telephone/telehealth consultations for most endocrinology/diabetes services (including pediatric endocrinology) -The provision of inpatient diabetes education and medical review by telephone where possible for patients admitted with COVID-19 to reduce exposure to essential diabetes staff 6, 8 2) Chinese Mainland -China's goal in its medical response to Covid-19 has been to improve the patient admission and cure rates and reduce the infection and fatality rates. A conditionspecific and category-based approach was applied to medical treatment of patients. Pooling premium resources to treat severe cases. By directing resources to Wuhan, China expanded the capacity of designated hospitals to deal with severe cases and increased the number of beds. Two hospitals with 1,000-plus beds each -Huoshenshan and Leishenshanwere built as specialist hospitals for treating infectious diseases, and a number of designated and general hospitals were expanded or remodeled. The number of beds for severe cases quickly increased from around 1,000 to more than 9,100. Early intervention for patients with mild symptoms. China has been quick to have patients with mild symptoms admitted to designated medical facilities for early medical intervention, and has done its best to prevent mild cases from worsening. The national clinical treatment network has been expanded to include more than 10,000 hospitals dedicated to the treatment of Covid-19 patients. A national network of medical treatment coordination has also been formed to provide technical support through online consultation. In Wuhan, faced with surging infections and considering that 80 percent of cases were mild, the city government mobilized resources to repurpose stadiums and exhibition centers into 16 temporary treatment centers. With some 14,000 beds, these centers were able to admit all confirmed mild cases for treatment. The 16 treatment centers received a total of more than 12,000 patients; 8,000 and more were cured and discharged; and more than 3,500 were transferred to hospitals. Temporary treatment centers, or Fangcang shelter hospitals, are a major innovative solution that provided enough beds to admit all confirmed cases, thus turning the tide in the battle against Covid-19. Based on scientific knowledge and accumulated evidence, research results and the diagnostic and therapeutic regimens that proved effective were incorporated in the national diagnosis and treatment plans. These include seven versions of the diagnosis and treatment protocol, three editions of the protocol for severe and critical cases, two editions of the manual for mild case management, two editions of convalescent plasma therapy treatment protocol, and one rehabilitation treatment program for patients discharged from hospitals 7 . 3) Japan -Since early April 2020 with the sharp increase in the number of COVID-19 cases, the health care systems in Japan has barely evaded collapse by ramping up the number of hospital beds dedicated to those with the disease (more than 12,000 beds nationwide) as well as by reallocating medical resources. That has accompanied postponing significant numbers of elective procedures and outpatient clinic visits. As of May 26th, 2020, there are 13,384 total dedicated beds for COVID-19 in facilities, and 1,942 mechanical ventilators. Korea have been making tremendous efforts to prevent the spread of the virus. As many as 74 hospitals have been designated as hospitals dedicated to COVID-19 and over 7,500 beds in total have been made operative in preparation for a surge in cases. As the number of confirmed cases decrease, there was a stage-by-stage bed reduction to ultimately operate 1,500-2,300 beds, viewed as the lower limit for emergencies. Aside from public hospitals, private medical centers are serving as main centers of treating patients with COVID-19. In addition, 3,729 medical staff were additionally allocated to support the hospitals, screening and treatment facilities. Specifically, the Korean government newly recruited and stationed 750 public health doctors and 96 army doctors, while continuing to recruit nurses. Most of them were dispatched to Daegu and Gyeongsangbuk-do, which is the major epidemic region in Korea. Work was done to strengthen the monitoring and online reporting of cases identified at fever clinics of medical facilities. All such cases had to be reported online to higher authorities within 2 hours; their test results sent back to the reporting clinics within 12 hours; and on-site epidemiological investigation completed within 24 hours -so that confirmed cases and asymptomatic carriers would be identified and reported without delay. As of May 31, a total of more than 740,000 close contacts had been traced and handled as appropriate. Providing free treatment for patients. Government funds for Covid-19 control were made available in advance to ensure that patients could receive timely treatment and local authorities could proceed smoothly with measures for medical treatment and epidemic control. 2) Chinese Mainland -All Covid-19 patients, including those with diabetes, received subsidies from state finance for any medical bills not covered by basic medical insurance, serious disease insurance, or the medical assistance fund. These also cover the diabetic medication, including insulin support for patients. Besides, urban and rural residents, 3) Hong Kong -Initially some patients with diabetes mellitus, they may have difficulty in sourcing alcohol swab, posing a challenge especially for those requiring insulin injections, in the initial period of COVID-19 outbreak. However, the supply of disinfectant products was stabilized in a reasonable time frame. 4) Japan -Although reduced, visits to clinics, hospitals, and pharmacies by those with diabetes had not been restricted in Japan. Likewise, distribution logistics in general has been constrained but maintained especially for medical supplies. Although some hospitals and clinics reported a shortage of alcohol swabs used for insulin injections and/or finger-pricking for blood glucose testing, no major incidence of shortage has been reported for medical supplies for those with diabetes including insulin. This is partly aided by temporary lifting of restrictions on telemedicine, which had been only limitedly covered by Japan's national care insurance. Now, willing medical providers are able to send prescriptions and medical supplies to their patients by consulting over communication tools such as phone and video conference. Continuity of medical care is relatively maintained by those means, but not ideally. For example, some diabetes specialists show concerns on patients' limited access to diabetes self-care education and support, which potentially deteriorates their glycemic control. We have some problems of insulin supply because borders are closed. The supply of insulin in Taiwan is sufficient to cope with both emergency demand and usual care. Perspectives in managing the pandemic in the country 1) Australia -It is recognized that that people with diabetes are at greater risk of serious outcomes during pandemics such as COVID-19 than people without diabetes. It is anticipated that effective management of blood glucose in people with diabetes and COVID-19 may lead to better outcomes and lower mortality rates. Whether the resources that have been developed and measures that have been implemented have had a positive effect on the health of people with diabetes is not yet known. Feedback from people with diabetes and health professionals has been positive and supportive of the proactive approach to this unprecedented pandemic. Australian healthcare professionals and researchers are also proactive in proposing and participating in national and international COVID-19 related research 6, 8 . China has made vigorous efforts to resume work and reopen schools. Since diabetic individuals might be susceptible to COVID-19 infection, the following principles for COVID-19 patients with comorbid diabetes were put forward by the Chinese Diabetes Society (CDS). For inpatients, blood glucose target should be individualized to minimize the risk for hypoglycemia after a careful evaluation. For out-patients, self-management of blood glucose and following doctors' advice are suggested 7 . 3) Hong Kong -Outdoor activities have been restricted for all, which may have a negative impact on exercise. Yet, people have cut down on dining as well, which may mean a healthier diet. Although the widespread lockdown seen in many other countries has not been implemented in Japan, a nationwide state of emergency was declared by the Japanese government in the middle of April 2020. This resulted in significant reduction of social and commercial activities in many sectors and it appeared that Japan may have passed the current apex of infection rate as of early May. It is, however, difficult to predict whether this pandemic will end soon in Japan and we are still undecided when and how to ease social and economic restrictions. The current transmission classification in the Philippines is identified as 22 clusters of cases with evidence of community transmission in highly urbanized areas (National Capital Region (NCR), Cebu and Davao). In spite of continued enhanced community quarantine in most affected regions in the country, several barangays (districts) are reporting a large increase in cases, resulting in local authorities to issue total lockdowns in these areas. Over 7,000 COVID-19 tests per day are being conducted by 23 accredited laboratories throughout the country using PCR tests. No rapid antibody test kit has as yet been validated by the WHO or DOH, so is not in use. and Korean government are especially cautious when caring for patients who are vulnerable to this viral disease. Subjects with diabetes are one of the top prioritized groups over any other chronic disease. The KDA have announced recommendations for people with in this COVID-19 outbreak. We will continue to do our best to prevent the spread COVID-19 in Korea and minimize deaths and complications related with COVID-19. Taiwan -There have been no indigenous cases of COVID-19 since April 22, 2020, and the Central Epidemic Command Center (CECC) in Taiwan will continue active surveillance and border control programs to prevent future outbreaks. Meanwhile, the academic facilities in Taiwan continue their work on improving laboratory diagnostic capacities, development of rapid testing, vaccination and antiviral agents. Although the risk of community transmission of COVID-19 in Taiwan is very low, the pandemic has changed Taiwanese ways of living and medical-seeking behaviors. How to track and educate patients with diabetes in Taiwan, as well as providing necessary medical support and diet consultations has become challenging. We will develop individualized online education programs, and promote efficient data sharing 23 between healthcare providers and patients via a National Health Insurance (NHI) MediCloud system. The WPR is so large and composed of such diverse countries and COVID-19 situations, no one conclusion can be developed. We see such diverse COVID-19 pandemic profiles in the WPR, and several creative diagnostic and therapeutic measures have been implemented, such as drive-through screening facilities, high-speed RT-PCR testing technologies, convalescent patients' plasma therapy (which seems to show some benefit in the WPR and globally). Although the numbers of confirmed cases are decreasing in the region, the war against the COVID-19 pandemic is not over, and many experts are recommending to prepare measures for potential second or third waves of the COVID-19 pandemic and for pandemics of other infectious agents in the future. A spirit of co-operation and knowledge sharing between countries and organizations is key to reduce the negative consequences of such infectious agents. World Health Organization, WHO Western Pacific Regional Action Plan for Response to Large-Scale Community Outbreaks of COVID-19 COVID-19 pandemic, coronaviruses, and diabetes mellitus Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis The Australian response to the COVID-19 pandemic and diabetes -lessons learned Fighting Covid-19 China in Action" released by The State Council Information Office 26 ofthe People's Republic of China COVID-19, Type 1 Diabetes Clinical Practice, Research, and Remote Medical Care: A View From the Land Down-Under Management suggestions for patients with diabetes and novel coronavirus pneumonia The authors declare no conflict of interest. The authors received no funding from an external source. 


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   key: cord-310159-l9hfmmbc authors: Chowdhury, Subhankar; Goswami, Soumik title: COVID-19 and type 1 diabetes: dealing with the difficult duo date: 2020-07-14 journal: Int J Diabetes Dev Ctries DOI: 10.1007/s13410-020-00846-z sha: doc_id: 310159 cord_uid: l9hfmmbc BACKGROUND: Coronavirus disease 2019 (COVID-19) has aroused global health concerns, particularly in relation to diabetes where it has been associated with poorer outcomes. The bulk of the evolving evidence in diabetes and COVID-19 relates to type 2 diabetes (T2D). Since there are a significant number of patients with type 1 diabetes (T1D) with unique concerns and challenges during the ongoing COVID-19 pandemic, we reviewed existing literature, relevant websites, and related guidelines to form this narrative review to help address key questions in this area. METHODS: We systematically searched the PubMed database up to May 31, 2020, and retrieved all the articles published on T1D and COVID-19. RESULTS: We found 18 relevant articles, each of which carried a part of the evidence regarding the risk of contracting COVID-19 in patients with T1D, effect of COVID-19 on development of T1D, outcomes in T1D with COVID-19, and special management issues in T1D in the light of COVID-19. These have been documented in the present review. CONCLUSION: COVID-19 with T1D presents special challenges. While the available evidence does shed some light, we need more evidence to deal with this difficult duo. Coronavirus disease 2019 (COVID-19) epidemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in December 2019 and has progressed rapidly into a pandemic since the first quarter of 2020 [1] . COVID-19 is commonly characterised by fever, cough, fatigue, shortness of breath, pneumonia, and other respiratory tract symptoms and may even progress to death in some [2] . Patients with older age, hypertension, male gender, heart disease, cerebrovascular disease, kidney disease, hyperglycemia, or history of smoking have been shown to have a higher risk of developing more severe disease and subsequent mortality [3] [4] [5] [6] . There have been several publications from the global scientific community on COVID-!9 in type 2 diabetes (T2D) but markedly fewer looking at type 1 diabetes (T1D). T1D constitutes about 5% of all diagnosed cases of diabetes and its global incidence is increasing at about 3% every year [7] . Given the global burden of T1D and unique challenges in treating T1D (more so in developing nations like India), this narrative review attempts to address key questions regarding COVID-19 and T1D. We systematically searched the PubMed database up to May 31, 2020 , and retrieved 18 articles published on T1D and COVID-19 besides looking at relevant websites and related guidelines to form this review. Diabetes patients have an increased risk of infection compared with the general population and the risk is even greater in those with T1D than in T2D [8] . These include bacterial, viral, and fungal infections of the respiratory tract, urinary tract, gastrointestinal system (including liver), skin and soft tissue, head and neck, and other systemic infections (e.g. HIV) [9] . This increased risk of infection is due to hyperglycemiainduced immune dysfunction (damage to the neutrophil function, depression of the antioxidant system, and humoral immunity), micro-and macro-angiopathies, and greater requirement of medical interventions in these patients [9] . Interestingly, in reports from Italy and China, COVID-19 cases with type 1 diabetes were apparently not reported despite a large number of people being infected and hospitalised [10] [11] [12] . Possible explanations for the same include a younger age of T1D patients, lower prevalence of T1D, and overexpression of CD8+ T lymphocytes in T1D which might play a protective role (CD8+ T lymphocytes show an increased apoptosis leading to lymphocytopenia in SARS-COV2 infection) [13] . However, population cohort studies covering all individuals registered with a general practice in England show that T1D patients do contract COVID-19 infection requiring hospitalisation in some [14, 15] . Presently, as testing for COVID-19 is still limited and as there could be many asymptomatic individuals with the infection, it remains unclear whether T1DM patients are more likely or less likely to contract COVID-19. A study in regions with a high prevalence of T1D (e.g. Scandinavian region) looking at the prevalence of COVID-19 infection with widespread community screening in those with and without T1D could possibly provide an answer. Since it is well established that uncontrolled hyperglycemia impairs immune function in all forms of diabetes, it would be logical to presume that T1D, particularly if not well controlled, could have an increased risk of infection and intensifying glycemic control could serve as a means of primary prevention [16, 17] . Viral infections are well known to be associated with the development of pancreatic autoantibodies leading to T1D in genetically predisposed individuals and coronaviruses were identified as one of the incriminating pathogens in the TEDDY study [18, 19] . Viral infections trigger autoimmune insulitis and pancreatic β-cell destruction through several mechanisms-virus amplification cycle and/or circulating viral antigens may directly damage β-cells and also lead to the release of sequestered islet antigens which are presented by overexpressed major histocompatibility complex class I proteins to the immune system, increasing the risk of autoantibody generation. Viral epitopes sharing homology to autoantigens could lead to cross-reactive antibody production against β-cells (molecular mimicry hypothesis). Also, viral infection leads to cytokine release and T cell activation which could hasten the development of T1D in genetically predisposed individuals [20] . SARS-CoV-2 might also bind to ACE2 in the pancreas and cause pancreatic injury, particularly in severe COVID-19 cases, thereby hastening the development of overt T1D in susceptible individuals [21] . As T1D development has already been related to coronavirus respiratory infections, it is very likely that an increasing incidence of T1DM may be triggered by the present pandemic and appropriately designed studies are necessary in this regard. Till such published evidence becomes available, practitioners have to be on an active lookout for the development of T1D after COVID-19 in predisposed individuals. There is a report of an individual presenting with diabetic ketoacidosis (DKA) as an inaugural feature of T1D where DKA symptoms were masked by COVID-19 symptoms; this is an area where we need to be vigilant as well [22] . While T2D and its associated comorbidities have established themselves as risk factors for increased hospitalisation, requirement of intensive care, and mortality with COVID-19, early anecdotal reports from global infection hotspots suggested that children with diabetes had a similar disease pattern compared with children without diabetes (less severe manifestations than adults) [23, 24] . On the contrary, a large population cohort study assessing the risk of in-hospital death for individuals registered with a General Practice in England showed that people with T1D had 3•50 (3•15-3•89) odds of dying in hospital with COVID-19 compared with those without diabetes which was attenuated to 2•86 when also adjusted for previous hospital admissions with coronary heart disease, cerebrovascular disease, or heart failure [14] . However, this study also found a very low absolute risk of in-hospital death for people with diabetes under 40 years of age implying that age was a stronger risk influencer than diabetes status [14] . Another study from England using national diabetes and mortality data showed that the adjusted hazard ratio (HR) for mortality in COVID-!9 with T1D of HbA1c > 10% compared with HbA1c 6.5-7% was 2·19 [15] . This study also found a Ushaped relationship between body mass index (BMI) and COVID-19 mortality with HRs for BMI > 40 kg/m 2 compared with 25-29.9 kg/m 2 being 2·15 (1·37-3·36) for T1D [15] . Evidence from these studies coupled with the fact that glycosylation of ACE2 receptors (which is necessary for cell entry of SARS-COV2) can be boosted by hyperglycemia makes a strong case for intensifying glycemic control for improving outcomes in T1D with COVID-19 [25] . a. Effect of chloroquine and hydroxychloroquine: There has been an increase in the use of chloroquine and hydroxychloroquine, both for the prophylaxis and treatment of COVID-19. Both these agents have been reported to cause hypoglycemia in patients with and without diabetes (even in those not on insulin or sulphonylureas) [26, 27] . Chloroquine is postulated to reduce blood glucose (BG) levels by stimulating insulin secretion and also by activating Akt to stimulate glucose uptake and glycogen synthase [28] . Hydroxychloroquine decreases insulin degradation at the cellular level, increases intracellular insulin accumulation, and stimulates insulin-mediated glucose transport [27] . There is a published report of an individual with T1D on insulin developing hypoglycemia after taking chloroquine prophylaxis while visiting a malaria endemic area following which this patient even maintained euglycemia without insulin for a temporary period [29] . Therefore, patients with T1D who are administered chloroquine or hydroxychloroquine need to be monitored closely for hypoglycemia and their insulin doses adjusted as necessary. b. Effect of "lockdown": Many countries across the world have imposed "lockdown" measures with restriction of movement and mandatory quarantine of individuals with or at risk of infection. While these measures have been lifted in certain countries, there is a distinct possibility of re-imposition of these measures if a "second wave" of infection appears. Since T1D is known to be greatly affected by alterations in daily routine, there are concerns that "lockdown" can worsen glycemic control in T1D due to restriction of outdoor physical activity, psychological stress on account of lack of physical interaction with acquaintances, irregular sleep pattern, and intake of less healthy diet [30, 31] . However, interestingly, there are several publications which have pointed to the contrary-there was either no deterioration in glycemic control or even improvement in glycemic control in T1D during "lockdown", particularly in those who continued exercising and in those who did not go out for work [32] [33] [34] . Possible explanations include greater parental control and absence of school-related stress in children and adolescents, eating every meal at home with regular timing and more consistent and precise carbohydrate counting, and reduction of workplace-related stress. Besides slowing of daily activities which might have helped in glycemic control, patients' apprehension of worsening of COVID19 outcomes could have contributed to improved compliance with physician advice resulting in good BG control. However, these studies have primarily looked at adolescents using a hybrid closed loop system and adults using continuous glucose monitoring with good glycemic control at baseline because of which these findings might not be generalisable to those with poorer control and/or not having access to these new technological tools. Another concern is interruption in the availability of insulin and glucose meter test strips in relatively remote area due to logistic issues associated with the "lockdown". In view of this, patients would be well advised to ensure sufficient stocks of essential medical supplies besides maintaining a regular schedule and staying physically active indoors in the interest of good disease control. Patients should be encouraged to pursue in-home physical activity (e.g. bodyweight exercise, jump rope, online lessons) as it can not only help improve glycemic control but also for psychological well-being, since physical activity reduces stress and anxiety and improves mood and sleep quality [35, 36] . c. Risk of DKA: While contracting an illness might increase the risk of development of DKA in those with known T1D, there are reports of delayed diagnosis of new-onset T1D leading to presentation with severe DKA [37] . Fear of contracting COVID-19 in a hospital setting, reduced access to hospital emergency departments due to travel restrictions, and hospital services remaining closed for non-COVID-19-related ailments could be some of the causes for this. Another reason could be delayed diagnosis on the part of doctors who are preoccupied with COVID-19 and might not consider DKA in the differential diagnosis when a patient presents with suspected symptoms either over the telephone or in person. Certain features of DKA overlap with viral illnesses in children and physicians should be on their toes to look out for polyuria, polydipsia, weight loss, Kussmaul's respiration, and a fruity odour in breath. d. Prevention of DKA: T1D patients who are ill should be advised to follow "sick day rules" which are recommended for any stressful situation to reduce the risk of DKA [38] . These include the following: 1. Insulin should never be stopped. 2. The insulin dose may need to be increased and it might be necessary to take additional doses of rapid acting insulin to bring down the BG levels ( food (rice-lentil broths and sugar-containing fluids) to provide energy and avoid starvation ketosis. 6. When the child is feeling sick or vomiting and ketone levels are negative or low (trace or small) with BG < 180-250 mg/dL, sugar-containing fluids in small amounts (at least 100 mL/h) should be administered to keep BG up. 7. BG should be maintained between 110 and 180 mg/ dL in otherwise stable individuals. In the following situations, T1D patients should promptly get in touch with their treating doctor: When not sure what to do 2. If they vomit repeatedly (not able to hold down any food or drink for more than 6 h) 3. If vomiting persists beyond 2 h (particularly in young children) 4. If BG stays high for more than 24 h 5. If they develop symptoms which could be indicative of their developing diabetic ketoacidosis (nausea, vomiting, abdominal pain, shortness of breath, confusion). 6. If blood ketones remain elevated > 1.5 mmol/L or urine ketones remain large despite extra insulin and hydration 7. In very young children (< 5 years) e. Management of DKA: Intravenous (IV) insulin is the standard of care for DKA but may pose a challenge in present times as it often requires admission to the intensive care unit (ICU). ICU beds may be reserved for or be at full capacity with COVID-19 patients besides ICU admission leading to an inappropriate risk of infection in young people with T1D. In this setting, it may be necessary to manage uncomplicated mild to moderate DKA outside the ICU setting with subcutaneous (SC) insulin [39] . SC rapid acting insulin analogs reach peak effect in 90-120 min and can be used for the treatment of uncomplicated mild to moderate DKA outside the ICU setting [40] . SC regular insulin is an alternative if rapid acting analogs are unavailable. SC rapid acting analogs (lispro/aspart) can be started at a dose of 0.15 U/kg 1 h after the commencement of IV fluid replacement. BG levels should be monitored every 1-2 h to maintain levels of around 200 mg/dL until DKA resolves. SC doses should be injected every 2 h until DKA resolution and the dose can be brought down to 0.1 U/kg if BG continues to decrease by > 90 mg/dL per hour. However, SC insulin may be unsuitable for those with severe dehydration or serious comorbid conditions. SC regular insulin every 4 h can be used if ph > = 7 at a starting dose of 0.13-0.17 U/kg which can be subsequently increased or decreased stepwise by 10-20% depending on BG values. The dosing frequency can be increased to every 2 h if acidosis does not improve [41, 42] . Basal insulin should be initiated once DKA has resolved and oral intake is tolerated. Once DKA has resolved and the child is able to drink adequately, the remaining volume of calculated fluid and potassium deficit can be administered orally to facilitate early hospital discharge thereby optimising the use of healthcare resources and also reducing the risk of contracting COVID-19. Intramuscular (IM) insulin may be used instead of SC insulin in those with poor tissue perfusion [39] . In individuals with T1D and DKA on continuous glucose monitoring system (CGMS), confirmatory BG monitoring with finger-prick capillary blood glucose should be performed in view of issues with CGMS accuracy in the presence of ketosis and rapidly changing BG levels [39] . f. Psycho-social issues: A questionnaire-based Danish cross-sectional study involving 2430 adult diabetes patients of whom one-third had T1D found that those with T1D were more likely to worry about being significantly affected due to diabetes and not being able to manage [43] . Therefore, special attention should be given to those with T1D in order to manage their anxieties by providing proper information, counselling, peer support, and access to support helplines. g. Use of technology: The COVID-19 pandemic has put the spotlight on telemedicine and brought it to the forefront of diabetes management. Telemedicine consultation minimises the risk of virus transmission by maintaining physical distancing thereby alleviating the anxiety of T1D patients and their caregivers. It also avoids the cost, time, and inconvenience of travel and waiting at the reception before consultation thereby increasing time for school or work. However, telemedicine does have its share of limitations including inability to perform a proper physical examination, lack of widespread availability of necessary Internet-related infrastructure in several developing countries, and difficulty to establish rapport and address behavior modification in patients [44, 45] . In settings with access to more advanced technology, remote monitoring of electronic data (CGMS, connected insulin pens, connected insulin pumps) enables physicians and other health-care professionals to intervene timely in patients whose condition is deteriorating based on available metrics which could help improve clinical outcomes [46] . The present COVID-19 pandemic has changed the way we deal with a number of diseases including T1D. Since we are in the midst of a relatively new and dynamic situation with evolving evidence, we need to be cautious and also rely on logical thinking and common sense to deal with the difficult duo of COVID-19 and T1D more effectively. Authors' contributions Both authors have contributed equally in all aspects. Conflicts of interest The authors declare that they have no conflict of interest. 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ICU network baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region Characteristic of and important lessons from the Coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention Prevalence and impact of diabetes among people infected with SARS-CoV-2 Lack of type 1 diabetes involvement in SARS-COV-2 population: Only a particular coincidence? Diabetes Research and Clinical Practice 19-and-Diabetes-Paper-2-Full-Manuscript.pdf. Accessed on 28 th Modification of-defensin-2 by dicarbonyls methylglyoxal and glyoxal inhibits antibacterial and chemotactic function in vitro Practical recommendations for the management of diabetes in patients with COVID-19 Type 1 Diabetes triggered by covid-19 pandemic: A Potential outbreak? Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study Viral infections in type 1 diabetes mellitus-why the β cells? ACE2 expression in pancreas may cause pancreatic damage after SARS-CoV-2 infection Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic The hypoglycemic effect of chloroquine Hypoglycemia due to hydroxychloroquine, an uncommon association but to keep in mind, case report and review of literature Chloroquine stimulates glucose uptake and glycogen synthase in muscle cells through activation of Akt Case report of chloroquine therapy and hypoglycemia in type 1 diabetes: what should we have in mind during the COVID-19 pandemic? Understanding differences between summer vs. school obesogenic behaviors of children: the structured days hypothesis A systematic review of physical activity and sedentary behavior intervention studies in youth with type 1 diabetes: study characteristics, intervention design, and efficacy Glycemic control among people with type 1 diabetes during lockdown for the SARS-CoV-2 outbreak in Italy Glycemic control in type 1 diabetes mellitus during COVID-19 quarantine and the role of in-home physical activity No deleterious effect of lockdown due to COVID-19 pandemic on glycemic control, measured by glucose monitoring, in adults with type 1 diabetes Coronavirus disease (COVID-19): the need to maintain regular physical activity while taking precautions Physical activity and mental health: the association between exercise and mood Unintended consequences of COVID-19: remember general pediatrics ISPAD Clinical Practice Consensus Guidelines 2018: sick day management in children and adolescents with diabetes Effect of puberty on the pharmacodynamic and pharmacokinetic properties of insulin pump therapy of youth with Type 1 diabetes. Diabetes Care Subcutaneous regular insulin for the treatment of diabetic ketoacidosis in children. Pediatr Diabetes Diabetic ketoacidosis: low-dose insulin therapy by various routes Diabetes and COVID-19: psychosocial consequences of the COVID-19 pandemic in people with diabetes in Denmark-what characterizes people with high levels of COVID-19-related worries? Integrating continuous glucose monitor data directly into the electronic health record: proof of concept Managing newonset type 1 diabetes during the COVID-19 pandemic: challenges and opportunities How COVID-19 Rapidly transformed clinical practice at the Harold Schnitzer Diabetes Health Center now and for the future Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations 


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   key: cord-310650-8lhkiw9p authors: Gamble, Anissa; Pham, Quynh; Goyal, Shivani; Cafazzo, Joseph A title: The Challenges of COVID-19 for People Living With Diabetes: Considerations for Digital Health date: 2020-05-15 journal: JMIR Diabetes DOI: 10.2196/19581 sha: doc_id: 310650 cord_uid: 8lhkiw9p The coronavirus disease (COVID-19) is a global pandemic that significantly impacts people living with diabetes. Diabetes-related factors of glycemic control, medication pharmacodynamics, and insulin access can impact the severity of a COVID-19 infection. In this commentary, we explore how digital health can support the diabetes community through the pandemic. For those living with diabetes, digital health presents the opportunity to access care with greater convenience while not having to expose themselves to infection in an in-person clinic. Digital diabetes apps can increase agency in self-care and produce clinically significant improvement in glycemic control through facilitating the capture of diabetes device data. However, the ability to share these data back to the clinic to inform virtual care and enhance diabetes coaching and guidance remains a challenge. In the end, it requires an unnecessarily high level of technical sophistication on the clinic’s part and on those living with diabetes to routinely use their diabetes device data in clinic visits, virtual or otherwise. As the world comes together to fight the COVID-19 pandemic, close collaboration among the global diabetes community is critical to understand and manage the sustained impact of the pandemic on people living with diabetes. The coronavirus disease (COVID-19) is a global pandemic and significantly impacts individuals living with diabetes. In China, Wu and McGoogan [1] reported that people living with diabetes who contracted the virus had a more than triple mortality rate of 7% in comparison to 2% in those without diabetes. These figures align with previous global pandemics, which were also associated with increased morbidity and mortality in people with diabetes [2] . During the 2009 H1N1 pandemic, Canadians living with diabetes had triple the risk of hospitalization and quadruple the risk of intensive care unit admissions [3] . The 2003 severe acute respiratory syndrome epidemic also resulted in increased hospitalization and disease severity for people with diabetes [4, 5] . As global pandemics continue to occur and the prevalence of diabetes increases [6] , the diabetes community will be increasingly confronted with ongoing public health challenges [7] . The World Health Organization has warned that older adults and those with pre-existing medical conditions like diabetes are at higher risk of COVID-19 exposure, complications, and death [8] . Since the majority of the diabetes population are older [9] and have multiple comorbidities of obesity, emphysema, hypertension, and heart failure [10, 11] , they are at greater risk of viral infection. Although data on COVID-19 presentation has yet to support an increased risk of viral contraction in people living with diabetes [12, 13] , evidence suggests that they may have worse outcomes should they contract the virus [13, 14] . Poor glycemic control is a significant contributor to COVID-19 severity. Hyperglycemic events can lead to diabetes ketoacidosis, which is a life-threatening condition that interferes with the immune response to mitigate sepsis and recovery [15] . Coronaviruses have also been shown to bind to their target cells through angiotensin converting enzyme-2 (ACE2). Fang et al [16] proposed that the expression of ACE2 is substantially increased in people managing their diabetes with ACE inhibitors and antihyperglycemic angiotensin II type-I receptor blockers [17] . As such, these individuals may be at an increased risk of developing severe and fatal COVID-19. To maintain adequate glycemic control, people living with diabetes are normally encouraged to eat well, exercise, and maintain good mental health [18] [19] [20] . However, efforts to minimize the risk of exposure to COVID-19 have required social distancing and quarantine practices that may exacerbate insulin sensitivity through lower levels of physical activity, abrupt changes in social routine, poor dietary diversity, and diabetes distress [21] [22] [23] [24] . Guidelines authored by prominent diabetes societies encourage the use of insulin as the preferred treatment during the global pandemic [25, 26] . However, the impact of COVID-19 on the global economy has compromised insulin production and access [27] . For people who are insulin-dependent, the risk of an insulin shortage or delayed delivery is deadly [28] . Health professionals are recommending people to have a 30-day supply of diabetes medication and supplies for their medical devices [29] . This advice may prove difficult to heed for the growing population of people in both urban (10.8%) and rural (7.2%) settings who experience socioeconomic disparities, specifically lower income, as they may not be able to afford adhering to such guidelines [13, 30, 31] . In addition, the shortage of commercial antibacterial products may impede sterilization techniques for insulin injections and blood glucose monitoring, and promote infection [32] . Significant decreases in traditional in-person clinic availability will require people to adopt and adjust to receiving digital diabetes care [33] . In response to social distancing guidance, outpatient diabetes clinics and family medicine practices have greatly curtailed their services to only the most urgent cases [34] . Even as restrictions are expected to