# indx_content

c0: cord-030631-cc79j9j4
c1: Marcus, Benjamin A.
c2: Typ-1-Diabetes: Früherkennung und Ansätze zur Prävention: Update 2020
c3: 2020-08-19
c6: 2249
c7: 109
c8: 38
c9: cord-030631-cc79j9j4.txt
c10: cord-030631-cc79j9j4.txt
c4:
  Die Ergebnisse dieser Untersuchung, die für mehr als die Hälfte der Behandelten eine Verdoppelung der Zeit bis Auch wenn derzeit noch nur davon ausgegangen werden sollte, dass sich für die behandelten Patienten der Beginn der Erkrankung weiter in die Zukunft verschiebt und der Effekt bei einer dauerhaft therapiebedürftigen Erkrankung moderat erscheinen mag, wirkt sich gerade bei Kindern jedes gewonnene klinisch gesunde Jahr noch weit mehr aus als im Erwachsenenalter.

c5:
  auch; auf; children; das; der; des; diabetes; die; mit; prevention; risk; teplizumab; typ-1; type; und; von; werden

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   key: cord-030631-cc79j9j4 authors: Marcus, Benjamin A.; Achenbach, Peter; Ziegler, Anette-Gabriele title: Typ-1-Diabetes: Früherkennung und Ansätze zur Prävention: Update 2020 date: 2020-08-19 journal: Diabetologe DOI: 10.1007/s11428-020-00668-x sha: doc_id: 30631 cord_uid: cc79j9j4 The incidence of type 1 diabetes is increasing, especially in young children. Early diagnosis is possible in the asymptomatic stage of islet autoimmunity. Screening is offered to high-risk families, but also feasible and useful in the general population, in studies such as Fr1da(plus) in Bavaria (Germany). Complications at clinical manifestation can be prevented by early diagnosis. Participation in experimental interventions to delay stage progression is possible. Numerous approaches to secondary prevention are being pursued. Treatment with the monoclonal antibody teplizumab successfully delayed progression to clinical diabetes in patients in stage 2. Infants at high risk for developing type 1 diabetes can be identified by genetic screening. Primary prevention pursues, among others, the goal of preventing the onset of the autoimmune reaction. The POInT trial aims to improve immune tolerance to insulin by oral exposure in high-risk children and to delay or prevent the onset of autoimmunity. Following up on the focus issue “Early detection and preventive treatment of type 1 diabetes” published in this journal in 2018, this article gives an update on selected developments over the past 2 years. Große prospektive Geburtskohorten haben unser Verständnis für die Entstehung des Typ-1-Diabetes und den natürlichen Verlauf dieser chronischen Autoimmunerkrankung entscheidend vorangebracht, und tun dies ist auch weiterhin. Wir kennen die genetischen Faktoren, die das Auftreten der Erkrankung begünstigen. Wir können einen Typ-1-Diabetes heute durch den Nachweis von Inselantikörpern diagnostizieren, lange bevor es zu Veränderungen des Glukosestoffwechsels oder gar zu Symptomen kommt. In einer bahnbrechenden Präventionsstudie konnten die klinische Manifestation bereits um mehrere Jahre hinausgezögert und die Betazellfunktion stabilisiert werden, was auch die Suche nach ei-ner kausalen Therapie befruchten könnte. Das immer bessere Verständnis der komplexen Vorgänge, die zur Fehlleitung des Immunsystems und zur fortschreitenden Zerstörung von Betazellen führen, eröffnet darüber hinaus verschiedene Ansatzpunkte, das Entstehen von Autoimmunität zu verhindern und den Prozess aufzuhalten. Im Themenheft dieser Zeitschrift Früherkennung und präventive Behandlung des Typ-1-Diabetes -Weichenstellungen für die Zukunft [1] vom Juni 2018 wurden diese Bereiche bereits ausführlich dargestellt. In diesem Beitrag sollen als Update ausgewählte neue Ergebnisse und Entwicklungen der letzten 2 Jahre vorgestellt werden. Der Nachweis von gegen unterschiedliche Betazellantigene gerichteten Autoantikörpern im Blut ist der etablierte und derzeit wichtigste Marker für den Autoimmunprozess, der den Typ-1-Diabetes charakterisiert. Es kommt zu einem Untergang der insulinproduzierenden Zellen der Bauchspeicheldrüse durch autoreaktive T-Zellen mit zunächst langsam, dann kurz vor der Manifestation rasch abnehmender Insulinproduktion. Eine gestörte Glukosetoleranz lässt sich erst feststellen, wenn bereits ein Großteil der Betazellen ihrer Funktion nicht mehr nachkommen kann. Die 4 wesentlichen Autoantikörper sind Insulinautoantikörper (IAA), Glutamatdekarboxylaseautoantikörper (GADA), Antikörper ge-gen das insulinomassoziierte Antigen 2 (IA-2A) und Zinktransporter-8-Autoantikörper (ZnT8A). Autoantikörpern markiert das Frühstadium des Typ-1-Diabetes Der Nachweis von 2 oder mehr dieser Autoantikörper beim asymptomatischen Kind ohne gestörten Glukosestoffwechsel ist inzwischen als eines der Frühstadien des Typ-1-Diabetes (Stadium 1) anerkannt. Beim Stadium 2 liegen zudem mäßig erhöhte Nüchternglukosewerte und/oder eine gestörte Glukosetoleranz vor. Der (neu) manifestierte Typ-1-Diabetes nach gültigen klinischen und laborchemischen Kriterien ist das Stadium 3 (. Tab. 1). Anhand In der COVID-19-Pandemie leistet die Fr1da plus -Studie einen über die Typ-1-Diabetes-Früherkennung hinausgehenden Beitrag zur epidemiologischen Forschung. Mit einem von italienischen Wissenschaftlern entwickelten, nichtkommerziellen Verfahren werden die Kapillarblutproben auch auf IgG-Antikörper (IgG: Immunglobulin G) gegen die Rezeptorbindungsdomäne des S-Proteins von SARS-CoV-2 ("severe acute respiratory syndrome coronavirus 2") untersucht. Der Luciferaseimmunopräzipitationstest (LIPS) funktioniert nach einem ähnlichen Prinzip wie der Nachweis von IAA [19] . Dabei wird auch auf anonymisierte Fr1da-Proben seit August 2019 zurückgegriffen. So kann die Immunitätslage von Kindern im stark betroffenen Bayern vor und im gesamten Verlauf der Pandemie ermittelt werden [13] . The incidence of type 1 diabetes is increasing, especially in young children. Early diagnosis is possible in the asymptomatic stage of islet autoimmunity. Screening is offered to highrisk families, but also feasible and useful in the general population, in studies such as Fr1da plus in Bavaria (Germany). Complications at clinical manifestation can be prevented by early diagnosis. Participation in experimental interventions to delay stage progression is possible. Numerous approaches to secondary prevention are being pursued. Treatment with the monoclonal antibody teplizumab successfully delayed progression to clinical diabetes in patients in stage 2. Infants at high risk for developing type 1 diabetes can be identified by genetic screening. Primary prevention pursues, among others, the goal of preventing the onset of the autoimmune reaction. The POInT trial aims to improve immune tolerance to insulin by oral exposure in high-risk children and to delay or prevent the onset of autoimmunity. Following up on the focus issue "Early detection and preventive treatment of type 1 diabetes" published in this journal in 2018, this article gives an update on selected developments over the past 2 years. Um zu prüfen, ob Teplizumab die klinische Manifestation verhindern kann, wurden in einer TrialNet-Studie Angehörige von Personen mit Typ-1-Diabetes behandelt, die selbst bereits ein Frühstadium mit multiplen Inselautoantikörpern und eine Dysglykämie oder gestörte Glukosetoleranz (Stadium 2) entwickelt hatten. Die Ergebnisse dieser Untersuchung, die für mehr als die Hälfte der Behandelten eine Verdoppelung der Zeit bis zur klinischen Erkrankung auf 4 Jahre ergaben, wurden im New England Journal of Medicine (NEJM) publiziert [14] . Somit konnte erstmals die Manifestation der Erkrankung wirksam hinausgezögert werden, was einen Durchbruch für die präventive Therapie des Typ-1-Diabetes darstellt. In die doppelblinde, randomisierte und plazebokontrollierte Phase-2-Studie wurden 76 Verwandte von Patienten mit Typ-1-Diabetes, 2 oder mehr Autoantikörpern und Dysglykämie eingeschlossen, mehrheitlich Kinder ab 8 Jahren und Jugendliche. Sie erhielten 2 Wochen lang 1-mal täglich Infusionen mit Teplizumab oder Kochsalz. Im Followup erfolgten mindestens halbjährlich Glukosetoleranztests, die Nachbeobachtungszeit betrug im Median etwas über 2 Jahre, 75 % der Probanden konnten über mehr als 3 Jahre nachverfolgt werden. Bei 19 (43%) der 44 mit Teplizumab behandelten Teilnehmenden und 23 (72 %) von 32 in der Plazebogruppe wurde ein klinischer Typ-1-Diabetes diagnostiziert. Im ersten Jahr nach der Behandlung war der Effekt besonders ausgeprägt: Hier manifestierte sich die Erkrankung nur bei 3 (7 %) Teilneh-mern in der Teplizumab-vs. 14 (44 %) in der Plazebogruppe. Jährlich erkrankten 14,9 % Auf den diesjährigen "Scientific Sessions" der "American Diabetes Association" (ADA) wurden Daten aus dem erweiterten Follow-up der Studie vorgestellt -und bei der medianen Hinauszögerung noch ein weiteres, 3., Jahr hinzugefügt. Zudem war Teplizumab in der