ease over time, there will be continued caution in visiting clinics. In light of these circumstances, the use of previously restricted forms of communication between providers and their patients have been allowed. Most forms of audio, video, or texting technology have been allowed by jurisdictions through not only relaxing privacy and security requirements but also reimbursing providers for these services. Even telephone calls have become an accepted modality for conducting a clinical visit, allowing those without sophisticated consumer devices like smartphones to access services [35] [36] [37] . For those living with diabetes, this is an opportunity to be able to access care with greater convenience while not having to expose themselves to infection in an in-person clinic. If the use of virtual visits continues after the pandemic eases-as they are expected to [38] -it opens up a great opportunity to provide more timely access to not only physician care but services that are often scarce for those living with diabetes [39] . With physical distances no longer a factor, virtualizing the care provided by diabetes educators, dieticians, and specialized mental health professionals could improve access further than what was previously possible with in-person encounters [40] . These successes can only be realized if broader digital health inequities of access and literacy are addressed within the diabetes community [41] . Perhaps more compelling than improving access to health services through virtual care, digital health apps can also create greater agency in self-care. A series of studies in recent years have demonstrated that diabetes smartphone apps with the ability to capture diabetes data and other self-reported factors can produce clinically significant improvement in glycemic control for both those living with type 1 diabetes and type 2 diabetes [40, 42, 43] . These outcomes were achieved without the benefit of a provider facilitating care through the app. Additional studies have since shown that outcomes can be further enhanced with the addition of virtual care and the active use of diabetes data sharing to enhance diabetes coaching and guidance [44, 45] . Despite the positive enablers for remote diabetes care, the ability to share diabetes device data back to the clinic remains a challenge [46] . As it stands, the current landscape of diabetes device data interoperability is a patchwork of proprietary technologies, open source tools, and restrictive electronic health record (EHR) policies. In the end, it requires an unnecessarily high level of technical sophistication on the clinic's part and on those living with diabetes to routinely use their diabetes device data in clinic visits, virtual or otherwise [47] [48] [49] . This technical burden will simply continue to hamper efforts to facilitate comprehensive virtual care. It continues to be a challenge to convince manufacturers of diabetes devices and EHR vendors to create truly interoperable systems to ease the burden on the diabetes communities [40] . It is hoped that the pandemic further reveals the flaws of the industry's business tactics to maintain exclusivity and their slow response in addressing the needs of the diabetes community. As the world comes together to fight the COVID-19 pandemic, close collaboration among the global diabetes community is critical to understand and manage the sustained impact of the pandemic on people living with diabetes. Figure 1 presents a summary of the challenges of COVID-19 for people living with diabetes and the opportunities of diabetes digital health to support them in this time of need. Contribution and access to trusted diabetes resources that can communicate actionable insights on the status of COVID-19 are needed to support the community through these challenging times [12, 13, [50] [51] [52] [53] [54] [55] . Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) Outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 -United States Diabetes and the severity of pandemic influenza A (H1N1) infection. Diabetes Care World Health Organization. SARS (severe acute respiratory syndrome Diabetes and other comorbid conditions were associated with a poor outcome in SARS International Diabetes Federation. 2019. IDF diabetes atlas 9th edition URL Commentary: COVID-19 in patients with diabetes World Health Organization. Coronavirus disease (COVID-19) pandemic URL Public Health Agency of Canada The impact of comorbid chronic conditions on diabetes care Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes Diabetes Canada Influenza virus and glycemic variability in diabetes: a killer combination? | iss. 2 | e19581 | p Novel Coronavirus (COVID-19) and diabetes: what you should know Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? SARS-CoV2: should inhibitors of the renin-angiotensin system be withdrawn in patients with COVID-19? Targeting diabetes distress: the missing piece of the successful type 1 diabetes management puzzle Exercise management in type 1 diabetes: a consensus statement Nutritional recommendations for individuals with diabetes Diabetes Canada Advances in exercise, physical activity, and diabetes Diabetes Canada Clinical Practice Guidelines Expert Committee Clinical considerations for patients with diabetes in times of COVID-19 epidemic Practical recommendations for the management of diabetes in patients with COVID-19 Van Nuys K, Insulin Access and Affordability Working Group. Insulin access and affordability working group: conclusions and recommendations Extra insulin supplies, medications advised for people with diabetes in wake of COVID-19 URL An open letter: working together to avoid diabetes supply interruptions during Covid-19 pandemic Socioeconomic status and mortality: contribution of health care access and psychological distress among U.S. adults with diagnosed diabetes Insulin injection abscesses caused by Mycobacterium chelonae Women's College Hospital. Centre for integrated diabetes care Coronavirus disease (COVID-19): for health professionals Manitoba doctors will be able to offer patient visits over telephone Internists commend CMS decision to pay for telephone visits to help physician practices during COVID-19 emergency Ontario implements virtual medical visits in bid to keep doctors, patients safe amid COVID-19 URL Has telemedicine's day finally come Challenges in diabetes care: can digital health help address them? A digital-first model of diabetes care Addressing equity in telemedicine for chronic disease management during the Covid-19 pandemic Mobile app-based interventions to support diabetes self-management: a systematic review of randomized controlled trials to identify functions associated with glycemic efficacy Effectiveness of mHealth interventions for patients with diabetes: an overview of systematic reviews Overcoming clinical inertia: a randomized clinical trial of a telehealth remote monitoring intervention using paired glucose testing in adults with type 2 diabetes Telemedicine in complex diabetes management Why download data: the benefits and challenges of more diabetes data A minority of patients with type 1 diabetes routinely downloads and retrospectively reviews device data A case study in open source innovation: developing the Tidepool Platform for interoperability in type 1 diabetes management Digital diabetes self-management: a trilateral serial Keeping our diabetes community healthy COVID-19 Update From LMC URL What you need to know about diabetes and the coronavirus URL Coronavirus and T1D: what you need to know and how to prepare Figure 1 . The challenges of COVID-19 for people living with diabetes and the opportunities of diabetes digital health. None declared. 15 .05.2020. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in JMIR Diabetes, is properly cited. The complete bibliographic information, a link to the original publication on http://diabetes.jmir.org/, as well as this copyright and license information must be included. 


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   key: cord-312875-gn6hg6oc authors: Infante, Marco; Ricordi, Camillo; Fabbri, Andrea title: Antihyperglycemic properties of hydroxychloroquine in patients with diabetes: risks and benefits at the time of COVID‐19 pandemic date: 2020-05-13 journal: J Diabetes DOI: 10.1111/1753-0407.13053 sha: doc_id: 312875 cord_uid: gn6hg6oc The antimalarial drug hydroxychloroquine (HCQ) has long been used as a disease‐modifying antirheumatic drug for the treatment of several inflammatory rheumatic diseases. Over the last three decades, various studies have shown that HCQ plays also a role in the regulation of glucose homeostasis. Although the mechanisms of action underlying the glucose‐lowering properties of HCQ are still not entirely clear, evidence suggests that this drug may exert multifaceted effects on glucose regulation, including improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance and reduction of systemic inflammation. Preliminary studies have shown the safety and efficacy of HCQ (at a dose ranging from 400 to 600 mg/day) in patients with type 2 diabetes over a short‐term period. In 2014, HCQ has been approved in India as an add‐on hypoglycemic agent for patients with uncontrolled type 2 diabetes. However, large randomized controlled trials are needed to establish the safety and efficacy profile of HCQ in patients with type 2 diabetes over a long‐term period. With regard to the COVID‐19 pandemic, several medications (including HCQ) have been used as off‐label drugs due to the lack of proven effective therapies. However, emerging evidence shows limited benefit from HCQ use in COVID‐19 in general. The aim of this manuscript is to comprehensively summarize the current knowledge on the antihyperglycemic properties of HCQ and to critically evaluate the potential risks and benefits related to HCQ use in patients with diabetes, even in light of the current pandemic scenario. This article is protected by copyright. All rights reserved. Since the 1940s, the antimalarial drugs chloroquine and hydroxychloroquine (HCQ) have been used as disease-modifying antirheumatic drugs (DMARDs) for the treatment of several inflammatory rheumatic diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). (1) Importantly, HCQ has shown a good safety and tolerability profile in most patients, even during pregnancy and breastfeeding. (1, 2) Intriguingly, a growing body of evidence coming from studies conducted over the last three decades suggests that HCQ plays also a role in the regulation of glucose homeostasis in individuals with and without diabetes. (3) Although the exact mechanisms of action underlying the glucose-lowering properties of HCQ are still not entirely clear and may differ between patients with and without diabetes, pre-clinical and clinical data suggest that HCQ could exert multifaceted effects on glucose homeostasis, namely: improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance and intracellular insulin and insulin-receptor complex degradation, increase of adiponectin levels, reduction of systemic inflammation, and/or reduction of inflammation-induced insulin resistance in adipocytes and skeletal muscle cells. (3) (4) (5) In this regard, a randomized study is currently underway at Washington University (MetaHcQ, Metabolic Effects of Hydroxychloroquine; ClinicalTrials.gov Identifier: NCT02026232) to evaluate the effects of 4- week HCQ administration (at a dose of 400 mg/day) on insulin sensitivity (determined by This article is protected by copyright. All rights reserved. Accepted Article hyperinsulinemic euglycemic clamp), fasting blood glucose, lipid profile and serum biomarkers of inflammation in subjects with T2D. Remarkably, several studies demonstrated that HCQ use is associated with a significantly reduced risk of developing diabetes in non-diabetic subjects with inflammatory rheumatic diseases, including RA, (6) (7) (8) SLE, (9) psoriasis, (8) and Sjögren syndrome. (10) In the early 1990s, an Italian 6-month randomized, placebo-controlled trial conducted by Quatraro et al. (11) in 38 T2D subjects first showed that the addition of HCQ (600 mg/day) to glibenclamide or insulin led to a significant reduction in glycated hemoglobin (HbA1c), accompanied by a 30% reduction in daily insulin dose among patients on insulin therapy. Thereafter, a Canadian randomized, placebo-controlled trial conducted in 135 obese patients with T2D refractory to sulfonylureas showed that the addition of HCQ (up to a maximum of 300 mg bid) reduced HbA1c by an absolute amount of 1.02% more than placebo after 6 months. (12) No significant HCQ-related side effects were reported in these studies, except for a severe hypoglycemic episode occurred in one patient treated with HCQ in combination with insulin. (11) Moreover, a retrospective study conducted in diabetic patients with concomitant rheumatic diseases (RA and SLE) showed that HCQ, when compared to methotrexate, was associated with a significantly greater reduction in HbA1c from pre-treatment baseline to its lowest value within 12 months of treatment initiation. (13) More recently, a 24-week prospective randomized trial (14) and two real-world, prospective observational studies of short duration (up to 24-48 weeks) (5, 15) conducted in India have shown that the use of HCQ (400 mg/day) as an add-on treatment in patients with T2D uncontrolled on a combination of two or more oral hypoglycemic agents (including metformin, sulfonylureas, pioglitazone, DPP-4 inhibitors, SGLT2 inhibitors, and alpha-glucosidase inhibitors) was welltolerated and led to a significant improvement of glucose control (assessed by HbA1c, fasting-and postprandial blood glucose) from baseline (without occurrence of severe hypoglycemia). This article is protected by copyright. All rights reserved. In India, diabetes has reached epidemic proportions over the last years and newer antidiabetic drugs pose affordability challenges due to their high cost. Based on the aforementioned preliminary results, HCQ (at a dose of 400 mg/day) has been approved in 2014 by the Drug Controller General of India (DCGI) as a third-line (add-on) hypoglycemic agent for patients with inadequately controlled T2D despite lifestyle management associated with sulfonylurea and metformin combination therapy. (16, 17) Thereafter, a vibrant debate about HCQ safety in T2D has arisen within the Indian scientific community. (18) (19) (20) (21) Animal and human studies support the existence of different molecular mechanisms underlying the antihyperglycemic properties of HCQ (and chloroquine). A study conducted by Halaby et al. (22) in cultured rat muscle cells and in a rat model of insulin resistance demonstrated that chloroquine can promote insulin-mediated glucose uptake and glycogen synthase activity by activating Akt. In 1991, Powrie et al. (23) conducted a randomized, placebo-controlled trial in 20 patients with T2D (referred to as "non-insulin-dependent diabetes mellitus") who were not receiving any antidiabetic medication and were only adopting dietary measures for diabetes management. The authors performed a hyperinsulinemic euglycemic clamp before and after a 3-day treatment with chloroquine (250 mg administered four times daily) or placebo, using a stable isotopically labelled D-glucose to calculate hepatic glucose production (Ra, rate of glucose appearance) and glucose utilization (Rd, rate of glucose disappearance). Notably, chloroquine led to a significant reduction in fasting plasma glucose and a significant rise in the total amount of exogenous glucose required to maintain euglycemia during the whole experiment, due to an increase in Rd (without changes in Ra). Also, chloroquine administration resulted in a 39% reduction in metabolic clearance rate of insulin at low-dose insulin infusion. More importantly, fasting C-peptide levels significantly increased throughout the study after chloroquine treatment, despite the initially lower plasma glucose values. A decreased feedback inhibition of C-peptide secretion was also reported during low-and high-dose insulin infusion (by 9.1% and 10.6%, respectively) (23) . Overall, these data suggest that chloroquine can improve fasting glucose levels in subjects with T2D by: (i) increasing peripheral glucose disposal (as evidenced by the increased overall glucose infusion rate required to maintain euglycemia, associated with an increase in Rd), (ii) reducing hepatic insulin clearance, and (iii) increasing endogenous insulin secretion both in the fasting state and during hyperinsulinemia. The assumption of the authors that chloroquine has a direct insulinotropic effect on pancreatic beta cells is strengthened by the fact that C-peptide has a negligible hepatic clearance and approximately half of the produced C-peptide is metabolized by the kidneys; in particular, the majority of total Cpeptide produced is degraded via peritubular uptake and approximately 5% is excreted unchanged in the urine. (24, 25) However, these findings cannot be directly translated to HCQ, even though chloroquine and HCQ display similar pharmacodynamic properties. (1) Thus, further investigation is warranted in this direction. A study conducted by Emami et al. (26) in diabetic rats showed that HCQ increased circulating insulin levels and reduced blood glucose levels in a concentration-dependent manner. In a subsequent study, the same authors found that HCQ can inhibit cytosolic insulin-metabolizing enzyme and intracellular insulin degradation in rat liver cells. (27) In 2012, Mercer et al. (28) showed that HCQ therapy (at a dose of 6.5 mg/Kg/day) for 6 weeks was associated with a significantly increase in insulin sensitivity index (ISI) -assessed by a 120-min oral glucose tolerance test (OGTT) -along with trends toward reduced insulin resistance (assessed by HOMA-IR) in non-diabetic obese subjects without systemic inflammatory conditions. Thereafter, Wasko et al. (4) confirmed similar results in a 13-week randomized, placebo-controlled study, showing that HCQ (400 mg/day) improved both beta-cell function (determined by the disposition index) and ISI (assessed by intravenous glucose tolerance test) in non-diabetic overweight or obese subjects. At variance with these findings, a randomized, placebo-controlled This article is protected by copyright. All rights reserved. Accepted Article cross-over trial conducted by Solomon et al. (29) in non-diabetic subjects with stable RA showed that treatment with HCQ for 8 weeks (at a dose of 6.5 mg/Kg/day, and not to exceed 600 mg/day) produced no significant change in ISI (assessed by 120-min OGTT) and insulin resistance (assessed by HOMA-IR) compared to placebo. These results may indicate that HCQ can prevent development of diabetes in patients with inflammatory rheumatic diseases -as it has been widely demonstrated - (6) (7) (8) (9) (10) through additional mechanisms other than improvement in insulin sensitivity. HCQ is a well-known anti-inflammatory and immunomodulatory agent able to reduce the production of pro-inflammatory cytokines, and is therefore used as a DMARD for the treatment of several inflammatory rheumatic diseases. (1, 30) With regard to the anti-inflammatory effects of HCQ in T2D, Amit Gupta (5) has recently shown that diabetic patients with higher baseline levels of highsensitivity C-reactive protein (hs-CRP >3 mg/L) exhibited a more pronounced, although not significant, improvement in glucose control from baseline to 48 weeks after the initiation of HCQ therapy, as compared to patients with lower baseline levels of hs-CRP (≤ 3 mg/L). Furthermore, patients with higher baseline hs-CRP levels also exhibited higher (although not significant) baseline levels of HbA1c, fasting-and postprandial glucose levels. (5) The previously mentioned study by Wasko et al. (4) conducted in non-diabetic overweight or obese subjects also found that HCQ (at a dose of 400 mg/day) significantly increased plasma levels of the adipokine adiponectin, which plays a key role in insulin resistance and metabolic syndrome by exerting anti-inflammatory actions and increasing insulin sensitivity. (31) (32) (33) Importantly, HCQ use up to 24 weeks (at a dose of up to 600 mg/day) in patients with T2D has also led to an improved lipid profile, which consisted of a significant reduction in total cholesterol, LDL-cholesterol and non-HDL cholesterol in different studies. (12, 14, 15) A randomized, placebocontrolled cross-over trial also found a significant reduction in total cholesterol and LDLcholesterol after 8 weeks of HCQ therapy (at a dose of 6.5 mg/Kg/day, and not to exceed 600 mg/day) in non-diabetic patients with RA. (29) Nevertheless, it is still not clear whether the potential This article is protected by copyright. All rights reserved. Accepted Article lipid-lowering properties of HCQ may depend on its anti-inflammatory actions rather than on other HCQ-related mechanisms. Interestingly, Type 1 Diabetes (T1D) TrialNet international network is currently investigating the potential ability of HCQ to prevent or delay the progression from normal glucose tolerance to impaired glucose tolerance or symptomatic T1D in subjects with islet autoimmunity, who are at increased risk of developing T1D (ClinicalTrials.gov Identifier: NCT03428945). Therefore, participants enrolled in this study are subjects in the stage 1 (islet autoimmunity) of T1D pathophysiology. (34) However, the current lack of data on safety and efficacy of HCQ in patients with established T1D does not allow for any conclusion concerning the use of this drug in T1D. Altogether, these findings suggest that HCQ regulates glucose homeostasis by virtue of multifaceted effects, which may allow for classifying this drug as an antidiabetic medication potentially acting as an insulin-sensitizing agent (insulin sensitizer), an anti-inflammatory agent and/or an insulinotropic agent (secretagogue) (Figure 1 ). Since chronic low-grade inflammation and islet inflammation have been linked to insulin resistance and beta-cell dysfunction in T2D, respectively, (33, (35) (36) (37) the anti-inflammatory actions of HCQ may be at the interface between its insulin-sensitizing effects and its insulinotropic properties. On the basis of pre-clinical data in animals, HCQ appears to have the ability to: (i) inhibit intracellular insulin and insulin-receptor complex degradation, (ii) increase circulating insulin levels, (iii) reduce blood glucose levels, and (iv) promote glucose uptake and glycogen synthase activity in skeletal muscle cells. Thus, it is tempting to speculate that HCQ is able to inhibit glucagon secretion by pancreatic alpha-cells and/or glucagon action in the liver. Additionally, it is still not clear whether the putative effect of HCQ on endogenous insulin secretion is mediated by a direct stimulatory effect on beta-cells, and/or by indirect effects involving the reduction of islet inflammation and/or the reduction of glucotoxicityand lipotoxicity-related beta-cell dysfunction following the improvement in metabolic control. Moreover, the lack of severe hypoglycemic episodes observed across the studies investigating the This article is protected by copyright. All rights reserved. Accepted Article use of HCQ as an antidiabetic medication in T2D (even when HCQ was administered in combination with sulfonylureas) may underlie a putative glucose-dependent insulin secretion mechanism mediated by HCQ. Yet, the occurrence of severe hypoglycemic episodes cannot be excluded in these studies, since they did not employ continuous glucose monitoring. Notwithstanding, we believe that all these speculations and unanswered questions may prompt the researchers to conduct future mechanistic studies in order to elucidate the exact mechanisms underlying the antihyperglycemic properties of HCQ in both subjects with and without diabetes. Even though HCQ is considered as one of the safest DMARD and has been widely used for the treatment of RA and SLE, (1) data on long-term safety and efficacy of HCQ in diabetes are still lacking. Therefore, the use of HCQ in patients with diabetes should be carefully evaluated, particularly in subjects with established microvascular and/or macrovascular complications. The most dreaded complication deriving from HCQ use is retinal toxicity. (1) However, current evidence suggests that high-dose and long-term (>5 years) use represent the most important predictors of HCQ-induced retinopathy. (1) Therefore, the American Academy of Ophthalmology recommends a maximum HCQ dose of ≤5 mg/kg actual body weight per day to markedly minimize the risk of retinopathy. (38) Also, HCQ-mediated cardiotoxic effects (including potentially lethal heart rhythm disorders, such as prolonged QT interval, ventricular arrhythmia and Torsades de Pointes) have been reported. (1, (39) (40) (41) Thus, baseline electrocardiography to evaluate for prolonged QT interval is advisable prior to and following the initiation of HCQ, particularly in high-risk subjects such as hospitalized patients and individuals taking other QT interval-prolonging drugs (e.g. macrolides such as azithromycin, quinolones, antihistamines, antiviral and antifungal drugs, antiarrhythmic medications, etc.). (2, (42) (43) (44) Risk factors for potentially lethal cardiac arrhythmias induced by HCQ include: (i) coexisting cardiac conditions such as cardiomyopathy, left ventricular This article is protected by copyright. All rights reserved. Accepted Article dysfunction, ventricular hypertrophy, coronary artery disease, heart failure, or bradycardia; (ii) history of bradycardia, prolonged QT interval, ventricular arrhythmia or (unexplained) syncope; (iii) family history of premature sudden cardiac death or cardiac ion channelopathies; (iv) pacemaker and implantable cardioverter-defibrillator use; (v) electrolyte abnormalities such as hypokalemia and hypomagnesemia; (vi) genetic and autoimmune channelopathies; (vii) systemic inflammation; (viii) concomitant use of azithromycin or other QT interval-prolonging agents. (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) With regard to the renal function, chronic kidney disease can result in reduced HCQ clearance, increased drug bioavailability and subsequent augmented risk of HCQ-related side effects. (1) Furthermore, certain drugs (such as tamoxifen, glycosides, methotrexate and ciclosporin) can influence the pharmacokinetics of HCQ. (1) These drug interactions can increase the risk of HCQrelated side effects and therefore require careful consideration. Besides the well-known contraindications to HCQ use (including known hypersensitivity to 4aminoquinoline compounds), (2, 44) other conditions or circumstances under which HCQ should be contraindicated or used with caution in the context of diabetes include the following:  Pre-existing retinopathy/maculopathy, history or risk for macular edema, and concomitant use of other oculo-toxic agents. (38, 52)  Diabetes complicated by hypoglycemia unawareness, repeated episodes of severe hypoglycemia and/or malnutrition, due to the potential risk for severe hypoglycemic episodes. Although HCQinduced severe hypoglycemia has mainly been documented in non-diabetic subjects, (53) (54) (55) there have been a few reports of severe hypoglycemic episodes occurred with the use of HCQ in patients with newly diagnosed T2D (56) and established T2D treated with multiple daily injection insulin therapy. (11, 57)  Pre-existing cardiomyopathy or heart failure, due to the possible risk of HCQ-related cardiotoxicity. (43) This article is protected by copyright. All rights reserved.  Pre-existing myopathy and/or neuropathy, due to the potential risk of HCQ-induced neuromyotoxicity. (58) (59) (60) (61) (62) (63)  Glucose-6-phosphate dehydrogenase (G6PD) deficiency, due to the potential increased risk of HCQ-related hemolysis crisis. (64) Interestingly, Heymann et al. (65) found a significantly higher proportion of G6PD-deficient patients among the diabetic population aged 45-64 years. However, a large retrospective study of 275 patients with rheumatic diseases examined the relationship between HCQ use and hemolytic anemia in G6PD-deficient patients, showing that 4% of patients had G6PD deficiency (11 subjects, all African American) and only 2 of them had episodes of hemolysis that occurred while not taking HCQ. (66) Based on these findings, authors did not support routine measurement of G6PD levels or withholding HCQ therapy in African American patients with G6PD deficiency. (66) Importantly, a proper risk-benefit assessment of HCQ use in diabetic patients should also be considered in relation to the current coronavirus disease 2019 (COVID-19) pandemic caused by the novel coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) (67, 68) and declared a global pandemic by the WHO on March 11, 2020. So far, several medications (including HCQ and chloroquine) have been used in hospital settings as off-label drugs for COVID-19 due to the current lack of proven effective therapies. (2, 45) However, a recent observational study conducted on 1,376 consecutive hospitalized patients with COVID-19 and moderate-to-severe respiratory illness showed that HCQ did not have a significant impact on the risk of intubation or death over a median follow-up period of 22.5 days. (69, 70) Despite the observational design of this study, these findings dot not support HCQ use for treatment of COVID- Importantly, diabetes has reached epidemic proportions over the last years, (73) affecting approximately 463 million people worldwide according to recent estimates. (74) Also, emerging evidence suggests that diabetes represents one of the most prevalent comorbidities in patients with COVID-19, (75) (76) (77) as well as a major risk factor for a worse prognosis of the disease. (76) (77) (78) (79) (80) (81) (82) (83) In light of these remarks, a pre-emptive and careful evaluation of all the potential risks and benefits related to HCQ is critical for a proper and cautious use of this drug in subjects with diabetes, particularly in the context of COVID-19. Over the last decades, several studies have shown that HCQ plays an important role in the regulation of glucose homeostasis through multifaceted effects, including improvement of insulin sensitivity, increase of insulin secretion, reduction of hepatic insulin clearance and intracellular insulin and insulin-receptor complex degradation, and reduction of systemic inflammation, among others ( Figure 1 ). Different studies have shown the safety and efficacy of HCQ use (at a dose ranging from 400 to 600 mg/day) in patients with T2D over a short-term period (up to 18 months). (5, 11, 12, 14, 15) In 2014, HCQ (at a dose of 400 mg/day) has been approved in India as an addon hypoglycemic agent for patients with inadequately controlled type 2 diabetes despite lifestyle management associated with sulfonylurea and metformin combination therapy. Nevertheless, concerns on long-term safety of HCQ in patients with T2D still persist due to the lack of robust data. Thus, large randomized controlled trials of long duration are warranted to establish the longterm safety and efficacy of this drug in the context of T2D. With regard to the current pandemic scenario, emerging evidence shows that patients with diabetes have a greater risk for adverse outcomes following COVID-19 infection. Although findings from clinical studies have suggested This article is protected by copyright. All rights reserved. Accepted Article limited benefit from HCQ in COVID-19 in general, (84) several randomized controlled trials are currently investigating the use of HCQ for prophylaxis of COVID-19. (72) Moreover, guidelines from different countries have listed some investigational drugs (including HCQ) as potential adjuvant treatment options, whilst cautioning to take into account the individual risk of harm. (84, 85) Therefore, a careful risk-benefit assessment of HCQ is required for the most cautious use of this drug in subjects with diabetes. Accepted Article without diabetes suggests that hydroxychloroquine regulates glucose homeostasis by virtue of multifaceted effects, including increase of insulin secretion, improvement of insulin sensitivity, reduction of hepatic insulin clearance and intracellular insulin and insulin-receptor complex degradation, increase of adiponectin levels, reduction of systemic inflammation, and/or reduction of inflammation-induced insulin resistance in adipocytes and skeletal muscle cells. Altogether, these actions may allow for classifying hydroxychloroquine as an antidiabetic agent by acting as an insulin-sensitizing agent, an anti-inflammatory agent and/or an insulinotropic agent (secretagogue). Since chronic low-grade inflammation and islet inflammation have been linked to insulin resistance and beta-cell dysfunction in type 2 diabetes, respectively, the anti-inflammatory actions of hydroxychloroquine may be at the interface between its insulin-sensitizing actions and its insulinotropic properties. *Effects observed with chloroquine in a rat model of insulin resistance. Abbreviations: CRP, C-reactive protein. 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Vademecum for the treatment of people with COVID-19 No funding received. We would like to thank Dr. Nathalia Padilla for her contribution to the comprehensive review of the literature. None declared. This article is protected by copyright. All rights reserved.Accepted Article 


id: cord-313829-pjscmen8
fulltext:
   key: cord-313829-pjscmen8 authors: Caballero, A.E.; Ceriello, A.; Misra, A.; Aschner, P.; McDonnell, M.E.; Hassanein, M.; Ji, L.; Mbanya, J.C.; Fonseca, V.A. title: COVID-19 in people living with diabetes: An international consensus date: 2020-07-06 journal: J Diabetes Complications DOI: 10.1016/j.jdiacomp.2020.107671 sha: doc_id: 313829 cord_uid: pjscmen8 The COVID-19 pandemic has added an enormous toll to the existing challenge of diabetes care world-wide. A large proportion of patients with COVID-19 requiring hospitalization and/or succumbing to the disease have had diabetes and other chronic conditions as underlying risk factors. In particular, individuals belonging to racial/ethnic minorities in the U.S. and other countries have been significantly and disproportionately impacted. Multiple and complex socioeconomic factors have long played a role in increasing the risk for diabetes and now for COVID-19. Since the pandemic began, the global healthcare community has accumulated invaluable clinical experience on providing diabetes care in the setting of COVID-19. In addition, understanding of the pathophysiological mechanisms that link these two diseases is being developed. The current clinical management of diabetes is a work in progress, requiring a shift in patient-provider interaction beyond the walls of clinics and hospitals: the use of tele-medicine when feasible, innovative patient education programs, strategies to ensure medication and glucose testing availability and affordability, as well as numerous ideas on how to improve meal plans and physical activity. Notably, this worldwide experience offers us the possibility to not only prepare better for future disasters but also transform diabetes care beyond the COVID-19 era. Chinese Geriatric Endocrine Society issued guidance to PLWD on coping with the situation. 19, 20 Expert recommendations on insulin treatment of hyperglycemia in patients affected with COVID-19 was also developed to guide hyperglycemia management in hospitalized patients. 21 Many endocrinologists offered free consultation to PLWD through internet-based consultation platforms. Based on the experience with SARS, it is predicted that this pandemic will be of short duration, so, advice has focused on how to discover and prevent hyperglycemic crisis. According to Chinese guidelines, a slight elevation of glucose above the recommended target is tolerable for a short period of time. But patients should be aware of early signs of significant hyperglycemia crisis and when to go to the hospital. A very detailed guidance for PLWD was created on how to access certified internet-based medical services and medical supplies through smartphones. A location-based GPS diabetes pharmacy map was also developed, providing information on pharmacies with insulin to ensure that PLWD are able to access their medicines through non-hospital channels. The map has been viewed by more than 2.3 million people and its related information has reached 5 million. For those PLWD urgently needing to see health care providers in hospital, information was J o u r n a l P r e -p r o o f based public media, such as Baidu (a Google equivalent) and WeChat, used by more than 800 million people living in China. The mean prevalence of diabetes in Europe in people affected by COVID-19 has been reported to be 33% by the WHO Europe Region. 22 Italy was the first country in Europe affected by . The situation in the north of the country was dramatic while in the southern area it remained under control. The second country showing a similar trend was Spain; the epidemic was very serious in the areas of Madrid and Barcelona and less so in other parts. Italy and Spain adopted the -lockdown‖ strategy quite quickly, closing almost all activities and keeping their citizens at home. This lockdown was also rapidly adopted in several other countries, possibly explaining why the disease left countries like Portugal and Greece virtually unaffected. Conversely, where the lockdown was adopted late in the appearance of COVID-19, the related morbidity was higher. For example, the UK experienced a high total number of cases, and Sweden a high number of cases as a proportion of their small population. Russia has a different story: at the beginning the situation was unclear but today this country displays the worst situation in Europe. The World Health Organization issues daily situation reports to communicate all updates by country and region. 23 J o u r n a l P r e -p r o o f but upon lifting the lockdown there has been a major surge. Mortality due to COVID-19 in India has remained lower than many other countries: ~3%. India has a huge number of patients with diabetes; specifically, 18 million patients above 65 years of age who are particularly vulnerable to mortality due to COVID-19. These large numbers of patients pose a major challenge in prevention and management. 24 Further, during the lockdown, patients with diabetes have increased snacking/carbohydrate intake and decreased physical activity, resulting in weight gain, which may de-stabilize glucose control. 25 A simulation model analysis showed a significant association between the duration of the lockdown and loss of glycemic control as well as associated complications. The predicted increment in HbA1C from baseline at the end of 30 days and 45 days lockdown was 2.26% and 3.68% respectively. Similarly, the predicted percentage increase in complication rates at the end of 30day lockdown was 2.8% for retinopathy, 9.3% for microalbuminuria, 14.2% for proteinuria, 2.9% for peripheral neuropathy, 10.5% for lower extremity amputation, 0.9% for myocardial infarction, and 0.5% for stroke. 26 These data show a likely increase of patients with diabetesrelated complications, adding to already huge numbers. In addition, according to another recent analysis, a 7% increase in diabetes risk will occur consequent to weight gain during lockdown. 27 If this occurs, millions of new cases of diabetes will be diagnosed in the near future. J o u r n a l P r e -p r o o f inability to access the online link, poor quality of picture, poor perception of sound, etc. 29 Indeed, many patients prefer telephone or smartphone-based tele-consults. One of the widely debated questions regarding the COVID-19 epidemic is why overall mortality due to COVID-19 in India lower than other countries. Adverse factors which could lead to increase in mortality are all too pervasive in Asian Indians: poorly controlled diabetes and hypertension, high prevalence of cardiovascular diseases, increased baseline sub-clinical inflammation, and increasing obesity. There could be other factors which could be protective but need research. Firstly, BCG vaccination may have a role in enhancing innate immunity. Countries which have a universal BCG vaccination (including India) have a lower mortality due to COVID-19 as compared to other nations. Second, cytokine storm, associated with high mortality in COVID-19 cases, may be muted in Indians due to previous recurrent infections (malaria, previous coronavirus, etc). These and several other issues have been discussed in a recent review. 