Lage, den C-Peptid-Abfall nach Manifestation nicht nur zu bremsen, sondern signifikant umzukehren. Dies könnte bedeuten, dass nicht nur die Zerstörung der Betazellen gestoppt, sondern auch die Insulinproduktion in dysfunktionalen Zellen teilweise wiederhergestellt wurde [26] . Auch wenn derzeit noch "nur" davon ausgegangen werden sollte, dass sich für die behandelten Patienten der Beginn der Erkrankung weiter in die Zukunft verschiebt und der Effekt bei einer dauerhaft therapiebedürftigen Erkrankung moderat erscheinen mag, wirkt sich gerade bei Kindern jedes gewonnene klinisch gesunde Jahr noch weit mehr aus als im Erwachsenenalter. Für eine individualisierte Sekundärprävention interessant wird die Tatsache, dass anhand von Biomarkern -HLA-Merkmalen (HLA: humanes Leukozytenantigen) und dem Fehlen von ZnT8A -abgeschätzt werden kann, bei welchen Patienten ein Ansprechen auf die Anti-CD3-Behandlung bessere Erfolgschancen hat [28] . Inzwischen wurden mehr als 60 Genloci identifiziert, die in unterschiedlichem Ausmaß für das Entstehen eines Typ-1-Diabetes prädisponieren. Die meisten davon sind mit der Immunantwort so-wie der Entwicklung und dem Erhalt von Toleranz gegenüber Antigenen assoziiert [4] . Die genetische Empfänglichkeitalleinführtaberwahrscheinlichnicht zum Entstehen der Inselautoimmunität. Es wird angenommen, dass Umweltfaktoren, die auf eine genetische Prädisposition treffen, entscheidend mit zur Initiierung des Autoimmunprozesses beitragen. Dabei liegt es nahe, dass dem frühen Säuglingsalter, in dem dieser Prozess noch nicht in Gang gekommen ist, eine besondere Bedeutung zukommt [23] . Nichtpharmakologische Interventionen zielen auf die Zusammensetzung der Ernährung und ggf. gezielte Supplementationen ab, auch das Darmmikrobiom rückt immer mehr in den Fokus [33] . In der interventionellen Präventionsstudie BABYDIET wurde gezeigt , dass -obwohl die zu frühe Einführung von Gluten mit der Beikost, vor dem 3. Lebensmonat, mit einem höheren Risiko einhergeht -eine darüber hinausgehende glutenfreie Ernährung das Entstehen der Inselautoimmunität nicht verhindert. Auch durch Elimination anderer potenziell antigener Proteine durch die Verwendung stark hydrolysierter Säuglingsmilch konnte in der prospektiven TRIGR-Studie die Diabetesinzidenz nicht gesenkt werden [16, 18] . Es lassen sich weiterhin keine über die allgemeingültigen Empfehlungen zu einer gesunden Säuglingsernährung hinausgehenden Ernährungsmaßnahmen zur Senkung des Typ-1-Diabetes-Risikos ableiten. Die Identifikation von Neugeborenen und Säuglingen mit einem hohen genetischen Typ-1-Diabetes-Risiko ist heute einfach und kostengünstig möglich, sodass sie auch in bevölkerungsweiten Studien angeboten werden kann. Die "Global Platform for the Prevention of Autoimmune Diabetes" (GPPAD), ein Netzwerk kooperierender Wissenschaftler und Institutionen [37] , führt dies seit 2017 regional in 5 europäischen Ländern durch. In Deutschland wird das Virusinfekte werden mit dem Typ-1-Diabetes in Verbindung gebracht, insbesondere virale Atemwegsinfekte in der frühen Kindheit und Infektionen mit Enteroviren und Durchfallerregern. Hier könnten zukünftig entsprechende Impfungen, z. B. gegen Coxsackie-Viren [31] , oder antivirale Therapien zur Senkung des Erkrankungsrisikos beitragen [10] . Dervorfast15 Jahreneingeführten Rotavirenimpfung wird ein kürzlich festgestellter geringer Rückgang der Diabetesinzidenz bei vollständig geimpften Kindern zugeschrieben. Hinweise hierzu lieferten retrospektive Auswertungen aus Australien und den USA [24, 27] , wobei die Ergebnisse einer weiteren amerikanischen Analyse dies zuletzt wieder in Frage stellten [11] . Zumindest lässt sich sicher sagen, dass auch die Rotavirenimpfungso wie alle anderen empfohlenen Schutzimpfungen -sich keinesfalls negativ auf das Typ-1-Diabetes-Risiko auswirkt. Die erstmalige, wirksame Verzögerung der Manifestation mit Teplizumab allein ist schon bemerkenswert [32] , die mögliche Reaktivierung zuvor nicht sezernierender Betazellen könnte auch die Entwicklung kausaler Therapien mit vorantreiben. In größeren Studien mit mehreren Behandlungszyklen und in der weite-ren langfristigen Nachbeobachtung der Studienpatienten wird das Potenzial der Substanz weiter untersucht werden. Die Kombination mit anderen, schon im frühen Stadium 3 in klinischen Studien eingesetzten, vielversprechenden und verträglichen Immunmodulatoren wie z. B. Abatacept oder niedrig dosiertem Antithymozytenglobulin, die an anderen Stellen der Pathogenese des Typ-1-Diabetes angreifen [5, 9] , sowie mit weiteren aufkommenden betazellregenerativen Therapien wird bereits geplant. Studien zur Früherkennung stoßen bei Eltern auf Zuspruch, und auch Familien, die bisher nicht von Typ-1-Diabetes betroffen waren, sind am Angebot primärer und sekundärer Präventionsstudien sehr interessiert. Die Möglichkeit, Komplikationen bei der Manifestation zu verhindern und erste Erfolge in der medikamentösen Sekundärprävention werden die schon länger geführte Debatte um eine Verstetigung und Ausweitung von Typ-1-Diabetes-Früherkennungsuntersuchungen, z. B. als zusätzliches Angebot bei den gesetzlichen Vorsorgeuntersuchungen, sicher befruchten [22] . Früherkennung und präventive Behandlung des Typ-1-Diabetes Typ-1-Diabetes im asymptomatischen Frühstadium Classification and diagnosis of diabetes: standards of medical care in diabetes-2020 Type 1 diabetes The challenge of modulating β-cell autoimmunity in type 1 diabetes Type 1 diabetes trialnet: a multifaceted approach to bringing disease-modifying therapy to clinical use in type 1 diabetes Predicting type 1 diabetes using biomarkers Birth and coming of age of islet autoantibodies A future for CD3 antibodies in immunotherapy of type 1 diabetes Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes Association betweenRotavirusvaccinationandtype1diabetes in children Teplizumab preserves C-peptide in recent-onset type 1 diabetes: two-year results from the randomized, placebo-controlled Protégé trial Etablierte Früherkennungsstudie zu Typ-1-Diabetes testet nun Tausende Kinder auch auf Antikörper gegen SARS-CoV-2 An anti-CD3 antibody, teplizumab, in relatives at risk for type 1 diabetes Landmark models to define the age-adjusted risk of developing stage 1 type 1 diabetes across childhood and adolescence Prevention strategies for type 1 diabetes: a story of promising efforts and unmet expectations Recruiting young pre-symptomatic children for a clinical trial in type 1 diabetes: Insights from the Fr1da insulin intervention study Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial Ketoacidosis at onset of type 1 diabetes in children up to 14 years of age and the changes over a period of 18 years in Saxony, Eastern-Germany: A population based register study Immunological biomarkers for the development and progression of type 1 diabetes Screening for type 1 diabetes: are we nearly there yet? Type 1 diabetes-early life origins and changing epidemiology Association of rotavirus vaccination with the incidence of type 1 diabetes in children Treatment of type 1 diabetes with teplizumab: clinical and immunological followup after 7 years from diagnosis Provention bio's teplizumab continued to significantly delay the onset of insulin-dependenttype1diabetes(T1D)inpresymptomatic patients Lower incidence rate of type 1 diabetes after receipt of the rotavirus vaccine in the United States Traveling down the long road to type 1 diabetes mellitus prevention Who is enrolling? The path to monitoring in type 1 diabetestrialnet'spathwaytoprevention Continuous glucose monitoring predicts progression to diabetes in autoantibody positive children A hexavalent coxsackievirus B vaccine is highly immunogenic and has a strong protective capacity in mice and nonhuman primates Delaying diabetes onset The human gut microbiome in early-onset type 1 diabetes from the TEDDY study Früherkennung des Typ-1-Diabetes in der Fr1da-Studie Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results Why is the presence of autoantibodies against GAD associated with a relatively slow progression to clinical diabetes? Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol Yield of a public health screening of children for islet autoantibodies in Bavaria 


c0: cord-254494-wbfgrez1
c1: Shi, Chunhong
c3: 2020-10-14
c6: 5755
c7: 255
c8: 39
c9: cord-254494-wbfgrez1.txt
c10: cord-254494-wbfgrez1.txt
c2:
  Barriers to Self-Management of Type 2 Diabetes During COVID-19 Medical Isolation: A Qualitative Study

c4:
  The purpose of this study was to explore perceived barriers among type 2 diabetes patients during isolation following their recovery from COVID-19. Perceived barriers to diabetes self-management described by diabetes patients indicated a lack of environmental resources and support strategies to meet their needs.