30 What will be the scenario for COVID-19 related mortality and hospitalization in the next 24 months? It is difficult to predict but some indicators are available from the model of Harpreet In summary, while overall mortality due to COVID-19 is lower in India than in other countries, the elderly population, where most patients with diabetes, hypertension and CVD are concentrated, remains at high risk. Several solutions are suggested in Table 1 . 32, 33 Perspective from the Middle East The Middle East (ME) has a huge range of variability in wealth, strength of the health system as well as in density of the population, where some countries are <2 million in population while others are >100 million. Consequently, these variations are also reflected in the response to COVID-19 with regards to the ability to implement robust social distancing, effective and timely use of protective measures, and in the ability to test suspected cases. Many studies on COVID-19 are ongoing and the results of these studies are not yet published. However, recent data from Kuwait are now available, although not yet peer-reviewed. 34 In a single hospital where 100% of COVID-19 patients were admitted, the total number of admissions was 417 persons and case fatalities were 14.4%, with mean age 54.2±11.09. Male gender represented 90% of all fatalities and diabetes was diagnosed in 40% of those who died. This observation matches the recent announcement by the United Arab Emirates government spokesperson, where 40% of COVID-J o u r n a l P r e -p r o o f years in Kuwait (36.7%) and in those aged 60-69 years (62.8%) . 35 Future data from other Middle East countries are eagerly awaited. One aspect was common across the ME: Ramadan fasting, as Ramadan this year started on 23 rd of April, which coincided with the peak of COVID-19 in many countries. While the majority of the ME population are Muslims, this issue extends to millions of Muslims globally where fasting during the month of Ramadan is something they await passionately each year. The vast majority of PLWD fast safely during Ramadan. 36 However, for some there is increased risk of hypoglycemia, hyperglycemia, ketoacidosis, dehydration, and thrombosis. 37 Furthermore, many PLWD are treated with SGLT2 inhibitors (SGLT2-I) in view of the recent cardiovascular outcomes trials. However, some were concerned about the possibility of dehydration during Ramadan fasting for people treated with this class of medication, as well as the concern regarding diabetic ketoacidosis in those patients with COVID-19 on SGLT2-I. In response to the question of the safety of Ramadan fasting for PLWD, the Diabetes and Ramadan International Alliance has provided guidance that is available on the IDF website. 38 As the coronavirus epidemic spread throughout the ME, many clinicians and PLWD looked for Approximately 25% of all cases of COVID-19 in the world have been reported in the U.S. Race/ethnicity has been recorded in only 48% of them. 41 Among these cases, racial/ethnic minorities stand out as being disproportionately affected by COVID-19. For example, 21.3% of COVID-19 cases are in Blacks, 34.3% in Latinos/Hispanics and 34.7% in non-Hispanic Whites while they represent 13.4%, 18.3% and 60.4% of the general U.S. population respectively. 41, 42 Most cases have been reported in people ages 18 to 44 years, followed by those ages 45 to 64 years. However, most hospitalizations indicating severe disease have been in individuals above 75 years. 41 The prevalence of diabetes is on the rise in the U.S. At the present time, it is estimated that at least 1 in 10 individuals above 18 years of age has diagnosed diabetes. However, among those Journal Pre-proof J o u r n a l P r e -p r o o f between 65-74 and among those above 75, approximately 2 in 10 have diagnosed diabetes. 43 It is not surprising then that diabetes has been frequently reported as an underlying condition in people diagnosed with COVID-19 but even more significantly among those who have been hospitalized and in those who have died from COVID-19. 11, 12 The COVID-19 pandemic is a reminder of a previous major disaster to hit the U.S.: Hurricane Katrina, during and after which PLWD were seriously affected by not having access to healthy meals, medications like insulin, etc. 44 Major disasters usually lead to worse diabetes control among most PLWD. People with lower socio-economic status and access to health care are often affected in a more impactful manner. 45 In response, the American Diabetes Association formed a disaster preparedness task force that made recommendations about diabetes management when faced with an emergency (Table 3) . 46 Clinicians should be reminded to access and use these resources, freely available online. Just as we teach all our patients that they should prepare for an emergency, so should healthcare provider organizations ensure that direct patient medical care will continue in some way, and that patients are aware of means by which they can access their medication-including experimental medications. There is no doubt that people with diabetes are not only widely affected by COVID-19 but very often have a more severe form of the disease. 4 We have learned that in addition to the presence of co-morbidities, the level of hyperglycemia during the disease can seriously affect the outcomes. 47, 48 The survival rate in hospitalized patients with type 2 diabetes with well-controlled J o u r n a l P r e -p r o o f blood glucose is almost 99% (considering a threshold of glycemia <10 mmol/L or <180 mg/dL), while above this threshold the survival rate is only 11%. 47 In the same study, hyperglycemia was associated with worse prognosis of COVID-19 in both people with and without diabetes. Hyperglycemia, particularly severe hyperglycemia, is often a marker of the severity of the underlying comorbidities. Thus, hyperglycemia can serve as a marker of high risk of morbidity and mortality in the COVID-19 infected patient, as was similarly observed for the SARS epidemic in 2006. 49 There is some evidence suggesting how hyperglycemia is generated or worsened during COVID-19, depicted in Figure 3 . SARS-CoV-2 may affect β-cells, causing a reduction of insulin secretion. 50 SARS-CoV-2 infection is also accompanied by a significant production of cytokines, which can induce insulin resistance. Both reduced insulin secretion and insulin resistance may result in hyperglycemia, which in turn may further decrease insulin secretion and increase insulin resistance. 50 Hyperglycemia also generates non-enzymatic glycosylation. Glycosylation of the ACE2 receptor can facilitate the entry of the SARS-CoV-2 into host cells. 50 Furthermore, acute hyperglycemia, either directly or through cytokine production, may provoke endothelial dysfunction and thrombus formation, which in turn can lead to organ damage and fatal outcome of the disease. 50 This hypothesis is consistent with the evidence of high levels of D-dimer in people with diabetes, particularly people with poor glycemic control, during the course of COVID-19. 48 J o u r n a l P r e -p r o o f Several important pathways have been linked between COVID-19 and diabetes that could be considered as targets for therapy related to diabetes and comorbidities. 51 The first is DPP-4, a known receptor for coronaviruses including MERS and SARS but not SARS-CoV-2. However, even though DPP-4 is involved in the inflammatory cascade, its role is minimal. There is currently no evidence that DPP-4 inhibitors (DPP-4I) have any beneficial effect on COVID-19infected patients. A second, interesting pathway is the enzyme angiotensin converting enzyme-2 (ACE2), which does function as a receptor of coronavirus, including SARS-CoV-2. It is known that ACE is involved in conversion of Angiotensin I to Angiotensin II and ACE inhibitors are commonly used in the management of hypertension. It's also known that ACE2 acts on Ang II to produce a fragment that is beneficial, as it is involved in increasing blood flow, is cardio-protective and decreases insulin resistance. ACE2 is also present in the pancreas, where its role in diabetes is unclear. A rational hypothesis is that in binding to ACE2 the virus may affect organs where it is present and thereby the SARS-CoV-2 virus may be affecting the pancreas and causing hyperglycemia. 51 Obesity is an additional contributing factor to the deleterious outcomes in PLWD and COVID-19 as its state of low-grade, chronic inflammation seems to be amplified following SARS-CoV-2 infection. We still need to better understand this effect before we can effectively target this exacerbated inflammatory state and its frequent coagulation response that seems to be the trigger for severe disease and mortality. Finally, the increase in blood glucose levels associated with COVID-19 described above could potentially occur not only in people with known diabetes but also in those with undiagnosed diabetes, prediabetes or with major predisposition to the disease. The potential deleterious effects of SARS-CoV-2 on ß-cells and on insulin resistance may partially explain the COVID-19-related new-onset diabetes cases identified in several countries/regions. 52 Understanding the precise mechanisms leading to this phenomenon will be extremely important in order to generate corresponding clinical management guidelines. As previously stated, PLWD are more prone to a serious form of COVID-19. Optimizing glycemic control is key to reducing the risk of serious disease as well as successfully treating people who have been hospitalized with COVID-19. 53 The comprehensive management of associated comorbidities and the evaluation of biomarkers for cardiovascular risk are equally important during this critical time. 54, 55 The principles of managing diabetes in association with any acute illness apply in those affected with COVID-19, with a few caveats. 56 The biggest challenge is for health care systems to manage seriously ill patients in isolation, with limited staff and the well-known challenges regarding the availability of personal protective equipment. These conditions limit the ability to implement glucose monitoring and intravenous administration of insulin and fluids. Despite these challenges, it seems prudent to target blood glucose levels below 10 mmol/L or 180 mg/dL as in most hospitalized patients with diabetes. Clinical studies to demonstrate this strategy is in fact conducive to better patient outcomes in the setting of COVID-19 are needed. Insulin therapy is the preferred strategy to improve glycemic control in hospitalized patients, and reducing the risk for ketoacidosis and hypoglycemia is a core goal. Insulin schemes either using subcutaneous basal-bolus therapy or intravenous continuous infusion can be used. Insulin doses may be higher than usual due to augmented insulin resistance in these patients. In light of a possible mortality benefit from the glucocorticoid dexamethasone in those with respiratory failure due to COVID-19 57 , the adoption of specific insulin strategies to address steroid-induced hyperglycemia is also needed. 58 Oral anti-diabetes medications can be used in mild COVID-19 cases without severe hyperglycemia as long as they are not contraindicated. As previously stated, there is insufficient evidence to specifically recommend DPP-4I for the treatment of diabetes in the setting of COVID-19. While metformin and SGLT-2I may have a beneficial effect in heart failure, and epidemiologic studies suggest a possible survival advantage among those treated with metformin 59 , these medications need to be tested in randomized clinical trials in the setting of COVID-19 before making any formal recommendations. Furthermore, clinicians should be very cautious about the risk of lactic acidosis or ketoacidosis in patients who are severely ill and not eating or hydrating themselves well while on these medications. Dehydration could also impose J o u r n a l P r e -p r o o f could interfere with ACE2 to decrease its breakdown, which in turn would facilitate the penetration of SARS-CoV2 into host cells. 60 However, the clinical implication is highly questionable to the point that several international organizations have made a very clear statement that providers should encourage patients to continue to use these medications if needed. 61, 62 Tracking blood glucose levels in hospitalized patients is key to achieving effective diabetes control. Until the epidemic hit, hospital continuous glucose monitoring (CGM) had not been approved by the U.S. Food and Drug Administration (FDA). Insufficient data as well as concerns about subcutaneous blood flow and the lag between true blood glucose and subcutaneous interstitial fluid glucose precluded its approval. However, further data supporting a reasonable correlation between CGM and a point-of-care blood glucose testing in non-ICU patients, 63 and between flash glucose monitoring and capillary blood glucose testing in hospitalized patients, 64 along with the urgent need to better manage patients with diabetes and COVID-19, prompted the FDA to grant approval for the use of CGM systems in the hospital. Adoption of CGM for inpatient use requires careful consideration and expertise, and more guidance would be beneficial for hospital-based clinicians. 58 The COVID-19 and diabetes pandemics have imposed an unprecedented challenge on the lives of millions of people around the world. Improving diabetes control in the outpatient setting at We have the obligation as health care professionals to raise awareness and address to the best of our abilities all social determinants of health that clearly increase the risk of diabetes, COVID-19 and many other health threats. We also have the opportunity to improve the lives of PLWD beyond the COVID-19 era by addressing patients as a whole, beyond the usual biomedical model. 65 The management of chronic diseases like diabetes has long been an enormous challenge. The current model of health care based on patients receiving services at clinics and hospitals has been effective for many but not all PLWD. The -forced‖ used of telemedicine or virtual care during this pandemic has been beneficial to many PLWD and other chronic conditions. Although it is clear that this option of care is not available to most people around the world, exploring how to improve the communication between providers and patients and families at home, in their own communities facing day to day challenges, may prove to be a more effective approach to managing the disease well beyond the COVID pandemic. Indeed, rather than going back to the pre-COVID-19 diabetes care model, we should take advantage of what we are learning and innovating during this time to improve diabetes care strategies in the post-COVID-19 era. In addition, this experience will help us be better prepared for future disasters (Figure 4 ). J o u r n a l P r e -p r o o f Finally, we recognize that as we all continue to learn about COVID-19 and its consequences, sharing our collective experience is critical to the ultimate goal of developing evidence-based recommendations to better guide the management of diabetes during this challenging time and beyond. J o u r n a l P r e -p r o o f Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical characteristics of coronavirus disease 2019 in China Clinical characteristics and outcomes of patients with severe covid-19 with diabetes Prognostic factors in patients with diabetes hospitalized for COVID-19: Findings from the CORONADO study and other recent reports COVID-19 and endocrine diseases. A statement from the Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations Predicting mortality due to SARS-CoV-2: a mechanistic score relating obesity and diabetes to COVID-19 outcomes in Diabetes and COVID-19: more than the sum of two morbidities Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome Covid-19: Black people and other minorities are hardest hit in US Is ethnicity linked to incidence or outcomes of COVID-19? Disparities in the population at risk of severe illness from COVID-19 by race/ethnicity and income Chinese Center for Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China Expert recommendations for diabetes management in primary care during the COVID-19 pandemic Guidance on diabetes management in the elderly during the COVID-19 pandemic Recommendations on insulin treatment in diabetes patients affected with COVID-19 COVID-19 weekly surveillance report: data for the week of 8 -14 World Health Organization. Coronavirus disease (COVID-2019) situation reports Clinical considerations for patients with diabetes in times of COVID-19 epidemic Estimation of effects of nationwide lockdown for containing coronavirus infection on worsening of glycosylated haemoglobin and increase in diabetes-related complications: a simulation model using multivariate regression analysis Increase in the risk for type 2 diabetes due to lockdown for COVID19 pandemic in India: a cohort analysis Telemedicine for diabetes care in India during COVID19 pandemic and national lockdown period: guidelines for physicians Roadblock in application of telemedicine for diabetes management in India during COVID19 pandemic The links between COVID-19 and diabetes, known and unknown Diabetes during the COVID-19 pandemic: a global call to reconnect with patients and emphasize lifestyle changes and optimise glycemic and blood pressure control COVID-19 pandemic and challenges for socio-economic issues, healthcare and National Health Programs in India Clinical characteristics of Coronavirus Disease 2019 (COVID-19) patients in Kuwait The prevalence of pre-diabetes and diabetes in the Kuwaiti adult population in 2014 Diabetes and Ramadan: practical guidelines International Diabetes Federation E-library. Diabetes and Ramadan: practical guidelines Available at: www.diabetesatlas.org/en The Hurricane Katrina aftermath and its impact on diabetes care: observations from "ground zero": lessons in disaster preparedness of people with diabetes Impact of a natural disaster on diabetes: exacerbation of disparities and long-term consequences American Diabetes Association statement on emergency and disaster preparedness: a report of the Disaster Response Task Force Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes Outcomes in patients with hyperglycemia affected by Covid-19: can we do more on glycemic control? Diabetes Care Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS Why is hyperglycemia worsening COVID-19 and its prognosis? Diabetes Obes Metab Coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications New-onset diabetes in Covid-19 Hyperglycemia and the worse prognosis of COVID-19. Why a fast blood glucose control should be mandatory Diabetes and Cardiovascular Disease (D&CVD) Issues of cardiovascular risk management in people with diabetes in the COVID-19 era COVID-19 and diabetes management: What should be considered? Practical recommendations for the management of diabetes in patients with COVID-19 Pragmatic Approach to Inpatient Diabetes Management during the COVID-19 Pandemic Metformin Treatment was Associated with with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers Heart Failure Society of America, and American College of Cardiology. Patients taking ACE-i and ARBs who contract COVID-19 should continue treatment, unless otherwise advised by their physician Continuous glucose monitoring in insulin-treated patients in non-ICU settings Implementation of continuous glucose monitoring This work was based on a livestreamed educational conference organized by the Postgraduate Medical Education department at Harvard Medical School and supported by an educational grant from Sanofi. The sponsor had no involvement in the conference content or in the development of this manuscript. We appreciate the assistance provided by Karen J. Kuc, MPH in the compilation and editing of the manuscript. 