c5:
  barriers; blood; covid-19; diabetes; isolation; management; participants; patients; self; study; support

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   key: cord-254494-wbfgrez1 authors: Shi, Chunhong; Zhu, Haili; Liu, Jun; Zhou, Jian; Tang, Weihong title: Barriers to Self-Management of Type 2 Diabetes During COVID-19 Medical Isolation: A Qualitative Study date: 2020-10-14 journal: Diabetes Metab Syndr Obes DOI: 10.2147/dmso.s268481 sha: doc_id: 254494 cord_uid: wbfgrez1 PURPOSE: Diabetes self-management behaviors are necessary to obtain optimum glycemic control, reduce the risk of complications, and improve health outcomes. The COVID-19 pandemic imposes an additional struggle for self-management by diabetes patients. Although previous studies have reported socio-demographic, behavioral, psychological, and cultural barriers to diabetes self-management, little is known about perceived barriers to diabetes self-management among patients during isolation following their recovery from COVID-19. The purpose of this study was to explore perceived barriers among type 2 diabetes patients during isolation following their recovery from COVID-19. PATIENTS AND METHODS: A qualitative, exploratory, and descriptive research design was utilized. Semi-structured telephonic interviews were conducted with 12 patients with diabetes who had been discharged from one COVID-19 designated hospital and underwent isolation in the designated facilities in Wuhan City, Hubei Province, China. Data were analyzed using Colaizzi’s seven steps. RESULTS: Barriers to diabetes self-management identified by patients with diabetes during isolation were categorized into five major themes: inadequate knowledge and behavioral beliefs, shortage of resources, suffering from health problems, negative emotions, and lack of support. CONCLUSION: Perceived barriers to diabetes self-management described by diabetes patients indicated a lack of environmental resources and support strategies to meet their needs. Efforts to remove barriers are important in assisting patients with diabetes to improve their quality of life and health outcomes. Coronavirus disease 2019 (COVID- 19) , which was declared a Public Health Emergency of International Concern by the World Health Organization (WHO) on 30 January 2020, has posed a severe threat to global public health. 1,2 Diabetes mellitus (DM) is a common chronic disease in China with a prevalence of 10.4%. 3 Although people of all ages are generally susceptible to COVID-19, patients with diabetes are at higher risk for COVID-19 due to the multiple concomitant chronic diseases and immunosuppression. 4, 5 According to the currently published literature, the prevalence of DM among COVID-19 patients and critically ill COVID-19 patients were 7.4-20.0% [6] [7] [8] [9] and 17%, 10 respectively. The Chinese Center for Disease Control and Prevention (China CDC) has stipulated that COVID-19 patients discharged from hospitals are subject to a 14-day period of isolation and medical observation. 11 As of midnight on August 19, 2020 , the total number of confirmed COVID-19 cases had reached 84,895 in China. 12 These facts indicated that a large number of COVID-19 patients with diabetes underwent isolation after being discharged from hospitals. Patients with diabetes recovering from COVID-19, who experienced the chronic hyperglycemic state and persistent inflammatory states, are at higher risk of COVID-19 reinfection and the occurrence and progression of DM complications. 13 There is a compelling need for this vulnerable population to reduce this risk through good blood sugar control during their isolation. However, ideal blood sugar levels cannot be maintained solely by anti-diabetic medications; 14 good self-management behaviors play a crucial role in DM treatment-especially for those with type 2 diabetes mellitus (T2DM). 15 Self-management refers to long-term, and effective decisions and behaviors, to maintain patients' well-being, which involves medical, behavioral, and emotional management. 16 Positive and effective self-management not only alleviates the progression of DM on physiological indicators but also improves the patients' quality of life. 17 Scholars from Stanford University pioneered the application of the concept and methods of self-management in a community-based diabetes self-management program. 18 These early studies have opened new channels for the prevention, control, and treatment of DM and substantially improved the quality of life of patients with diabetes. 19 Promoting effective diabetes self-management has long been a challenging issue for the health systems, healthcare providers, community workers, and patients with diabetes. 20 Although the data regarding diabetes management for T2DM patients recovering from COVID-19 during isolation remain scarce, notably, previous studies have reported that among Chinese T2DM patients, only 22.76%-40.09% have achieved optimal glycemic control (hemoglobin A1c level<7.0%, 53 mmol/mol) 21-23 and 9.20%-16.43% have manifested good self-management behaviors. 21, 24 This raises the issue of how to identify factors that hinder diabetes selfmanagement and to address these potential barriers. Studies in developed countries such as the United States, Canada, the United Kingdom, and Singapore have found that common barriers to self-management include poor communication between patients and healthcare providers, limited accessibility to healthcare facilities, lack of family support, inadequate disease knowledge and limited disease treatment methods, lack of motivation for change, physical and cognitive disorders, limited access to diabetes education, and financial barriers. [25] [26] [27] [28] [29] [30] [31] [32] Evidently, factors that hinder diabetes self-management are complex and multifaceted. However, the barriers to diabetes self-management for patients with diabetes recovering from COVID-19 during their isolation are not precisely known. To date, a considerable amount of literature on glycemic treatment and control in COVID-19 patients with preexisting DM has been published. 33, 34 Most studies, however, focused on hospital and physician practice, while few studies investigated or mentioned self-management among patients with diabetes during their isolation following recovery from COVID-19. A qualitative study is an ideal design for an in-depth understanding of the feelings and experiences of patients with diabetes. Such studies are of great significance to elucidate the perceived barriers to diabetes self-management among isolated patients. This study addressed a gap in this field by interviewing patients with diabetes subjected to medical isolation after recovering from COVID-19 to gain a deeper understanding of the barriers to diabetes self-management, and provide new perspectives and approaches for the design of interventions and formulation of policies. This study adopted a descriptive qualitative methodology to collect data through telephonic interviews, which provided a rich and thick description of the participants' perceptions of barriers to diabetes self-management. A phenomenological approach was used to achieve an indepth understanding of the factors hindering diabetes selfmanagement from the patient's perspective. 35 Participants were recruited through purposive sampling based on the following inclusion criteria: (1) T2DM patients with a disease duration of greater than 1 year, (2) COVID-19 patients with diabetes after being discharged from the hospital, (3) had stayed at designated isolation sites for at least 7 days, (4) spoke and understood Chinese (Mandarin), and (5) agreed to participate in the study. Patients with type 1 DM or younger than 18 years old were excluded. The primary researchers of this study, who were nurses at a designated COVID-19 hospital in Wuhan City, Hubei Province, China, contacted patients who met the inclusion criteria through the contact information listed on their medical records. The sample size was determined by data saturation-when no new information was obtained during the last two interviews. 36 Variations in age, education level, and duration of diabetes were considered to ensure diversity in the perception of barriers to self-management. We followed the consolidated criteria for reporting qualitative research to report the findings of this study. 37 Semi-structured, in-depth telephonic interviews were conducted from February 20 to March 4, 2020, at a convenient time after dinner (approximately 19:00-20:00 Beijing Time) in a quiet and comfortable environment. Before each telephonic interview, the primary researchers explained the objectives and methods of the study to the participants, promised to perform confidentiality measures, and obtained verbal informed consent from all participants. All interviews were recorded using a cellphone and a recording pen (Newsmy V29, 16 GB internal memory) with the consent of the participants. An interview guide (Table 1 ) was used to conduct the interviews, which consisted of a series of open-ended questions regarding the various aspects of self-management. The interview guide was tested using pre-interviews with two patients of diabetes not included in the actual study, which resulted in corrections of the language and content. During the formal interviews, the interviewees were encouraged to express their thoughts and perceptions thoroughly and probing questions, such as, "Can you please elaborate on this?" were included to increase the depth of the discussion. The nonverbal information (eg, tone of voice, pause) and the important statements stressed by the patients were documented during the interview. Each interview lasted between 15 and 30 minutes. Each audio recording was transcribed by a co-author within 24 hours of the interview and reviewed by another author who interviewed the patients to ensure accuracy of the transcript. The interviews, raw transcripts, and data analysis were conducted in Mandarin Chinese. Data analysis was conducted by two co-authors using Colaizzi's seven-step method 38 to extract themes and sub-themes. The detailed steps were as follows: (1) reading and re-reading raw data transcribed from the audio recordings; (2) marking and extracting significant statements pertaining to the investigated phenomena; (3) coding recurrent important viewpoints; (4) summarizing all coded viewpoints; (5) elaborating and articulating the meanings of the viewpoints; (6) integrating, categorizing, and refining similar viewpoints into themes; and (7) returning the formulated themes to the interviewees for validation. All authors agreed with the data analysis results. To ensure the rigor of the study, the four criteria of dependability, credibility, transferability, and confirmability were In this study, 12 participants were interviewed. Table 2 shows the demographic information of the participants. Barriers to diabetes self-management were categorized into five themes: inadequate knowledge and behavioral beliefs, shortage of resources, suffering from health problems, negative emotions, and lack of support, as indicated in Table 3 . Respondents in the study were found to have poor knowledge, inadequate self-care behavior and low-level beliefs regarding diabetes self-management. The theme "inadequate knowledge and behavioral beliefs" emerged from all discussions that contained three sub-themes, namely, limited diabetes knowledge, confusion about taking medications, and low adherence to self-monitoring of blood glucose. Most participants (n=11) alluded to the fact that inadequate diabetes knowledge challenged their management of blood glucose. They often asked for help from those around them (eg, daughter or father). They had limited knowledge regarding diet management and physical exercise. Some of them even believed that refraining from sweets and carbohydrate-rich foods or insisting on physical exercise alone could achieve good glycemic control. One female patient stated, "My knowledge regarding diabetes has been gained from my daughter, who is a nurse. She told me which foods I can or cannot eat." (P6) Another male participant stated, "My dad also has diabetes. He controls this disease through exercise and obtains good outcomes, so I control my blood glucose by exercising." (P2) A similar view was expressed by another patient, "I know a little about diabetes. I pay little attention to it in daily life and just engage in exercise to control my glucose." (P9) All participants voiced their concerns about medication treatment. More than half of the patients were unfamiliar with the use of hypoglycemic agents. They were confused about taking medications, with most uncertainty involving the names, usage and side effects of the medications, which prevented participants from effectively managing their disease. A female patient expressed unfamiliarity with the usage of hypoglycemic agents: I am worried whether I take too much acarbose. I take two tablets with each meal, and I do not know if it is too much . . . The doctor told me to alternate between metformin and acarbose, which made me confused. (P7) A male patient stated, The hypoglycemic medicines prescribed by the doctor when I was discharged from hospital were different from what I used at home; maybe the effects are the same. I do not know whether these medicines are better or worse than the previous ones, I cannot judge them. (P4) Low Adherence to Self-Monitoring of Blood Glucose Among all patients, only one brought test strips and needles to the isolation site. They paid little attention to blood Most of the isolation facilities were converted from hotels or high school premises at short notice in response to the demand during the COVID-19 pandemic period. The shortage of resources at these facilities was another issue discussed by all patients. This theme consisted of four subthemes: limited space for exercise, unavailability of blood glucose monitoring, absence of a diabetic diet, and undersupply of hypoglycemic medications. At the isolation sites, the participants were largely confined to their rooms because of social distancing policies. All participants described that they exercised daily but could only do so in their rooms or corridors. As a male patient's transcripts showed, Regular blood glucose monitoring is essential for glycemic control in diabetes. Among all interviewees, only one had performed daily blood glucose monitoring; the remaining participants mentioned that they had not monitored their blood glucose at the isolation sites due to the unavailability of blood glucose monitoring. An elderly female patient stated, All participants were concerned with diet, which is a crucial tool for managing T2DM. 40, 41 In particular, 5 participants clearly expressed that the diet provided at the isolation sites was unsuitable for patients with diabetes. As stated by Participant 12, "Many food items at the isolation site contain sugar . . . I have no choice but to avoid food items with sugar . . . There is no diabetic diet." (P12) Another female patient further added, Approximately half of the participants faced issues regarding the shortage of hypoglycemic medications, or medication changes, due to the non-supply of medications at the isolation sites. One participant mentioned, Another female patient stated, "The medicines prescribed by the hospital are not enough, I don't know if they can last till the end of the isolation period" (P8). The participants described that they experienced hyperglycemia, physical discomfort, and insomnia during the mandatory isolation after contracting COVID-19, which discouraged them from self-managing the diabetes and reduced their motivation to self-manage their diabetes. Suffering from health problems is an important obstacle to adherence to self-management behavior. Two thirds of the participants stated that their blood glucose levels increased and became difficult to control after contracting COVID-19. The unsteady blood glucose made them feel frustrated and impeded their self-efficacy in their journey of diabetes management. As described by one participant, The elevation of blood glucose after contracting COVID-19 was also mentioned by another female patient. "After getting COVID-19 . . . My blood glucose was above 20 [mmol/L]. It has never been so high over the last 20-odd years." She continued, "Blood glucose is difficult to control; I can hardly manage it well." (P12) Of note was that half of interviewees still experienced physical discomfort after COVID-19 treatment and hospital discharge such as tiredness, shortness of breath, aches and pains, or a headache. These physical symptoms prompted them to focus on COVID-19 recovery and treatment while ignoring the self-care of diabetes. Another patient also experienced physical discomfort. Nearly half of the participants experienced insomnia at the isolation facilities as they were unaccustomed to their isolation environments, subjected to activity constraints, and engaged in fewer social activities. Insomnia led to their fatigue, poor concentration, and tension during the day and disrupted their diabetes management routine. The following examples demonstrated this experience. High contagious infectivity, potential fatality of COVID-19, loneliness in the isolated room, and difficulties in maintaining blood glucose levels elicited negative emotions in the participants. Three quarters of patients with diabetes expressed unpleasant or unhappy emotions toward COVID-19 and the isolation environment. Such emotions can cloud their judgments and reduce rationality in decision-making on self-management behaviors. Negative emotions as a barrier to self-management, emerging from the transcripts, included three sub-themes: stigma, dissatisfaction, and anxiety. Participants may have perceived stigma for suffering from COVID-19. They feared discrimination from others and avoided full disclosure about their disease to both peers and healthcare workers, thereby influencing the way they view the disease and approach their self-management. A female patient expressed, The isolated patients faced various inconveniences at the isolation sites. Some of them complained about the lack of supplies (especially medications) and expressed dissatisfaction with the living conditions and diets provided at the sites. Dissatisfaction affected their activation of diabetes self-care and discouraged their behaviors toward diabetes self-management. One participant complained, "The isolation site offers nothing just serves for isolation . . . There's no fruit, no medicine . . . There are too many difficulties for us to manage diabetes." (P8) A male participant expressed his dissatisfaction toward the isolation site, This place isn't as good as the hospital, the room is really tiny . . . the (medical) service here (isolation site) isn't so professional compared with the hospital . . . I just try to control my blood sugar by eating less food. (P9) Patients with diabetes often felt stressed and worried about the medication, diabetes supplies, and blood sugar levels. A third of the patients expressed that they were somewhat worried or anxious. This emotional distress often brings about negative consequences for diabetes and further affects their self-management behaviors indirectly. A participant stated, Most patients with diabetes who underwent forced isolation perceived a lack of guidance and support. These patients described their experiences as a struggle to trudge along a difficult path of diabetes self-management, as they were unable to seek help from anyone under the constraints of social isolation. Lack of support as a theme was expressed by most respondents, which had two subthemes: lack of professional guidance, and lack of family support. Most healthcare providers at isolation facilities had been temporarily extracted from various healthcare departments, who might have had little diabetes knowledge and only took responsibility for COVID-19 prevention and education. The participants expressed the view that they felt helpless with regard to managing their diabetes without professional guidance. For instance, a participant stated, "Every morning, [healthcare providers] only ask if we feel comfortable and measure our body temperature . . . blood glucose is not monitored at the isolation site." (P7) Another patient complained that "The doctors here show little concern for us . . . the healthcare providers differ from those at the hospital in terms of professional levels." (P6) The COVID-19 isolation policy prohibits face-to-face visits from family members, which greatly affects the patient's access to family support. In addition, COVID-19 is characterized by familial aggregation, which also reduced the sources and types of family support provided to the participants. As stated by a divorced female participant, During the isolation period, I have made no phone calls to my family and friends . . . my family members are also staying at the isolation sites, so it is too inconvenient . . . Another participant expressed that she could not get actual assistance from her family members as they could only express their concern over the phone, "The concern from my family is of no use . . . sometimes they can't even send things to me because non-staff entering the isolation site is forbidden." (P12) This exploratory and descriptive qualitative study reported the barriers to self-management of T2DM patients who had recovered from COVID-19 during medical isolation. Five major themes were identified: inadequate knowledge and behavioral beliefs, shortage of resources, suffering from health problems, negative emotions, and lack of support. Self-management is essential for prognosis and glycemic control in patients with T2DM. Understanding the barriers to self-management will help patients make changes and better manage their diabetes. Our results showed that limited knowledge regarding DM is a major barrier to diabetes self-management. Participants tended to gain diabetes knowledge from the experiences of people around them. The common assumption was that low educational levels (average below high school) and old age (mean age: 59.75 ±7.93 years) limited their abilities to acquire medical information and seek better healthcare resources. Similarly, studies conducted in Ethiopia 42 and Iraq 43 have indicated that a lack of appropriate information/knowledge hinders self-management among patients with diabetes. A study by Ji et al showed that diabetes knowledge is positively correlated with overall self-management behavior. 23 Specifically, the higher the level of knowledge on diabetes, the better the self-management behavior of patients with diabetes. 44 Additionally, most patients also expressed their confusion about taking medication. Low education and lack of diabetes knowledge might provide a possible explanation for this. Previous studies have indicated that difficulties and frustrations in taking medications prevented diabetes patients from effectively self-managing. 45 In addition, low adherence to self-monitoring of blood glucose posed another barrier to diabetes self-management, which was consistent with the findings of Tewahido et al 42 and Mikhael et al. 43 This is more commonly associated with the patients' economic position, fear of needles, the erroneous belief that blood glucose will remain normal with timely medicating, physical activity, and dietary modifications. A study by Ji et al 21 also demonstrated that blood glucose monitoring was the lowest priority of patients with diabetes when compared to medications, diet, and physical activity. The results of this study emphasized the importance of improving self-management knowledge and behavioral beliefs in patients with diabetes. Efforts directed toward practical and person-centered diabetes selfmanagement education and support programs are necessary to improve patients' knowledge and behavioral beliefs and self-management levels. A shortage of resources was frequently identified as the key factor that inhibited diabetes self-management in this study. Issues such as limited space at the isolation sites, unavailability of blood glucose monitoring resources, absence of a diabetic diet, and undersupply of hypoglycemic medications, were repeatedly mentioned by the participants. For instance, some participants expressed that the standardized diet at the isolation sites led to the inability to perform self-management in accordance with their specified nutrition plans. This finding was consistent with previous findings that residing in a community with limited healthy foods and the absence of safe exercise environments may be an important barrier to diabetes self-care and glycemic control. 46, 47 For all participants in this study, the provision of resources needed for diabetes selfmanagement by the isolation facilities was a significant issue. However, as was widely recognized, the locations used for isolation of COVID-19 patients had a unified layout and lacked the facilities conducive to diabetes selfmanagement. This finding suggests that creating a favorable environment for self-management of chronic diseases at the isolation sites, such as the provision of a diabetic diet and blood glucose monitoring as part of a daily health management program, is extremely important for the improvement of the quality of life and health of patients. Suffering caused by the disease was a great barrier that emerged from the transcripts. This is consistent with the findings of Hu et al, 45 in which patients' physical suffering kept them from properly managing their disease. Moreover, the results of the present study provided additional evidence that COVID-19 may result in elevated blood glucose levels, which was congruent with the findings reported by Ilias et al 48 and Brufsky. 49 Persistently high blood glucose may cause frustration in patients, thereby affecting their passion towards self-management. Five participants in this study stated that they suffered from severe insomnia. In keeping with our findings, Xue et al 50 also reported significant sleep problems (eg, difficulty falling asleep, early awakenings) in the forced isolation population. In addition, poor sleep quality has been found to be significantly associated with decreased adherence to dietary, lower self-care adherence, and poorer diabetes control. 51 Given disease related suffering, it is imperative for healthcare and COVID-19 isolation organizations to develop and implement strategies to deliver continuous care for discharged COVID-19 patients, especially those with diabetes. Negative emotions were discussed as a psychological barrier to self-management. Half of the participants felt stigmatized, which was mainly manifested as societal rejection; one-third complained about poor service at the isolation sites, and one-third expressed anxiety. Although the public health response to COVID-19 has been essential in preventing and containing the epidemic, it may also have aggravated the stigmatization of patients. 52, 53 Forced isolation and the associated measures have disrupted the social lives of patients with diabetes, resulting in them feeling fearful and trapped. Armitage et al 54 reported that social isolation exposes older adults to greater risks of negative emotions such as depression and anxiety. An online study conducted in Italy reported that longer isolation times, combined with smaller physical spaces, led to a deterioration in mental health. 55 Moreover, psychological distress affected the medication adherence and self-management of patients with diabetes. 31 Kato et al 56 found that the nonadherence behaviors of patients with diabetes may be a response to the internalization of stigma. Self-stigma is a negative independent factor that affects the self-care behavior of patients with T2DM. 57 Our results confirmed these findings and suggested that greater emphasis should be placed on the mental health of this vulnerable population, and healthcare and COVID-19 isolation organizations should adopt multifaceted strategies to eliminate potential drivers of negative emotions in isolated patients. This study revealed that the lack of professional guidance from healthcare providers (eg, self-care measures, maintenance of target blood glucose, monitoring of complications) is a common barrier to diabetes selfmanagement. Healthcare providers play a unique role in delivering person-centered diabetes self-management education, supporting interventions, and assisting patients to undertake protective self-care behaviors. 