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   key: cord-314500-89ovdnxl authors: Dunachie, Susanna; Chamnan, Parinya title: The double burden of diabetes and global infection in low and middle-income countries date: 2018-12-04 journal: Trans R Soc Trop Med Hyg DOI: 10.1093/trstmh/try124 sha: doc_id: 314500 cord_uid: 89ovdnxl Four out of five people in the world with diabetes now live in low- and middle-income countries (LMIC), and the incidence of diabetes is accelerating in poorer communities. Diabetes increases susceptibility to infection and worsens outcomes for some of the world’s major infectious diseases such as tuberculosis, melioidosis and dengue, but the relationship between diabetes and many neglected tropical diseases is yet to be accurately characterised. There is some evidence that chronic viral infections such as hepatitis B and HIV may predispose to the development of type 2 diabetes by chronic inflammatory and immunometabolic mechanisms. Helminth infections such as schistosomiasis may be protective against the development of diabetes, and this finding opens up new territory for discovery of novel therapeutics for the prevention and treatment of diabetes. A greater understanding of the impact of diabetes on risks and outcomes for infections causing significant diseases in LMIC is essential in order to develop vaccines and therapies for the growing number of people with diabetes at risk of infection, and to prioritise research agendas, public health interventions and policy. This review seeks to give an overview of the current international diabetes burden, the evidence for interactions between diabetes and infection, immune mechanisms for the interaction, and potential interventions to tackle the dual burden of diabetes and infection. There are now 336 million people with diabetes living in low-and middle-income countries (LMIC). 1, 2 Diabetes increases susceptibility to infection and worsens outcomes for diseases such as tuberculosis (TB), 3 and the under-recognised tropical disease melioidosis. 4, 5 Current international treatment guidelines for diabetes are based on research conducted in high-income countries focussed on preventing adverse cardiovascular outcomes and early death. There is a lack of evidence upon which to base guidelines for people living in LMIC, where there is an increased burden of infectious diseases compared with high income countries. Diabetes has traditionally been viewed as a 'disease of the wealthy', mostly found among elderly people in developed countries. Now, however, diabetes affects every strata of society, and has become a fast-growing problem in poorer communities. The Global Burden of Disease (GBD) study estimated there were 1.4 million deaths worldwide from diabetes in 2016, 6 representing a 31% increase from 2006. Of the estimated 425 million people with diabetes worldwide, four-fifths currently live in LMIC and increasing numbers of children and young adults have been diagnosed with the disease. 1 This number is projected to increase to 629 million by 2045, and most of the rising burden will occur in LMIC ( Figure 1 ). In addition, diabetes is more likely to be undiagnosed or poorly treated in LMIC. 1 Data from the NCD Risk Factor Collaboration 2 show that agestandardised diabetes prevalence in adults has increased or remained unchanged since 1980 in every country. 2 Importantly, the burden of diabetes has increased faster in LMIC than in high-income countries. 2 This rising prevalence of diabetes in LMIC is believed to be associated with many factors, including ageing populations, urbanisation, cultural and social changes, dietary changes, physical inactivity, changes in diagnostic criteria and screening practices, better treatment and survival, and increasing trends in overweight and obesity. Classification of diabetes Table 1 shows the current classification of diabetes by WHO and the American Diabetes Association (ADA), 7, 8 which includes four clinical and aetiological classes: type 1 diabetes (T1DM), type 2 diabetes (T2DM), gestational diabetes mellitus, and other specific types of diabetes due to other causes. T1DM is caused by an autoimmune reaction which destroys the insulin-producing beta cells in the islets of the pancreas, leading to no or low production of insulin. T2DM is the most common type of diabetes, accounting for approximately 90% of all cases of diabetes worldwide. 1 It is characterised by an inadequate production of insulin and an inability of the body to respond fully to insulin, defined as insulin resistance. It is important to note that assigning a type of diabetes to an individual is often reliant on the circumstances present and additional testing at the time of diagnosis, and that many patients with diabetes do not easily fit into a single class. In LMIC, it is often unknown which type of diabetes a person has, and therefore this review will use the general term 'diabetes', but >90% of patients with diabetes in LMIC are believed to have T2DM. 1 Table 2 summarises the modifiable and non-modifiable risk factors for T2DM, which is a disease caused by a complex interplay between genetic and environmental factors. 9 The rapid increase in the prevalence of diabetes over recent decades suggests that environmental and lifestyle factors might play an increasingly important role in the development of the disease. It is generally recognised that people with diabetes are at increased risk of infection and worse outcomes, 10, 11 including diabetic foot infection, urinary tract infections (especially from Tuberculosis (TB) is a leading cause of disease and death worldwide, with an estimated 9 million cases of TB and 1.2 million deaths in 2017. 6 Diabetes is associated with a threefold increased risk of developing TB, 3 and increased risk of death or treatment failure in TB. 12 The GBD group reported diabetes accounting for 10.6% of the TB mortality in HIV-negative people. 13 In 2017, 790 000 cases of TB were attributable to diabetes, 14 and the absolute numbers of people with TB-diabetes co-morbidity is now similar to people with TB-HIV co-infection. More than half of the world's TB cases occur in five countries, 15 which have significant prevalence rates and total numbers of diabetes cases in adults aged 20-79 years as follows: China (10.9%, 114 million), India (8.8%, 73 million), Indonesia (6.2%, 10 million), Philippines (6.2%, 3.7 million) and Pakistan (6.9%, 7.5 million). 1 There is evidence that the presence of clinical TB disease drives stress hyperglycaemia, impacting on clinical outcomes and response to treatment. 16 As rates of diabetes continue to rise, and the TB epidemic continues, there is a pressing need for bidirectional screening in countries facing the double burden of TB and diabetes. Work in India has shown success at screening newly diagnosed TB cases for diabetes, 17 due to the availability of a simple screening blood test (HbA1c) and the use of existing systems established to screen TB cases for HIV. Screening people with diabetes for TB is more difficult due to the reliance on symptom questionnaires followed by chest xray. A blood test to diagnose TB in this setting is highly desirable, but current interferon gamma release assays (IGRAs) do not have sufficient sensitivity and specificity for this purpose. Diabetes is also associated with higher rates of Mycobacterium leprae. 18, 19 The greatest increased risk for infection in people with diabetes is seen for the grossly under-recognised tropical disease melioidosis, which is caused by the Gram-negative bacterium Burkholderia pseudomallei. People with diabetes have a twelvefold increased risk of melioidosis, and over half of all cases of melioidosis have diabetes. 20 B. pseudomallei is an environmental saprophyte with a predilection for rice paddy fields, and melioidosis is typically seen in adults in middle age and above, often in rice-farming communities. A broad range of clinical presentations are seen, including pneumonia, acute sepsis with bacteraemia, abscess formation in any organ site, chronic subacute disease and latency. 21, 22 Transmission of the bacterium to humans occurs via three routes: inhalational, cutaneous via skin abrasions and ingestion of contaminated drinking water. 23 The disease is commonly diagnosed in Southeast Asia and Northern Australia, but is now known to be present in 45 countries across tropical regions, with an estimated annual 165 000 cases and 89 000 deaths. 24 If rates of diabetes continue to rise as predicted, coupled with an increased reliance on older people for rice farming due to exodus of the younger generation to urban areas, then the burden of melioidosis will also rise. Studies in high-income countries have shown that people with diabetes have high rates of infection from many common bacteria, 25 but some bacterial species are more frequently reported in association with diabetes. Diabetes is an established risk factor for invasive infection with Staphylococcus aureus. 26 S. aureus is the commonest cause of tropical pyomyositis, an infection of skeletal muscle featuring intramuscular abscesses that is commonly seen in tropical regions and can account for 1-4% of acute admissions. 27 Pyomyositis occurs less frequently in temperate zones, where diabetes is a known risk factor. 28, 29 While diabetes has been reported in some case reports of tropical pyomyositis, 30 further research is needed to establish the Box 1. Relationship between diabetes and susceptibility/increased disease severity for significant pathogens in low-and middle-income countries. See text for discussion of evidence. 31 Diabetes was associated with around a threefold increased risk of infection with S. enteritidis following exposure in a US hospital outbreak. 32 People with diabetes have an increased risk of Klebsiella infections, 33 especially Klebsiella liver abscess in Asia. 34, 35 Scrub typhus is a febrile illness caused by the Rickettsial group intracellular pathogen Orientia tsutsugamushi. Around a million cases a year occur in Asia, 36 and it is believed to exist in other tropical regions outside Asia. 37 Diabetes was an independent risk factor for more severe disease in a prospective study of eschar-positive scrub typhus. 38 It remains to be established why diabetes confers much greater susceptibility to, and worse outcomes for some bacteria than to others. Several of the bacteria most closely associated with diabetes, such as M. tuberculosis and B. pseudomallei, are predominantly intracellular bacteria. Impairments in phagocyte function and adaptive T cell immunity in diabetes may contribute to increased susceptibility to intracellular pathogens. Diabetes is associated with antimicrobial resistance (AMR). Diabetes status is associated with increased rates of drug resistance in TB, including multidrug-resistant TB. 39, 40 Besides TB, people with diabetes are over-represented in cohorts with multi-drugresistant infections, 41 but there is a lack of evidence at present of higher rates of AMR in bacterial isolates from people with diabetes compared with isolates from non-diabetics. What is clear is that increasing rates of AMR will have a larger impact on people with diabetes, due to their higher risk of infection and increased need for healthcare exposure and interventions. Dengue causes an estimated 101 million clinical cases per year and 37 800 deaths. 6 An association between diabetes and severe presentations of dengue is now broadly accepted. 42 However, studies are typically retrospective, often small in nature, and use varying definitions of severe dengue. In a metaanalysis of five case-control studies of acute dengue, diabetes was associated with an increased risk of a severe clinical presentation of dengue compared with either asymptomatic infection or non-severe acute dengue, 43 although given the limited data, the authors emphasised this was only suggestive of a link. This finding has been supported by further studies in Malaysia 44 and China. 45 A systematic review 46 to evaluate the contribution of non-communicable diseases (NCDs) to the development of severe dengue identified 16 relevant publications and gives a clear overview of this literature, but given the heterogeneity of the studies the authors concluded that the existing literature was inadequate for meaningful estimation of the impact of diabetes and other NCDs on dengue severity. The following year a Canadian group 47 reported a nearly three-fold higher prevalence of diabetes in 3236 patients in 22 studies with severe dengue than the prevalence of diabetes in 9067 subjects in 13 studies with non-severe dengue. The same analysis found hypertension, heart disease and obesity (conditions interrelated with diabetes) to be significantly more prevalent in severe dengue, and also reported a four-fold increased prevalence of diabetes in severe West Nile fever cases by the same methodology, supporting an earlier study 48 . The authors acknowledge the multiple limitations of this approach, including the heterogeneity of the studies and publication bias for studies included. There is clearly a need for further high-quality epidemiological studies to further define the association. There is some evidence that diabetes is associated with more severe disease in chikungunya disease, 49 but there is a current lack of data for analysing the relationship with Zika virus. Other viral infections may be associated with diabetes. People with diabetes are an at-risk group for clinical illness, disease severity and death from influenza, 50 with a meta-analysis of 234 articles 51 showing diabetes to be a risk factor for death from pandemic influenza (predominantly H1N1), although there was a lack of high-quality cohort studies to demonstrate this in seasonal influenza. It is estimated that 260 million people are chronic carriers of the hepatitis B virus (HBV), 52 and HBV has recently been described as a neglected tropical disease. 53 A number of studies have shown a higher prevalence of HBV in people with diabetes, [54] [55] [56] and people with chronic HBV are reported to have an increased risk of developing diabetes, 57 although this has not been demonstrated to date in sub-Saharan Africa. 58, 59 In addition, diabetes is associated with disease progression of HBV, 60-62 which has also been reported for hepatitis C. 63 Varicella zoster virus (VZV) causes chickenpox as a primary infection which can reactivate as herpes-zoster (shingles), especially in older people. Diabetes is an established risk factor for shingles. 64, 65 Diabetes is considered a risk factor for Middle East Respiratory Syndrome (MERS). A recent systematic review 66 identified 58 published works for analysis, with several reporting diabetes as a risk factor for infection and death, but meta-analysis to quantitate the increased risk of diabetes across the studies was not possible due to the small number of studies addressing this risk factor. People living with HIV (PLHIV) who receive combined antiretroviral therapy (ART) now have excellent long-term survival, but increased rates of metabolic disorders such as impaired glucose tolerance, hyperlipidaemia and body morphological changes (lipodystrophy syndrome) have been reported. 67 Increased rates of insulin resistance in PLHIV could occur due to the proinflammatory effects of chronic viral infection, direct effects of ART, and also indirect effects of ART such as dyslipidaemia and body fat distribution changes. Although studies in high-income Western countries have shown inconsistent results as to whether HIV infection increases the risk of T2DM or merely represents earlier diagnosis in a closely monitored population, 68 there is evidence that HIV increases the risk of diabetes in Asian and African populations. A study in Taiwan suggested PLHIV to be as much as sixfold more likely to develop diabetes than the rest of the population, 69 and a recent Thai study of PLHIV showed diabetes developed at a younger age compared with the general population. 70 Increased rates of diabetes have also been reported in PLHIV in South Africa, 71 Tanzania 72 and Ethiopia. 