58 Other qualitative studies have reported similar findings whereby patients with limited resources were particularly challenged when seeking medical services or obtaining care and support. 59, 60 Apart from the scarcity of guidance from healthcare providers, the participants also identified the lack of family support as another barrier to diabetes selfmanagement. During the isolation period, it is difficult for diabetes patients to obtain knowledge, care, and material support from their family members, although this support was essential for promoting lifestyle changes and improving self-management behavior in patients with diabetes. 23 Such a result matches the findings of previous studies, which considered family members, friends, and peers of patients with diabetes as primary promoters of selfmanagement. 30, 59, 61 Similarly, quantitative studies have also indicated that a higher level of social support is associated with better adherence to recommended selfmanagement behaviors. [62] [63] [64] In conclusion, there was insufficient support to encourage diabetic selfmanagement of the isolated patients. Such problems may be resolved by establishing electronic blood glucose records and a remote consultation system to provide practicable diabetes self-management education and support, and by enhancing telephonic and internet-based family support. This study had several limitations. First, we obtained data from a small geographical area (Wuhan City) and a small, convenient sample (12 patients with diabetes), which might limit the generalizability of the findings. Second, our analysis was based on interview data. Therefore, it was impossible to explore the differences between the demographic characteristics (such as gender and education level) of the barriers to diabetes selfmanagement. Third, this study explored barriers to diabetes self-management from the patients' perspectives, without considering the experience of healthcare providers and family members. Fourth, qualitative studies have inherent limitations, such as the tendency for subjectivity during data analysis. Future research should collect data from larger samples or adopt a multicenter approach to obtain a broader view of barriers to diabetes self-management. Our findings provide insight into barriers to diabetes selfmanagement among T2DM patients during isolation following recovery from COVID-19. We found that inadequate knowledge and behavioral beliefs, shortage of resources, suffering from health problems, negative emotions, and lack of support were barriers to self-management among patients with diabetes. Understanding these barriers is beneficial for the formulation of targeted strategies, such as creating favorable isolation environments, strengthening medical and social support, and implementing patient-centered diabetes care, to promote successful self-management. At present, as many countries around the world are still in the critical period of pandemic prevention and control, greater concern should be paid to patients with diabetes during isolation. In addition, open dialogue among patients, healthcare providers, family members, and policy makers can be established to better support patients' diabetes journey and improve health outcomes. This study was approved by the Ethics Committee of Hunan Academy of Traditional Chinese Medicine Affiliated Hospital (Approval No.202003-09). We explained the objective, process, and methods of the study to the participants and obtained verbal informed consent prior to each telephonic interview. Participants were assigned anonymous identification numbers (P1, P2, etc), and personally identifiable information was deleted from the transcripts to protect patient privacy. The interview data were kept strictly confidential, and all audio recordings and transcripts were stored in a passwordprotected computer. Interviewees were free to withdraw from the study at any time without any reason. Pneumonia of unknown etiology in Wuhan, China: potential for international spread via commercial air travel Surveillance case definitions for human infection with novel coronavirus (nCoV): interim guidance v1 Guidelines for the prevention and treatment of type 2 diabetes in China Covid-19 and diabetes mellitus: unveiling the interaction of two pandemics COVID-19 pandemic, coronaviruses, and diabetes mellitus Clinical characteristics of coronavirus disease 2019 in China Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan Clinical features of patients infected with 2019 novel coronavirus in Wuhan Prevalence of diabetes mellitus in 2019 novel coronavirus: A meta-analysis Notice on the novel coronavirus pneumonia discharged patients' revisit and reexamination work plan (Trial Implementation) Are people with uncontrolled diabetes mellitus at high risk of reinfections with COVID-19? Prim Care Diabetes Guidelines for the prevention and treatment of type 2 diabetes in China (2013) Effectiveness of self-management training in type 2 diabetes: A systematic review of randomized controlled trials Self-management education: history, definition, outcomes, and mechanisms Technology and diabetes self-management: an integrative review Community-based diabetes self-management education: definition and case study Community-based peer-led diabetes self-management Challenges to developing diabetes self-management skills in a low-income sample in North Carolina, USA. Health Soc Care Community Self-management behaviors and glycemic control in patients with type 2 diabetes mellitus Effects of depression, diabetes distress, diabetes self-efficacy, and diabetes self-management on glycemic control among Chinese population with type 2 diabetes mellitus Selfmanagement behaviors, glycemic control, and metabolic syndrome in type 2 diabetes Characterizing a sample of Chinese patients with type 2 diabetes and selected health outcomes Perceptions of diabetes self-care management among older Singaporeans with type 2 diabetes: A qualitative study Barriers and facilitators to evidence-based care of type 2 diabetes patients: experiences of general practitioners participating to a quality improvement program Factors contributing to attrition behavior in diabetes self-management programs: a mixed method approach Cultural barriers impeding ethnic minority groups from accessing effective diabetes care services: A systematic review of observational studies. Divers Equal Health Care Self-care management programme for older adults with diabetes: an integrative literature review Facilitators and barriers to Type 2 diabetes self-management among rural African American adults Psychosocial factors in medication adherence and diabetes self-management: implications for research and practice Exploring structural barriers to diabetes self-management in Alberta First Nations communities Clinical considerations for patients with diabetes in times of COVID-19 epidemic Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes Qualitative Inquiry and Research Design: Choosing Among Five Approaches Saturation and Run Off: How Many Interviews are Required in Qualitative Research Consolidated criteria for reporting qualitative research (COREQ): a 32-item checklist for interviews and focus groups Psychological Research as the Phenomenologist Views It Naturalistic Inquiry The prevention and control the type-2 diabetes by changing lifestyle and dietary pattern Dietary and nutritional approaches for prevention and management of type 2 diabetes Self-care practices among diabetes patients in Addis Ababa: A qualitative study Self-management knowledge and practice of type 2 diabetes mellitus patients in Baghdad, Iraq: A qualitative study Modelling of diabetes knowledge, attitudes, self-management, and quality of life: A cross-sectional study with an Australian sample Perceptions of barriers in managing diabetes: perspectives of Hispanic immigrant patients and family members Neighborhood social environment and patterns of adherence to oral hypoglycemic agents among patients with type 2 diabetes mellitus Direct and indirect effects of neighborhood factors and self-care on glycemic control in adults with type 2 diabetes Hyperglycemia and the novel Covid-19 infection: possible pathophysiologic mechanisms Hyperglycemia, hydroxychloroquine, and the COVID-19 pandemic Sleep problems and medical isolation during the SARS-CoV-2 outbreak Effect of poor sleep quality and excessive daytime sleepiness on factors associated with diabetes self-management. The Diabetes Educator How Do We Balance Tensions Between COVID-19 Public Health Responses and Stigma Mitigation? Learning from HIV Research Social reaction toward the 2019 novel coronavirus (COVID-19). Social Health and Behavior COVID-19 and the consequences of isolating the elderly Forced social isolation and mental health: A study on 1006 Italians under COVID-19 quarantine A qualitative study on the impact of internalized stigma on type 2 diabetes self-management Association between self-stigma and self-care behaviors in patients with type 2 diabetes: a cross-sectional study Overcoming barriers to self-management: the person-centred diabetes foot behavioural agreement A qualitative exploration of facilitators and barriers for diabetes self-management behaviors among persons with type 2 diabetes from a socially disadvantaged area Are patients with type 2 diabetes not aware or are they unable to practice self-care? A qualitative study in rural South India Theory of planned behavior: social support and diabetes self-management Social support and self-management behaviour among patients with Type 2 diabetes The effect of social support on glycemic control in patients with type 2 diabetes mellitus: the mediating roles of self-efficacy and adherence Association between social support and self-management behaviors among patients with diabetes in community Original research, review, case reports, hypothesis formation, expert opinion and commentaries are all considered for publication. The manuscript management system is completely online and includes a very quick and fair peer-review system We would like to express our gratitude to the Hunan Academy of Traditional Chinese Medicine Affiliated Hospital for the approval and support of this study and all participating patients for providing valuable information regarding barriers to the self-management of DM. Furthermore, we wish to express our gratitude to the Hunan Academy of Traditional Chinese Medicine for providing financial and material support. Finally, we thank our advisors Dr. Chunyan Li and Dr. Yinhua Zhang for their contribution of valuable insights in the process of this study. The authors report no conflicts of interest in this work. 


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c1: Golledge, Jonathan
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  The Potential Role of Sensors, Wearables and Telehealth in the Remote Management of Diabetes-Related Foot Disease

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  Given the established effect of leg ischemia on foot temperature and the exclusion of participants with this problem from prior trials [17] [18] [19] [20] 24] , the role of home foot temperature monitoring in people with PAD remains unclear. Recently, a further clinical trial reported on the efficacy of foot temperature monitoring performed at only monthly intervals at an out-patient clinic, rather than at home [24] .

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  dfd; diabetes; foot; monitoring; patients; people; plantar; pressure; risk; sensors; temperature; trial; ulcers

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   key: cord-260119-pgu2crhs authors: Golledge, Jonathan; Fernando, Malindu; Lazzarini, Peter; Najafi, Bijan; G. Armstrong, David title: The Potential Role of Sensors, Wearables and Telehealth in the Remote Management of Diabetes-Related Foot Disease date: 2020-08-13 journal: Sensors (Basel) DOI: 10.3390/s20164527 sha: doc_id: 260119 cord_uid: pgu2crhs Diabetes-related foot disease (DFD), which includes foot ulcers, infection and gangrene, is a leading cause of the global disability burden. About half of people who develop DFD experience a recurrence within one year. Long-term medical management to reduce the risk of recurrence is therefore important to reduce the global DFD burden. This review describes research assessing the value of sensors, wearables and telehealth in preventing DFD. Sensors and wearables have been developed to monitor foot temperature, plantar pressures, glucose, blood pressure and lipids. The monitoring of these risk factors along with telehealth consultations has promise as a method for remotely managing people who are at risk of DFD. This approach can potentially avoid or reduce the need for face-to-face consultations. Home foot temperature monitoring, continuous glucose monitoring and telehealth consultations are the approaches for which the most highly developed and user-friendly technology has been developed. A number of clinical studies in people at risk of DFD have demonstrated benefits when using one of these remote monitoring methods. Further development and evidence are needed for some of the other approaches, such as home plantar pressure and footwear adherence monitoring. As yet, no composite remote management program incorporating remote monitoring and the management of all the key risk factors for DFD has been developed and implemented. Further research assessing the feasibility and value of combining these remote monitoring approaches as a holistic way of preventing DFD is needed. Diabetes-related foot disease (DFD), including foot ulcers, infection and gangrene, is one of the 10 leading causes of the global