71 Older ART drugs such as stavudine and zidovudine are known to increase the risk of metabolic syndrome and diabetes, and are used less now, so future studies may not confirm this relationship. Parasitic Malaria remains one of the world's largest causes of mortality from infectious diseases, with an estimated 213 million cases and 720 000 deaths per annum. 6 In 2010, researchers reported a 46% increased risk of malaria in people with diabetes 73 in a case-control study in an urban setting in Ghana. The malaria was predominantly P. falciparum, asymptomatic and diagnosed by PCR. The comparison of probability of malaria infection was made between patients with diabetes (n=675) and a control group (n=791) comprising patients attending hypertension clinics, patients attending other hospital clinics, and hospital staff. The groups were not matched in that the diabetes group were older by a mean of 7.6 years and had a socio-economic profile associated with greater poverty, and the adjusted odds ratio for diabetes as a risk factor for P. falciparum infection was just outside significance in a multivariate analysis adjusting for these parameters (adjusted OR 1.36, 95% CI 0. 98-1.90 ). This report is very interesting, but there have been no further published clinical studies addressing the relationship between diabetes and malaria. If diabetes increases the risk of malaria this would be of huge significance on a global scale. As India is a country with a high burden of both diabetes and P. vivax malaria, 74 one might expect evidence of a relationship between diabetes and vivax malaria to emerge from research in this region. Further prospective studies with well-matched cohorts, and research into the effect on outcomes for people with malaria is needed. Diabetes has been linked to increased risk of cutaneous 75,76 and visceral leishmaniasis, 77 and diabetes and hyperglycaemia were more frequently reported in cardiomyopathy caused by Trypanosoma cruzi (Chagas disease) than in controls. 78 There are a lack of data on the relationship between diabetes and most neglected tropical diseases (reviewed 79 ) and prospective studies of people with diabetes in tropical regions are needed to evaluate this. Some interesting findings have been reported for a lower risk of diabetes following helminth infections including schistosomiasis, strongyloides and filariasis, as reviewed by Berbudi and colleagues. 80 The mechanism for such a protective effect could be by helminth infection inducing a shift towards type 2 (anti-inflammatory) immune responses, and reducing chronic low-grade inflammation. A mouse model 81 demonstrated greater insulin sensitivity following S. mansoni infection in mice fed a high-fat diet, with an increase in type 2 cytokines and the ratio of M2 to M1 macrophages in white adipose tissue. Further research is evaluating whether helminth-derived molecules could be developed as novel therapeutic approaches to diabetes and metabolic syndrome. 82 In addition, a prospective randomised-control trial of helminth eradiation by albendazole therapy in Indonesia 83 is underway evaluating the impact of helminth infections on insulin resistance. The mechanisms by which diabetes confers altered susceptibility to infections are likely to be via multiple effects on the human immune system. People with diabetes have altered skin flora, including increased colonisation with S. aureus. 84 Breaches in the skin's integrity as a physical barrier to infection occur more commonly in diabetes due to the impact of chronic hyperglycaemia on peripheral nerves and vascular supply. Diabetes and its treatment has an impact on the composition of the gut microbiome, 85 and the pivotal role of the gut microbiome in modulating human innate and adaptive responses via pathogen recognition receptor pathways and secretion of immunomodulatory molecules by gut bacteria is now emerging. 86 In vitro, mild hyperglycaemia may favour pathogen growth, and while the contribution of this to human susceptibility to infection is unknown, glycosuria favours urinary tract infections. In addition, hyperglycaemia has a number of immunosuppressive effects, including impairment of neutrophil degranulation, complement activation and phagocytosis. 50 Hyperglycaemia does not, however, appear to be a key mechanism for the increased susceptibility to TB. 87 Diabetes is associated with endothelial dysfunction, oxidative stress and chronic inflammation. 88 In infections like dengue, this may support a shift towards an excessive pro-inflammatory response, leading to the cytokine storm, shock, vasculopathy and coagulopathy that feature in severe dengue. 47 Finally, people with diabetes have higher rates of hospital admissions, 1 which exposes them to hospital-acquired infections and the risk of AMR. There is overlap between the spectrum of pathogens that people with diabetes have, notably increased susceptibility to such as S. aureus and invasive fungi, and the infections seen in chronic granulomatous disease (CGD), 89 which is congenital deficiency in phagocytic function. This suggests impairment of neutrophil and macrophage function in people with diabetes as a key mechanism of susceptibility. This is supported by studies showing impaired neutrophil migration, phagocytosis and intracellular killing in the host response to B. pseudomallei in people with diabetes. 90 However, people with CGD are not known to have increased susceptibility to viral infections, and therefore this impairment of phagocyte function is unlikely to be the only cause of increased susceptibility to infection in diabetes. The literature on humeral responses to infection in people with diabetes does not suggest that poor antibody response is a dominant mechanism for the increased susceptibility to infection seen in diabetes. Most studies support adequate induction of antibodies in response to licenced antibody-inducing vaccines in people with diabetes [91] [92] [93] . Higher antibody responses to influenza vaccine were seen in a US study of elderly people with diabetes compared with elderly non-diabetic people, 94 and antibodies induced by natural exposure to melioidosis were higher in those with diabetes. 95 Such higher responses in diabetes could be due to chronic hyperactivation of the innate immune response in T2DM resulting in polyclonal B-cell stimulation and enhanced antibody production to stimuli. 96 Beyond neutrophil changes, people with diabetes have alterations in the function of several cell types including macrophages, S. Dunachie and P. Chamnan Natural Killer cells, CD4 T cells and CD8 T cells function. 97 T cell responses are known to be important in host defence against intracellular pathogens, with intracellular antigens presented to CD8 T cells via the MHC Class 1 antigen presentation pathway, and digested antigens from both extracellular and intracellular sources presented to CD4 T cells via the MHC Class 2 system. HIV results in reduction of CD4 T cells, and the huge increased risk of TB seen in advanced HIV demonstrates the importance of CD4 cells in defence against TB. There is evidence of impaired antigenspecific T cell responses in people with diabetes in response to early TB 97 , B. pseudomallei 20 and VZV 98 , although in established TB the cellular response appears to be higher in diabetes. 97 In addition, differences in the regulation and orchestration of the immune response are seen in dengue. 99 For further detailed discussion of immune mechanisms, the reader is referred to a number of excellent reviews of immune impairment in diabetes. 97, 100 Overall, diabetes can impair the immune system at a systemic, cellular and molecular level, but it is the alteration of T cell function that is most amenable to boosting with targeted vaccination strategies. Acute infection is known to lead to hyperglycaemia as a consequence of the stress-response activation of the hypothalamicpituitary-adrenal axis to increase secretion of cortisol and other hormones which promote peripheral insulin resistance, alongside alteration of insulin-receptor signalling by pro-inflammatory cytokines (reviewed 101 ). Sepsis-related hyperglycaemia may be a risk factor for future development of T2DM, 101 and stress hyperglycaemia induced by chronic infections such as TB may contribute to the global burden of diabetes. 16 Concerted international efforts to stem the tide of advancing diabetes in LMIC are urgently required. Implementation of evidencebased approaches that are effective at both prevention and early intervention for diabetes are needed. Such approaches require behavioural changes in diet and physical inactivity, raising public awareness of diabetes, and convincing policy-makers and the public alike of the benefits of early diagnosis for disease reversal and management. One of the targets for the UN's Sustainable Development Goal 3 (Good Health and Well-being) is to reduce by one-third premature mortality from NCDs through prevention and treatment by 2030, with action on diabetes essential. Actions include implementation of National Diabetes programmes and extension of health promotion activities. 1 Tackling the interaction between diabetes and infection requires a greater understanding of the immune mechanisms underlying the altered susceptibility to infection seen in diabetes, and knowledge of how therapeutic management of diabetes impacts on risk of infection. It is likely that tight control of hyperglycaemia lowers the risk of infection, although this has yet to be comprehensively demonstrated in prospective studies. Current international treatment guidelines for T2DM are based on research conducted in high-income countries focussed on preventing adverse cardiovascular outcomes and early death. There is a lack of evidence on which to base guidelines for people living in LMIC, and choice of glucose-lowering therapy may impact on infection risk and outcomes. For example, there is emerging evidence for beneficial infection outcomes in people with diabetes taking metformin compared with other therapies, [102] [103] [104] and glyburide/glibenclamide has been associated with anti-inflammatory properties and lower mortality in melioidosis. 105 Vaccination remains the cornerstone in controlling infectious diseases, and people with diabetes are prioritised as a high-risk group for vaccination against a range of pathogens including pneumococcus, influenza and VZV. Development of highly efficacious vaccines against intracellular infections such as TB, melioidosis and leishmaniasis, to which people with diabetes are at greater risk, is an important priority, and progress requires consideration of how to overcome the specific immune impairments seen in diabetes. Characterising the impact of diabetes on protective immunity is particularly important for melioidosis, where more than half of all cases occur in people with diabetes, and cost-effective implementation of a successful vaccine is likely to involve targeting this group. 106 B. pseudomallei therefore represents an exemplar pathogen for defining the immune deficits in diabetes, and how to overcome them. The collision of diabetes and the world's global infections is a highly neglected area. More research to clearly define the epidemiology and illuminate successful interventions needs prioritising. The majority of the evidence for associations between diabetes and specific infections relies on the use of relatively small retrospective case-control studies, and meta-analysis approaches are limited by the heterogeneity of patient-level factors across studies. Diabetes is interrelated with obesity, hypertension and cardiovascular diseases that share similar risk factors and are each linked to adverse disease outcomes, rendering elucidation of the precise contribution of diabetes to excess morbidity and mortality difficult. The causal interaction between diabetes and infection rates and outcomes is also challenging. For some chronic viruses such as HBV and HIV, the association with diabetes may represent increased risk of diabetes by pathogenesis mechanisms resulting in insulin resistance related to chronic inflammation, rather than the other way around. High-quality, large prospective epidemiology studies are needed to quantitate the problem, alongside randomised controlled trials of interventions to define optimal treatment strategies in diabetes. Raising awareness of the interaction of diabetes and infection with policy-makers, and ensuring the engagement of social scientists, health economists and the pharmaceutical industry in developing new strategies to fight this double burden in LMIC is vital. Authors' contributions: SD and PC wrote and reviewed the manuscript together. International Diabetes Federation Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants Diabetes mellitus increases the risk of active tuberculosis: a systematic review of 13 observational studies The epidemiology of melioidosis in Ubon Ratchatani, northeast Thailand Melioidosis epidemiology and risk factors from a prospective whole-population study in northern Australia GBD Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980-2016: a systematic analysis for the Global Burden of Disease Study World Health Organization. Definition and diagnosis of diabetes mellitus and intermediate hyperglycaemia. Geneva: World Health Organization American Diabetes A. 2. 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Parasitic helminths and their beneficial impact on type 1 and type 2 diabetes Chronic helminth infection and helminth-derived egg antigens promote adipose tissue Transactions of the Royal Society of Tropical Medicine and Hygiene M2 macrophages and improve insulin sensitivity in obese mice Schistosoma Infection and Schistosoma-Derived Products Modulate the Immune Responses Associated with Protection against Type 2 Diabetes Helminth infections and type 2 diabetes: a cluster-randomized placebo controlled SUGARSPIN trial in Nangapanda Nasal colonization with Staphylococcus aureus in patients with diabetes mellitus Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota Interactions Between the Microbiota and the Immune System The effect of hyperglycaemia on in vitro cytokine production and macrophage infection with Mycobacterium tuberculosis Cellular and molecular mechanisms of endothelial dysfunction in diabetes Chronic granulomatous disease Human polymorphonuclear neutrophil responses to Burkholderia pseudomallei in healthy and diabetic subjects Effects of Risk Factors on Anti-HBs Development in Hepatitis B Vaccinated and Nonvaccinated Populations Prospective clinical trial of hepatitis B vaccination in adults with and without type-2 diabetes mellitus Safety, humoral and cellmediated immune responses to herpes zoster vaccine in subjects with diabetes mellitus Young and elderly patients with type 2 diabetes have optimal B cell responses to the seasonal influenza vaccine Antibodies in Melioidosis: The Role of the Indirect Hemagglutination Assay in Evaluating Patients and Exposed Populations Elevated B Cell Activation is Associated with Type 2 Diabetes Development in Obese Subjects Immunological mechanisms contributing to the double burden of diabetes and intracellular bacterial infections Comparison of Varicella-Zoster Virus-Specific Immunity of Patients with Diabetes Mellitus and Healthy Individuals Increased Production of Interleukin-4, Interleukin-10, and Granulocyte-Macrophage Colony-Stimulating Factor by Type 2 Diabetes' Mononuclear Cells Infected with Dengue Virus, but Not Increased Intracellular Viral Multiplication The impact of diabetes on the pathogenesis of sepsis Hyperglycemia in sepsis is a risk factor for development of type II diabetes Metformin and other glucoselowering drug initiation and rates of community-based antibiotic use and hospital-treated infections in patients with type 2 diabetes: a Danish nationwide population-based cohort study Metformin as adjunct antituberculosis therapy Metformin Use and Severe Dengue in Diabetic Adults Glyburide Is Antiinflammatory and Associated with Reduced Mortality in Melioidosis Melioidosis vaccines: A systematic review and appraisal of the potential to exploit biodefense vaccines for public health purposes Acknowledgements: None. Ethical approval: Not required. 