disability burden [1] . About 40% of people who develop DFD Hyperten sion Outpatient blood pressure measuremen t Cuff-less blood pressure monitor [13] Better implementation of anti-hypertensive medications and more frequent monitoring Better informed management of blood pressure and reduced progression of macro and microvascular disease and mortality Abnormal gait Not routinely managed Gait and activity monitor [14] Gait retraining and encouraging remote physical activity Reduce gait abnormalities potentially reducing plantar pressures and ulcer incidence Periphera l artery disease Vascular laboratory assessment using ultrasound or Doppler Foot blood supply sensor [15] Earlier identification of complications and prompt medical management . The diagram outlines the key areas for prevention that can be targeted with sensors, wearables and telemedicine. Table 1 . Examples of sensors and wearables with potential value for preventing DFD. Pre-ulcerative lesions Visits to podiatrist Home foot temperature monitor and mobile phone applications [9, 10] Offloading of "hot spots" following confirmed persistent temperature differences Reduced progression of at-risk sites prone to develop foot ulcers Elevated plantar pressures Offloading footwear Plantar pressure monitor [11] Warning systems to stimulate offloading and better design and modification of footwear Improved offloading with reduced ulcer development Elevated plantar pressures and tissue stress Patient education Footwear adherence monitor [11] Behaviour change support counselling informed by objective data Improved offloading adherence Hyperglycaemia Capillary glucose monitoring Continuous glucose monitor [12] Intensive glycaemic control Better informed management of hyper and hypoglycaemia and reduced progression of macro and microvascular disease Hypertension Outpatient blood pressure measurement Cuff-less blood pressure monitor [13] Better implementation of anti-hypertensive medications and more frequent monitoring Better informed management of blood pressure and reduced progression of macro and microvascular disease and mortality Most foot ulcers develop due to repetitive trauma on the feet of people with a loss of protective sensation, such as those with diabetic peripheral neuropathy (DPN) [2] . Recurrent trauma results in local inflammation, or a "hot spot", which can be detected by an elevated temperature at the affected site [16] . This offers a means to identify people who are likely to develop foot ulcers for immediate foot care, such as the removal of calluses and modifications of footwear, to achieve better offloading to reduce this repetitive trauma and in turn the hot spot [2] . Most previous studies have used infra-red thermometers to measure foot temperature at multiple sites on both feet and compare identical sites on opposite feet [17] [18] [19] [20] . Prior research suggests that a temperature difference between identical sites on opposite feet of >2.2 • C (equivalent to~4 • F) on two consecutive days can accurately predict ulcer development [21, 22] . It has recently been reported that the difference between the median of temperature at six key locations on one foot (the hallux, first, third and fifth metatarsal heads, the mid-foot and heel) and ambient temperature is also able to predict foot ulcer development with an excellent sensitivity, although with limited specificity [23] . This potentially allows people with a unilateral foot ulcer and those with prior unilateral major amputation to also be monitored for the hot spots that are predictive of impending ulcers. Given its predictive value, regular foot temperature monitoring offers the opportunity to instigate urgent offloading and foot care, such as callus removal, to prevent an impending foot ulcer. Four randomised controlled trials have examined the efficacy of daily home foot temperature monitoring to signal the need for offloading in people at risk of diabetes-related foot ulcers [17] [18] [19] [20] . Three of these trials [17] [18] [19] , which were performed by the same team and included a total of 427 participants, reported a significant and substantial reduction in foot ulcer incidence in those allocated to home foot temperature monitoring. The other trial [20] , performed by a different research group and including only 41 participants, reported no significant effect of home foot temperature monitoring and urgent offloading on foot ulcer incidence [20] . A larger randomised trial involving 304 participants is currently examining the cost-effectiveness and cost-utility of home foot temperature monitoring [9] . Recently, a further clinical trial reported on the efficacy of foot temperature monitoring performed at only monthly intervals at an out-patient clinic, rather than at home [24] . A thermal camera was employed to identify "hot spots" in order to advise on interventions, such as reductions in physical activity and improved offloading of the concerned area [24] . The trial included 110 people with a past history of a diabetes-related foot ulcers and reported no benefit of the intervention in preventing foot ulcers or improving health-related quality of life [24] . It is possible that these contrasting findings relate to the less-frequent monitoring of foot temperature performed, which may have missed an opportunity for the early identification of at-risk patients. These findings suggest the potential benefit of applying modern technology to regularly monitor foot temperature remotely in the participant's home in contrast to less frequent monitoring in outpatient clinics. The International Working Group on the Diabetic Foot (IWGDF) recently gave only a weak recommendation for the use of home foot temperature monitoring based on the moderate quality of evidence [25] . This likely reflects the small size of prior trials, limitations in the design of the previous trials and the practical difficulties of implementing home foot temperature monitoring. The previous trials testing home foot temperature monitoring [17] [18] [19] have excluded people with peripheral artery disease (PAD), which is an established risk factor for foot ulceration, thereby limiting the generalizability [20] [21] [22] . Both PAD and DPN have been reported to influence foot temperature [23] . In a recent thermal imaging study, participants with PAD had a significantly higher foot temperature than those that did not have PAD [26, 27] . In contrast, previous studies have reported a positive correlation between foot temperature and ankle brachial pressure index, implying that people with PAD have a lower foot temperature [28] . This disparity might relate to whether people with severe PAD are studied or not. Furthermore, prior clinical experience and recent reports of infrared thermography show that foot temperature rises immediately following successful revascularization in correlation with the increase in the ankle brachial pressure index [29] . Given the established effect of leg ischemia on foot temperature and the exclusion of participants with this problem from prior trials [17] [18] [19] [20] 24] , the role of home foot temperature monitoring in people with PAD remains unclear. The ongoing trial of home temperature monitoring detailed above only excludes people with critical limb ischemia (defined as a systolic ankle blood pressure <50 mmHg, systolic toe blood pressure <30 mmHg or transcutaneous oxygen pressure <30 mm Hg) and therefore will better clarify the role of home temperature monitoring in people with milder forms of PAD [9] . Accepting the need for additional evidence for home foot temperature monitoring in larger numbers of people at risk of DFD with broader inclusion criteria, there are also some practical challenges to implementing this preventative approach. Previous trials have required participants to separately measure temperature at 12 locations on their feet using an infrared thermometer daily [9, [17] [18] [19] . Importantly, all trials to date have used the same type of hand-held device, which has been found to be a time-consuming method and may not be feasible for the majority of people with diabetes, such as those that have impaired vision, impaired mobility or who have multiple comorbidities which all have impacts on self-care motivation. There is therefore interest in developing sensors to better automate home foot temperature monitoring to make this measurement much more user-friendly. The most advanced, currently described system for the automated measurement of foot temperature is the Podimetrics Mat [23, 30] . This is a wireless mat that is designed to remotely monitor the temperature of the plantar surface of the foot with minimal involvement from the patient [30] . If the mat is stepped on for a period of about 20 s, it automatically takes a thermogram of both feet. The thermogram accurately measures temperature over the range of 15 to 40 • C and transmits the data securely to an approved server managed by the manufacturer. Foot temperature asymmetry is automatically calculated based on the thermogram. In a prior study of 129 participants with a past history of diabetes-related foot ulcers, a temperature difference of 2.2 • C between common sites on both feet correctly predicted 97% of foot ulcers, with an average lead time of 37 days and a false-positive rate of 57% [30] . Increasing the temperature threshold to 3.2 • C decreased sensitivity to 70% but reduced the false-positive rate to 32%, with approximately the same lead time of 35 days. About 86% of the participants used the system at least 3 days a week. However, this device is not commercially available outside of the United States of America and may also be too expensive for individual use. Other options for remotely monitoring foot temperature include a thermal camera incorporated into a mobile phone, insole devices or optical fiber based smart textiles, such as smart socks or insoles [10, 27, [30] [31] [32] . Smart phone infrared thermal imaging cameras have excellent agreement with more established infrared imaging systems and thus appear suitable for use in clinical practice [33] . These devices may need more development to allow patients to use them easily at home, and the cost of such devices may be a potential limitation. Smart socks have been tested in small numbers of people with DPN and been shown to be able to accurately and repeatedly measure temperature at multiple sites on both feet [31, 32] . However, whether it is feasible to use these regularly over a prolonged follow-up process is not currently clear and remains to be investigated. A large randomised trial of 300 participants with severe DPN is currently evaluating the effectiveness of daily home-based foot temperature measurements using an intelligent sensor-equipped insole combined with photo documentation in preventing foot ulcers [10] . Results from this trial will provide larger-scale evidence on the value of this approach. DPN leads to loss of intrinsic foot muscles and changes in foot shape [2] . These changes can promote areas of high pressure within the plantar surface of the feet during standing or walking [2] . A prior meta-analysis suggests that people with DPN and a history of foot ulcers have higher plantar pressures during walking than those with DPN who have not had an ulcer [32] . The IWGDF guideline strongly recommended that people with a history of foot ulcers use footwear designed to reduce their high plantar pressures [25] . Plantar pressures are traditionally measured in clinical practice using highly designed pressure plates or insoles with pressure sensors located within health care or research facilities [34] . Systems such as the Pedar ® (Novel, Munich, Germany) and F-Scan™ (Tekscan Inc, Boston, MA, USA) are now available that can reproducibly measure plantar pressures within footwear [35] . These systems have been used to confirm that therapeutic footwear is effective at reducing plantar pressures [35] . They are also being extended to measure plantar pressures and other tissue stress on the plantar surface of the feet during everyday activity [36] . Patient access to such systems is limited, however, as they are only available in a small number of research or clinical settings, require specific protocols for obtaining data and are not available for home monitoring [37] . These systems differ in relation to the types of sensors used to measure plantar pressure; for example, some have large capacitive sensors and others have smaller resistive sensors or piezoelectric sensors which are more temperature-sensitive. Therefore, the user should be familiar with the advantages and disadvantages of each system, as this determines the application and the quality of data obtained [36, 38, 39] . Smart insoles, such as the SurroSense Rx system (Orpyx Medical Technologies, Calgary, Alberta), have now been developed that can monitor plantar pressures and provide alerts directly to wearers [40] . This system consists of a pressure-sensing insole that contains eight pressure sensors: three positioned under the metatarsal heads, two under the lateral plantar surface, one under the heel, one under the hallux and one under the lessor toes. The wearer receives an alert when sustained pressure is detected (pressure exceeding 35-50 mmHg and lasting over a 15-min period) and a pressure map of each foot showing the area where pressure is sustained [40] . The alert thresholds are based on the integration of pressure data over time. The correct therapeutic response to the alert is the offloading of the area with sustained pressure within 20 min of detection. In a study of 17 people with a past history of foot ulcers, those receiving a great number of alerts (at least one alert every two hours) wore their offloading for longer and had better adherence in responding to alerts [40] . Most participants felt that the insoles were useful and achieved good performance [40] . In a recent clinical trial [41] , 58 patients with DPN and a recent history of a plantar foot ulcers were studied. They were randomly assigned to either an intervention group that received audio-visual alerts via a smartwatch linked to the SurroSense Rx insole system and offloading instructions when aberrant pressures were detected or a control group that did not receive any alerts. This trial reported a 71% reduction in ulcer incidence in the intervention compared with the control group (incidence rate ratio 0.29, 95% CI, 0.09-0.93; p = 0.037) [41] . However, this trial had a small sample size and a large dropout of 35% during the wearing-in period of the insole system and a further 50% dropout in the intervention group during follow-up [42] . In addition, the pressure feedback system used recorded pressure at a low sample frequency and failed to measure peak pressures. Importantly, 89% of alerts were received during static weight bearing positions and only 11% during walking in the study [42] . Therefore, the usability and ease of implementing this type of device remains to be demonstrated in well-powered clinical trials. Further evidence is needed for the widespread adoption of home plantar pressure monitoring. Therapeutic footwear specifically designed to the shape of the patients' feet and targeted to reduce >25% of peak plantar pressures is an established part of the management of people with DPN [25] . Such footwear is strongly recommended by the IWGDF guideline [25] . However, prior randomised trials of offloading insoles or footwear have shown inconsistent results, with only four of the eight trials reporting a reduction in the incidence of foot ulcers [43] [44] [45] [46] [47] [48] [49] [50] . A likely contributor to the inconsistent results of these trials is the variation in adherence to offloading. In one of the trials, for example, it was reported that custom-made offloading footwear did not significantly reduce foot ulcer incidence [49] ; however, among the 71 participants that adhered to their custom-made offloading footwear for 80% of the time they were weight bearing, there was a significant reduction in the incidence of foot ulcers of 50% compared to the control group [49] . This emphasizes the importance of adherence to wearing offloading footwear in order for it to be effective. In order to facilitate footwear use, accurate and objective data on adherence are needed. Temperature sensors (thermistors) placed inside therapeutic footwear have been used to monitor offloading use [49] . Combining such sensors along with activity monitors allows footwear adherence as a proportion of daily weight-bearing activity to be estimated [49] . A previous study showed that a temperature threshold of 25 • C to indicate that footwear was worn had a sensitivity of 95%, a specificity of 99%, a negative predictive value of 99% and a positive predictive value of 99% in determining footwear use [51] . Past research also demonstrates that these temperature sensors are a valid method of estimating footwear adherence compared to adherence measured using a time-lapse camera [52] . It is anticipated that small sensors will soon become available that can accurately monitor an individual's footwear use and activity and provide "live" data seamlessly to remotely located health practitioners [53] . This objective footwear adherence data may be used to inform remotely delivered motivational interviewing aimed at increasing the frequency of offloading [54] . Further developments are needed before this approach can be implemented in a remote management program. It should be noted that there is a paucity of commercially available sensors for monitoring adherence easily and accurately, and most of the aforementioned sensors have only been used in a research context [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] . The optimal control of glucose, blood pressure and lipids is frequently not well implemented among people that develop DFD [56] . People with DFD have an increased risk of all-cause mortality (relative risk (RR) 1.89, 95% confidence intervals (CI) 1.60, 2.23) and fatal myocardial infarction (RR 2.22, 95% CI 1.09, 4.53) compared to people with diabetes without DFD [57] . In people with a history of diabetes-related foot ulcers, the risk of cardiovascular mortality is about 50% over 10 years and the annual mortality rate is estimated to be about 6% [58] . This emphasizes the importance of optimizing medical management in this population. Glycaemic control is important for preventing both macro and microvascular complications, and a meta-analysis of past randomised trials suggests that intensive glycaemic control prevents amputations [59] . In clinical practice, diabetes management is usually informed by self-monitoring of blood glucose [60] . Wearable or implantable sensors are now available for the continuous monitoring of glucose [60] ; these use enzymatic technology to monitor interstitial fluid rather than blood glucose [61] . These sensors can measure glucose up to every 5 min non-invasively for a period of about one week, after which most devices need to be replaced [56] . Such sensors have been incorporated into closed loop systems which provide automated insulin delivery to people with type 1 diabetes with improvements in glycaemic control [62] . Recent meta-analyses of randomised trials comparing self-monitoring and the continuous automated monitoring of glucose in people with type 2 diabetes suggest that continuous monitoring facilitates better glycaemic control [61, [63] [64] [65] . The use of such devices is now recommended by the North American guidelines for some patients, such as those with poor glycaemic control (HbA1c ≥ 9%) [66] . A recent trial showed that flash glucose monitoring (measuring interstitial fluid glucose) can be implemented in the primary care environment, although it may not be superior to Sensors 2020, 20, 4527 7 of 15 traditional methods as measured by HbA1c at 12 months [12] . The application of continuous glucose monitoring for people with diabetes who are at a high risk of complications such as DFD may have substantial benefits, but access to this technology is currently limited to selected patients due to the current high expense of such monitoring systems. High blood pressure is another important risk factor for complications in people with DFD. Anti-hypertensive medications, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, have been shown to reduce the incidence of cardiovascular events in people at risk of DFD, such as those with PAD [67] . Control of blood pressure is, however, frequently suboptimal in people at risk of DFD [68] . In a recent study of 2773 people with PAD, about 40% had a systolic blood pressure above the target level of 140 mmHg [68] . Currently, blood pressure is monitored through the assessment of pulsation linked with an inflatable cuff placed around the upper arm. Novel cuff-less wearable devices have now been developed for the estimation of blood pressure and may provide a more practical way of repeatedly monitoring blood pressure and facilitating better management [13, 69] . These devices use varying methods, such as pulse transit time, laser Doppler flowmetry and artery vibration, to calculate blood pressure. Some of these devices are available commercially, such as from TMART Technologies Limited, China and Somnomedics, Germany, and some-but not all-have been shown to accurately measure blood pressure in small numbers of people with comparable results to classical cuff-dependent machines and also intra-arterial assessments [69] [70] [71] . The accuracy and value of these devices in improving the medical management of people at risk of DFD need further evaluation. People at risk of DFD also require lipid control. The intensive lowering of low-density lipoprotein has proven efficacy in reducing major adverse cardiovascular and limb events in people at risk of DFD, such as those with PAD and diabetes [4, 72] . Low-density lipoprotein sensors have also been built, although further development and testing is needed before they will be ready for widespread use [73] . Medication non-adherence is often defined as taking less than 80% of the prescribed treatment [74] . Due to a variety of factors including cost and regimen complexity, adherence to diabetes treatment is often poor and is reported to vary from 23% to 77% across differing populations [75, 76] . In order to achieve optimal control of risk factors, it is important that patients adhere to prescribed medications. Sensors have now been developed that are capable of monitoring medication ingestion; for example, Proteus Discover provides data on medication taking and physical activity to both patients and practitioners [77] . It consists of an ingestible sensor, a wearable sensor patch, a patient mobile app and a provider Web portal. After being swallowed, the ingestible sensor is activated and sends a signal with a specific code that is detected by the patch. When the ingestible sensor pill is taken with medication, it can measure medication ingestion adherence. The patch also can measure activity, heart rate and step count. Data from the patch are transmitted to a mobile device to be viewed by the patient and then to the Cloud and onto a Web portal for a practitioner to view. The mobile device app prompts the patient to take their medication doses as scheduled. A previous study suggested that Proteus Discover can improve control of blood pressure, low-density lipoprotein and HbA1c [77] . Such sensors could have a role in people at risk of DFD, but this needs further testing and consultation with patients and other key stakeholders. There is a lack of head-to-head clinical trials comparing the various types of sensors or monitors available for remote medical management described above; more importantly, the control arms in clinical trials of remote monitoring systems have varied substantially. Therefore, there is an ongoing need to assess the suitability of these sensors for optimizing medical management in people at risk of DFD. People with DPN often have an abnormal gait, which likely contributes to high plantar pressures and the risk of foot ulcers [78] . The assessment of gait is complex, but wearables have now been developed that are capable of monitoring it remotely [79] . Such information can be potentially used for the design of a gait retraining program aimed at reducing plantar pressures and risk of ulceration. Artificial intelligence systems, such as the Gait-Enhancing Mechatronic System (GEMS) (Samsung, Seoul, Korea), have also been developed to improve gait and redistribute foot pressure, although their exact role in health care is not currently clear [80] . Other web-based and remotely delivered methods of physical therapy and rehabilitation may provide further ways to improve gait in people with DPN [81] . A clinical trial is currently in progress to test whether a remotely delivered physical therapy program can improve DPN symptoms and severity as well as gait and function [14] . Artificial intelligence has also been applied to the development of a robotic systems for assessing DPN that are potentially able to screen people for their risk of developing DFD [82] . There is a current Cochrane review that is reviewing the evidence of the accuracy of all potential simple tests for screening DPN to supply more comprehensive evidence [83] . There is also interest in the development of sensors to determine foot perfusion [15] ; the vascular early warning system (VEWS), for example, functions by using infrared optical sensors placed on the toe and dorsum of the foot to measure changes in blood volume within the microvasculature during foot elevation [15] . These sensors have not been tested in well-powered randomissed clinical trials or in comparison to standard care [84] . One challenge with assessing these systems in clinical contexts is that standard care can vary substantially between health services, countries and continents; therefore, the role of such systems in delivering preventative medicine remains unanswered but is an exciting future area of research. It is possible that remotely delivered gait rehabilitation programs may reduce the risk of DFD. For people with DFD, treatment and education typically occur in an outpatient clinic weekly or bi-weekly. Although remote monitoring methods for people with DFD using smartphone applications have been developed, these are still in their infancy and have not been widely tested or implemented [85] [86] [87] . Despite their potential application in remote DFD monitoring, the diagnostic accuracy of mobile phone images is reported to be poor and therefore should not be used as a stand-alone diagnostic instrument for DFD [88] . This is a rapidly evolving area; therefore, novel mobile phone applications and remote monitoring methods may improve over time. Telehealth is an established means of performing medical consultations [89] . The benefit of using telehealth for managing foot ulcers has been demonstrated in several meta-analyses and systematic reviews [90] [91] [92] . Most of the evidence comes from two clinical trials [93,94]: the first trial evaluated the effectiveness of a telehealth intervention made up of 2:1 online:standard outpatient consultations compared to a usual care intervention consisting of three standard outpatient clinic visits on ulcer healing in 374 people [93] . The authors reported no significant difference in ulcer healing or amputation between the two methods but did show an increased risk of mortality in the remote monitoring group (HR = 8.68, 95% CI: 6.9-10.88). This was a surprising finding that was not explained by any of the studied covariates [93] . A more recent cluster randomised controlled non-inferiority trial of 182 adults evaluated telehealth [94] . Weekly telemedicine consultations via an interactive Web-based ulcer record and a mobile phone for communication with the healthcare specialist in addition to outpatient clinic visits every 6 weeks was compared to visiting the outpatient clinic every second week [94] . The trial showed no difference in time to ulcer healing and a superiority in prevention against amputation (mean