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   key: cord-316943-ef3i96bo authors: Sciberras, Justine; Camilleri, Lara Maria; Cuschieri, Sarah title: The burden of type 2 diabetes pre-and during the COVID-19 pandemic – a review date: 2020-10-19 journal: J Diabetes Metab Disord DOI: 10.1007/s40200-020-00656-4 sha: doc_id: 316943 cord_uid: ef3i96bo INTRODUCTION: Diabetes Mellitus is a chronic disease and a global epidemic. It is a known fact that co-morbidities, including Diabetes Mellitus, pose a higher risk of infection by COVID-19. Additionally, the outcomes following infection are far worse than in people without such co-morbities. Factors contributing to the development of type 2 diabetes mellitus (T2DM) have long been established, yet this disease still bestows a substantial global burden. The aim was to provide a comprehensive review of the burden of diabetes pre-COVID-19 and the additional impact sustained by the diabetes population and healthcare systems during the COVID-19 pandemic, while providing recommendations of how this burden can be subsided. METHODOLOGY: Literature searches were carried out on ‘Google Scholar’ and ‘PubMed’ to identify relevant articles for the scope of this review. Information was also collected from reliable sources such as the World Health Organisation and the International Diabetes Federation. RESULTS: T2DM presented with economic, social and health burdens prior to COVID-19 with an significant ‘Disability Adjusted Life Years’ impact. Whilst people with diabetes are more susceptible to COVID-19, enforcing lockdown regulations set by the Public Health department to reduce risk of infection brought about its own challenges to T2DM management. Through recommendations and adapting to new methods of management such as telehealth, these challenges and potential consequences of mismanagement are kept to a minimum whilst safeguarding the healthcare system. CONCLUSION: By understanding the challenges and burdens faced by this population both evident pre-covid and during, targeted healthcare can be provided during the COVID-19 pandemic. Furthermore, implementation of targeted action plans and recommendations ensures the care provided is done in a safe and effective environment. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40200-020-00656-4) contains supplementary material, which is available to authorized users. Diabetes Mellitus is a chronic disease resulting from the reduction in the body's response to insulin production by the pancreas either due to an increase in insulin resistance or due to decreased insulin production [1] . In the past three decades, incidence of diabetes has quadrupled worldwide [2] . Diabetes has also classified as the 7th leading cause of death globally in 2016 [3] . According to the recent data published by the International Diabetes Federation, 463 million adults (20-79 years) suffered from diabetes in 2019. If not adequately controlled, the global diabetes prevalence is expected to increase by approximately 51% in 2045 [4] . The contributing factors for the development of type 2 diabetes (T2DM) can be broadly divided into genetic and environmental factors. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40200-020-00656-4) contains supplementary material, which is available to authorized users. Some specific risk factors include, obesity, smoking, leading a sedentary lifestyle, age and also the presence of Metabolic Syndrome [5, 6] . The pathophysiology and the underlying risk factors have long been established, yet the incidence of diabetes is still on a progressive incline [7] The 2019 coronavirus SARS-COV2 pandemic has further increased the burden on the diabetes population, those at risk of dyglcyaemic changes as well as the healthcare services [8] . The aim of this article was to provide a comprehensive review of the burden of diabetes pre-COVID-19 and the additional impact sustained by the diabetes population and healthcare systems during the COVID-19 pandemic, while providing recommendations of how this burden can be subsided. A literature search was carried out in July 2020 through 'PubMed' and 'Google Scholar' using the keywords 'T2DM', 'COVID-19' and 'Public Health'. Articles were then filtered using several inclusion criteria including; English language, Human studies and Literature type. The latter mainly included Systematic reviews, Meta-Analysis and literature reviews. The authors then filtered the resulting articles by title and abstract and the remaining 65 articles which fitted the aim of this review were thus considered. Additionally, information was also collected from reliable reports such as those of the World Health Organization (WHO) and International Diabetes Federation (IDF). Having an understanding of the impact of T2DM at an individual, community and population level is paramount for public health authorities and policymakers alike. The burden of a disease can be quantified in terms of the quality of life, morbidity, premature mortality, economic and healthcare impact [9] . Public health policies and plans for provision of services all depend on the general population's state of health and comorbid diseases which change over time. Developed in the 1990s, the DALYs metric is used to gauge the total burden of a disease by considering the number of years lost to a disease, premature mortality, or disability. It is also used to compare health and life expectancy globally. Such a calculation gives policy makers a better understanding of the overall duration of life in comparison to duration spent in poor or good health [9] . A global observation of the incline in DALYs across 10 years comparing individuals at different age categories (15-49 years, 50-69 years vs 70+ years) adapted from the Global Burden of Disease website can be seen in Figs. 1, 2 and 3 respectively. [10] . As seen in the graphs, the higher incidence of T2DM at a younger age range is contributing to the increase in DALYs. This will place a strain on healthcare costs and economic healthcare services as well as [10] decreased work productivity and increased likelihood of early retirement or mortality. This will ultimately be a burden on the country's economy. The universal rise in life expectancy has left policy makers questioning whether individuals maintain a good quality of life during these additional years, as reported by the Global Burden of Disease (GBD) Study and illustrated in Figs. 1, 2 and 3. Such evaluations are extremely relevant to decisions involving extension of retirement ages and health care stipulations. Namely to increase efforts for risk prevention of non-communicable diseases such as T2DM from early stage of the disease. Great inequalities between the burden of a disease and healthy life expectancy are present globally irrespective of a country's quintile on the socio-demographic index or between sexes [11] . This implies that quantity is more prevalent than quality of life worldwide. The disabling outcomes of a disease such as T2DM has considerable implications for the health care system plans and disbursements [12] . Economic status and healthcare T2DM presents with economic, social and health burdens not only for the individual but also for families and careers as well as the healthcare system. Additionally, employment is another social factor which is often impacted, leading to further strain on the country's economy [13] . A country's ability to prevent T2DM lies in the presence of an identification and targeting strategy aimed at high risk individuals. This is dependent on the infrastructure and human resources available with a consequential effect on the management plan of the diagnosed individuals [13] . Furthermore, statistical data regarding epidemiology would be essential for health care providers in the identification of the risk factors contributing to T2DM at a country level. This would aid in surveilling, diagnosing, monitoring as well as treating T2DM. In previous studies diabetes was reported to be more common with individuals with high socio-economic status [14] [15] [16] . In contrast, a recent study reported that a higher T2DM prevalence was associated with individuals having a lower socioeconomic status due to limited access to health care and [17] . Moreover, this factor was also observed in low and middle income Asian countries experiencing fast economic advancement [16] . Coronaviruses are enveloped viruses known to cause respiratory infections in humans. Whilst most of these viruses are harmless and cause mild symptoms, a novel virus known as SARS (severe acute respiratory syndrome) -COV 2 as well as COVID-19 emerged in December of 2019, which proved to be more harmful than the previously known coronaviruses [18] . It is now a known fact that co-morbidities such as obesity, diabetes mellitus (DM), hypertension as well as advanced age all increase the chances of being infected with COVID-19 [19] . Additionally, reports from the Centres for Disease Control and Prevention stated that patients with diabetes and metabolic syndrome might be 10 times more likely to die due to COVID-19 [20] . There are several possible mechanisms which can make diabetic patients more susceptible to COVID-19. Some of these mechanisms include; impaired macrophage activity; impaired neutrophil recruitment and cytokine storm. However, the one mechanism which seems to be considered most is the increased viral load due to the virus entering the cells efficiently. In fact, the receptor which this virus uses is the Angiotensin-converting enzyme 2(ACE2) receptor which can be found expressed by various tissues including lungs, kidneys, pancreas and the heart [18, 21] . Firstly, the SARS CoV-2 Spike protein bind to the ACE2 cell surface where the S protein is then primed by the cellular proteases such as TMPRSS1 and furin. Priming involves cleaving the S protein at the S1/S2 domains, allowing the virus to fuse to the cell surface [18] . Virions are then taken up into endosomes where the SARS CoV 2 is cleaved and possibly activated by Cathepsin L [22] . Inside the cell SARS CoV 2 replicates itself whilst ACE catalyzes the conversion of Angiotensin I to Angiotensin II and ACE 2 converts Angiotensin II to Ang 1-7 [23] . Since ACE 2 receptors are also found in the pancreas, the entry of coronavirus in the pancreatic cells may result in acute beta cell dysfunction [21] . Finally this may lead to a state of acute hyperglycaemia which if left uncontrolled predisposes the diabetic individual to a greater risk of infection and also a higher chance of mortality [24, 25] . Certain medications prescribed to diabetic patients such as GLP-1 agonists, Angiotensin Receptor Blockers (ARB's) and Angiotensin converting enzyme inhibitors (ACEI's) are thought to upregulate ACE2 expression [26] . ACEI initially inhibits the Angiotensin converting enzyme (ACE) leading to decreased angiotensin I levels. This possibly causes a negative feedback loop that ultimately upregulates more ACE2 receptor which can now interact with the decreased Angiotensin I substrate available [27, 28] . Additionally, evidence of a 5-fold increase in ACE2 levels with lisinopril and a 3-fold increase in ACE2 levels with losartan was also published [26, 29] . Therefore, due to the ACE 2 receptor being expressed in various tissues as well as due to the upregulation of ACE2 receptor there is thus an increase in potential binding sites for SARS-CoV-2. This mechanism takes place in patients with diabetes and/or hypertension since they usually take ACEI or ARB's. Hence, infection by COVID-19 may be more severe in these patients [30, 31] . Whilst the above mentioned mechanism seems to confirm that ARB's and ACEI's upregulate ACE2 expression, other studies which contradict this have been published. These studies claim that the administration of these medicines is actually beneficial to patients infected with COVID19 [32] [33] [34] [35] . Lack of exercise One of the many mitigation legislations put forward by governments along with public health authorities to contain the spread of COVID-19 was to institute social-distancing restrictions along with the closure of gyms and parks [36] . Furthermore, the population was advised to limit going out of their homes unnecessarily [25, 37] . Exercise has long been established to be an important requisite as part of the diabetes management and prevention plans [38] . Several studies carried out over the years found that lifestyle interventions including 150 min/week of physical activity and diet-induced weight loss of 5-7% reduced the risk of progression from impaired glucose tolerance (IGT) to Type 2 diabetes by 58% [39] [40] [41] . A systematic review and meta-analysis carried out on structured exercise interventions also concluded that structured exercise programs had a statistically and clinically significant beneficial effect on glycaemic control [42, 43] . Consequently, the World Health Organization (WHO) released a guideline called 'Stay Physically Active during Quarantine' which contains possible ways to stay active during COVID-19. The use of online classes and videos were encouraged as were frequent walking breaks around the house [44] . The mandated lockdowns resulted in the limited access to fresh fruit and vegetables. Individuals including those with diabetes might have resorted to the consumption of long shelf-life canned or packaged foods that are typically high in calories and/or fats, with a potential increase in the consumption of carbohydrates [45] [46] [47] . Such food consumption increases the risk of weight gain and impose a higher cardiovascular, thrombotic and respiratory complications [48, 49] . The concurrent presence of obesity within the diabetes population poses additional detrimental effects on the functioning capabilities of the lungs lead to a decrease forced expiratory volume (FEV) and forced vital capacity (FVC) [50] . Additionally, it has been hypothesized that pulmonary lipofibroblasts together with normal adipocytes play a role in the pathogenic response of COVID-19. This is believed to be brought about by the increased expression of the ACE-2 receptors which turns the adipocytes into reservoirs for the virus. Moreover, the adipocytes aid in the transdifferentiation of lipofibroblasts into myofibroblasts leading to pulmonary fibrosis. Consequently, the presence of fibrosis leads to severe outcomes of the COVID-19 infection among the diabetesobese population [51] . A recurrent issue during lockdown appeared to be an increased 'mental stress' and changes in sleeping habits [52] . Anxiety mainly stemmed from contracting the virus, being restricted to the place of residence for a long period of time and also not being able to meet with loved ones [53] . The increased levels of anxiety were reported by more than 80% of the participants from North India who stated that they were worried about COVID-19, out of which 12.5% reported difficulties in sleeping [54] . Another study carried out in China reported that 53.8% of participants sustained a moderate to severe impact on their mental health due to COVID-19 pandemic [55] . Fig. 1 in the supplement material is a guideline released by the National Diabetes Service Scheme (Australia) intended in helping with management of worries and anxiety related to COVID-19 and diabetes [56] . Similarly, The European country of Malta also released a set of recommendations to help the local diabetic population in managing their condition as well as to reduce anxiety related to COVID-19 [57] The National Health Service (NHS) also published 'GUIDANCE FOR: Supporting people with Diabetes during the COVID-19 pandemic' which compiles informative websites that the diabetic population might need to access during these difficult times [58] .Apart from these guidelines, a number of countries including the European country of Malta, set up designated helpline to provide aid to all those experiencing mental health issues including the diabetes population [36, [56] [57] [58] . Whilst COVID-19 and the subsequent stress can be a source of sleep disturbance, one has to also take into account diet; lifestyle and diseases [55] . In fact, shorter sleep duration and unstable sleeping patterns have been linked to obesity and cardiovascular problems [59, 60] . An association was also found between sleep disorders and patients with T2DM, where increased rates of insomnia, excessive sleeping during the day and a more frequent use of sleep medications were reported [61] . These changes in sleeping patterns may be due to the T2DM itself as well as due to complications which come with it such as polyuria and peripheral nephropathy [62] . Lockdown restrictions challenged individuals including those with diabetes with inadequate Vitamin D levels due to low sunlight exposure during this pandemic [25] . Vitamin D deficiency can lead to an increased mortality and morbidity due to COVID-19 [63] Vitamin D supplementation is not only thought to decrease the risk of infection but it is also being suggested as a cure for infection patients [64] Vitamin D has numerous mechanisms through which it decreases the risks of microbial infections and death. These mechanisms can be grouped into three main categories; physical barrier, cellular natural immunity and adaptive immunity [65] . It was observed that infected elderly with diabetes had an elevated fasting blood glucose as opposed to their HbA1C which remained stable [66] . However, during the acute phase of the COVID-19 infection it is essential that strict glucose control is maintained to prevent the occurrence of complications [66, 67] . A number of healthcare recommendations and guidelines have been issued during these unprecedent times by different stakeholders including the Institute for Healthcare Excellence on managing the diabetic population pre-COVID-19 [68] . Examples of these recommendations can be found as part of the supplement material (Supplement Tables 1, 2 Change in healthcare services due to COVID-19 Individuals with diabetes are not always able to self-cafe and modify drug doses, especially those in marginalised and disadvantaged populations as well as elderly deprived of social support. These populations are dependent on health professionals [69] . In such cases, where no designated point of reference is available, managing their own condition can place further psychological stress on the patients, which might have been the case during the COVID-19 lockdown periods. Complications arising from poorly managed blood glucose such as Diabetic Ketoacidosis raises the risk for morbidity and mortality. This will not only put a strain on an individual and the family unit but also on the health care system [70] . Most outpatient services were temporary halted during the pandemic whilst those that continued their services were challenged due to staff reduction as these were deployment to frontline duties or illnesses [36] . Hence, ensuring that delivery of care does not cease during this pandemic was a great feat. Virtual care was a tool employed by many countries in an attempt to continue provision of service whilst also preventing nosocomial exposure to COVID-19. Telehealth was consequently beneficial for countries, such as USA,UK and India, when providing a service in distant locations with shortage of staff [71] [72] [73] . Using such technologies enabled imparted education to individuals with diabetes about changes in insulin dosing as well as general self-care. The ongoing communication empower individuals and allow them to independently manage their condition. Studies carried out prior to the pandemic indicated that virtual communication can successfully lower Hb A1c [74] . Practitioners through telemedicine can further emphasize the importance of controlling glucose levels as well as relate the potentially improved outcomes of COVID-19 if encountered [75] . However, such a tool is not always viable due to limited accessibility, acceptance and knowledge on the use of technology. In fact, some individuals still requested to be seen in the traditional face-to-face setting [76] . Moreover, practitioners in developing countries should always consider financial implications of therapies on an individual. Simple treatment regimens and low-cost therapy should ideally be prescribed especially to underprivileged populations [75] . The guidelines observed in Supplement Fig. 3 have formulated by the British National Health System (NHS) to assess the risk of COVID-19 susceptibility before setting up an outpatient assessment or follow up [77] . Healthcare professionals can potentially encounter clients who are awaiting result or have been confirmed as COVID-19 positive. Hence it is essential to encourage staff to wear PPEs whilst also adhering to recommended sanitisation procedures; especially in aerosol generating practices. Such procedures should also be enforced in hospital routine activities such as waste, food, utensil and laundry handling. Bornstein et al., compiled a list of guidelines for healthcare workers to follow when dealing with diabetic patients in different scenarios. These guidelines can be found in Fig. 2 in the supplementary material [78] . Easy and practical recommendations that were compiled by Wang et al., (2020) that can be relayed to patients are listed in Fig. 3 which can be accessed in the supplement material [77] . The extensive impacts on health revealed by this pandemic has demonstrated the vulnerability of individuals with noncommunicable diseases (NCDs) [79] . A study carried out in Italy showed that 96% of patients that died in hospitals had previous comorbidities, with T2DM being second highest amongst hypertension, malignant tumours, cardiac and respiratory diseases [80] . The link between NCD and COVID-19 mortality has also been made in USA, China and Spain [79, 81, 82] . Measures undertaken for NCDs included quarantine and physical distancing. This could potentially result in poor management of the condition by both the patient -through behavioural risk factors -and the healthcare professional [83] . Rescheduling of routine medical tests and appointments can further hinder management as well as limited access to primary healthcare centres, pharmacies and transport. All these factors will make it tougher to ensure continuity of care. Research from other pandemics indicates that exacerbation of NCDs occurs without proper healthcare management [84] . This is due to stress that is brought about by changes in routine, uncertain economic situations and new regulations which will ultimately raise rates of disability, morbidity and mortality in patients with NCDs [79] . The importance of T2DM management to avoid serious repercussions on health and overall economy is not a new concept. Hence it is important to equip patients with the right knowledge about the current pandemic and its possible effects on their overall health. It is crucial, now more than ever, to ensure that patients have direct contact with a healthcare practitioner to mitigate any queries or concerns that they may have. This will ultimately empower individuals to adhere to recommendations whilst also avoiding extra stressors which may exacerbate hyperglycaemic effects such as kidney failure, amputation, nerve damage and heart disease [85] . T2DM has been a global burden for decades; however, additional burden has been imposed with the onset of COVID-19 pandemic. Consequently, at a global level, healthcare systems as well as the diabetes population were impacted during this pandemic. Mitigation restrictions that were aimed to curb the spread may have imposed a higher burden on the diabetes population. Having an understanding of the different challenges and subsequent burden faced by this vulnerable population will enable healthcare professional, healthcare provision and policy makers to provide targeted action plans. Funding No funding was received to conduct this study. 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