difference: 8.3%, 95% CI: 16.3%, −0.5%) in the intervention group [94] . An important factor to note in these trials was that the intervention arms all included some face-to-face consultations with a health care professional. Based on anecdotal evidence, at present, there appears to be a range of different approaches to telemedicine that are used globally, ranging from mobile phone-based consultations, hospital-based remote management consultations and the phone-based review of patients. However, how such approaches should be designed in line with face-to face care has not been well defined in the literature. There has been limited study of the value of telehealth consultations in preventing rather than treating DFD. The COVID-19 pandemic has provided a stimulus for studies testing the use of remote monitoring technologies and telehealth consultations in preventing DFD [7, 8] (see Table 2 ). Table 2 . Currently available and required evidence for the remote assessment and prevention of diabetes-related foot disease. Home foot temperature monitor A number of small RCTs show a decreased incidence of foot ulcers in people performing home-based temperature monitoring Lack of a widely tested and user-friendly way of identifying "hot spots" Generalizability from prior smaller studies in select populations [9, 10] Plantar pressure monitor Possible to monitor plantar pressure remotely and use patient alarms to warn patients of impending sites of tissue breakdown as reported in one small RCT Unclear if technology can be further developed to be more user-friendly and whether the findings are applicable and would be effective on a widespread basis [11] Footwear adherence monitor Technology has been developed to accurately measure footwear adherence Need for widespread testing of value of using devices Patients' views on use of adherence monitoring is still unclear [11] Continuous glucose monitor Highly developed area of monitoring and tested in multiple RCTs with proven benefit in improving glycaemic control (HbA1c) Whether this remote monitoring improves outcomes in people at risk of developing DFD remains unclear [12] Cuff-less blood pressure monitor Technology developed to assess this reported to be accurate in a small number of studies Currently unclear whether these devices can be used on a widespread scale [13] Foot blood supply and sensation assessment Technology still in the early developmental stages for monitoring The benefit of these devices in improving clinical outcomes need to be further evaluated in RCTs [15, 82] Legend: PAD = peripheral artery disease, RCT = randomised controlled trial, HbA1c = glycated haemoglobin A1c, DFD = diabetes-related foot disease. Sensors, wearables and telehealth approaches capable of remotely monitoring the key risk factors for DFD have been developed. We believe that the utilization of sensors, wearables and telemedicine approaches outlined in this review-and those currently under development-will offer an innovative means to approach the assessment of risk factors in people with DFD. It remains to be seen what broad impact these can have on the prevention of DFD. The COVID-19 pandemic may provide the stimulus for the innovative and pragmatic large-scale testing of a technological approach to preventing DFD in efforts to keep feet safe, intact and at home. The authors declare no conflict of interest. Global Disability Burdens of Diabetes-Related Lower-Extremity Complications in 1990 and Diabetic Foot Ulcers and Their Recurrence Randomized trial of the effects of cholesterol-lowering with simvastatin on peripheral vascular and other major vascular outcomes in 20,536 people with peripheral arterial disease and other high-risk conditions Lipid management in people with peripheral artery disease Prevention of foot ulcers in the at-risk patient with diabetes: A systematic review Major Adverse Limb Events and Mortality in Patients With Peripheral Artery Disease: The COMPASS Trial 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 All Feet On Deck-The Role of Podiatry During the COVID-19 Pandemic: Preventing hospitalizations in an overburdened healthcare system, reducing amputation and death in people with diabetes The cost-effectiveness and cost-utility of at-home infrared temperature monitoring in reducing the incidence of foot ulcer recurrence in patients with diabetes (DIATEMP): Study protocol for a randomized controlled trial Study protocol for a randomized controlled trial to test for preventive effects of diabetic foot ulceration by telemedicine that includes sensor-equipped insoles combined with photo documentation Pressure-Sensing Insoles in the Neuropathic Ulcer Treatment Pathway (PINUP) Use of professional-mode flash glucose monitoring, at 3-month intervals, in adults with type 2 diabetes in general practice (GP-OSMOTIC): A pragmatic, open-label, 12-month, randomised controlled trial Effect of Home Blood Pressure Monitoring via a Smartphone Hypertension Coaching Application or Tracking Application on Adults With Uncontrolled Hypertension: A Randomized Clinical Trial Study protocol for a randomized controlled trial on the effect of the Diabetic Foot Guidance System (SOPeD) for the prevention and treatment of foot musculoskeletal dysfunctions in people with diabetic neuropathy: The FOotCAre (FOCA) trial I Assessment of the Utility of a Vascular Early Warning System Device in the Assessment of Peripheral Arterial Disease in Patients with Diabetes and Incompressible Vessels Infrared dermal thermometry: The foot and ankle stethoscope Skin Temperature Monitoring Reduces the Risk for Diabetic Foot Ulceration in High-risk Patients Home monitoring of foot skin temperatures to prevent ulceration Preventing diabetic foot ulcer recurrence in high-risk patients: Use of temperature monitoring as a self-assessment tool A pilot study testing the feasibility of skin temperature monitoring to reduce recurrent foot ulcers in patients with diabetes-a randomized controlled trial Monitoring neuropathic ulcer healing with infrared dermal thermometry Predicting neuropathic ulceration with infrared dermal thermometry Unilateral remote temperature monitoring to predict future ulceration for the diabetic foot in remission Infrared thermography and ulcer prevention in the high-risk diabetic foot: Data from a single-blind multicentre controlled clinical trial on behalf of the International Working Group on the Diabetic Foot. 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c0: cord-276256-gmlsoo2z
c1: Avilés-Santa, M. Larissa
c3: 2020-10-10
c6: 9707
c7: 307
c8: 30
c9: cord-276256-gmlsoo2z.txt
c10: cord-276256-gmlsoo2z.txt
c2:
  Current State of Diabetes Mellitus Prevalence, Awareness, Treatment, and Control in Latin America: Challenges and Innovative Solutions to Improve Health Outcomes Across the Continent

c4:
  Integrating social determinants of health into diabetes care demonstrated objective improvements in patient knowledge and cardiometabolic parameters [233] . Many interventions on diabetes care have focused on patients and/or clinicians as the primary recipients or enablers of the interventions.

c5:
  america; care; chronic; control; countries; diabetes; diabetes mellitus; disease; factors; health; health care; latam; latin; mellitus; patients; population; prevalence; risk; studies; study; type

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   key: cord-276256-gmlsoo2z authors: Avilés-Santa, M. Larissa; Monroig-Rivera, Alberto; Soto-Soto, Alvin; Lindberg, Nangel M. title: Current State of Diabetes Mellitus Prevalence, Awareness, Treatment, and Control in Latin America: Challenges and Innovative Solutions to Improve Health Outcomes Across the Continent date: 2020-10-10 journal: Curr Diab Rep DOI: 10.1007/s11892-020-01341-9 sha: doc_id: 276256 cord_uid: gmlsoo2z PURPOSE OF REVIEW: Latin America is the scenario of great inequalities where about 32 million human beings live with diabetes. Through this review, we aimed at describing the current state of the prevalence, awareness, treatment, and control of diabetes mellitus and completion of selected guidelines of care across Latin America and identify opportunities to advance research that promotes better health outcomes. RECENT FINDINGS: The prevalence of diabetes mellitus has been consistently increasing across the region, with some variation: higher prevalence in Mexico, Haiti, and Puerto Rico and lower in Colombia, Ecuador, Dominican Republic, Peru, and Uruguay. Prevalence assessment methods vary, and potentially underestimating the real number of persons with diabetes. Diabetes unawareness varies widely, with up to 50% of persons with diabetes who do not know they may have the disease. Glycemic, blood pressure, and LDL-C control and completion of guidelines to prevent microvascular complications are not consistently assessed across studies, and the achievement of control goals is suboptimal. On the other hand, multiple interventions, point-of-care/rapid assessment tools, and alternative models of health care delivery have been proposed and tested throughout Latin America. SUMMARY: The prevalence of diabetes mellitus continues to rise across Latin America, and the number of those with the disease may be underestimated. However, some local governments are embedding more comprehensive diabetes assessments in their local national surveys. Clinicians and public health advocates in the region have proposed and initiated various multi-level interventions to address this enormous challenge in the region. Within the last couple of decades, non-communicable diseases (NCDs) have gained worldwide attention, especially in low-and middle-income countries (LMIC), where they have been increasingly recognized and prevalent [1, 2] . Among the NCDs, diabetes mellitus has become a global health challenge [1, 3, 4] . Type 2 diabetes mellitus-the most common form of diabetes-due to its rather silent disruption may be a current uninvited companion to over 465 million persons worldwide. In 2019, it was estimated that the number of persons with diabetes in Latin America (LatAm) was 31.6 million [5, 6] and is predicted that by 2030, the number will increase to 40.2 million, and to 49.1 million by 2045 [6] . Because of its multi-organ and multi-system impact, diabetes has been associated with both acute and long-term complications that affect not only health care needs and costs but also wellbeing and productivity [7, 8] . Within the last decade, it has also been recognized as one of the leading causes of death in some LatAm countries [9] [10] [11] [12] [13] [14] [15] and an important risk factor This article is part of the Topical Collection on Diabetes Epidemiology for cardiovascular diseases (CVD), which is the leading cause of death in LatAm [14, 16] . Far from being a monolithic group, the LatAm population is highly heterogeneous, with various populations reflecting diverse genetic ancestry, ethnicity, culture of origin, sociopolitical contexts, environmental exposures, and beliefs and practices [17, 18] . Levels of inequality in LatAm remain among the highest in the world [19] [20] [21] [22] . All these factorscoupled with biological susceptibility, income, education, access health care, cultural influences on nutrition, health, selfimage, and self-care-influence the development of diabetes in LatAm. We conducted a review of the most current publications on the state of prevalence, awareness, treatment, and control of diabetes mellitus across LatAm. By laying out a detailed accounting of what is known, we aim to identify population, clinical, and health care needs, and opportunities for future research studies and potential interventions. We conducted the search using the PubMed electronic database as the primary scientific literature source. LatAm was defined as the countries in the Western hemisphere which were previously colonized by Spain, Portugal, or France. A combination of keywords was used to define the scope of the searches: diabetes prevalence, awareness, treatment, control, guidelines of care, adherence, retinopathy, nephropathy, neuropathy, foot care, fundoscopic exam, and urine albumin, and searched under LatAm and by each individual country. Hispanics/Latinos living in the USA were not included in the search. We limited the search to publications since 2000 to reflect the most recent research on the prevalence of diabetes across LatAm countries, assessments of awareness, treatment, and control of diabetes (glycemic control), blood pressure and low-density lipoprotein cholesterol (LDL-C), and adherence to guidelines for care recommended by the American Diabetes Association (ADA) [23] [24] [25] and the Latin American Diabetes Association (ALAD) [26] , and specifically hemoglobin A1c (HbA1c) measurement, fundoscopic exam, foot exam, and urine albumin excretion test. We included literature written in English, Spanish, French, and Portuguese. In addition to PubMed, when available, we manually searched each country's Ministry of Health and the Pan American Health Organization (PAHO) websites and accessed published and downloadable national health surveys performed during the selected timeframe. Since most available studies did not distinguish between type 1 and type 2 diabetes mellitus, our review is centered on diabetes mellitus (diabetes, henceforth) in general. Because their specific mechanisms of disease and clinical implications, gestational diabetes mellitus, and type 1 diabetes merit separate reviews. The earliest contemporary reports on the prevalence of diabetes mellitus among adults throughout LatAm date from the 1950s and 1960s [27] [28] [29] , when most countries were beginning to experience epidemiologic transitions [30, 31] . In 2001, Barceló reported an incidence of type 1 diabetes in LatAm in the range 0.1 cases/100,000 in Venezuela to 17.4 cases/ 100,000 in Puerto Rico [32] . However, the authors highlighted a handful of reports on the prevalence of type 2 diabetes and underlined the near absence of surveillance for the disease throughout the LatAm region [32] . From 2005 to 2020, the prevalence of diabetes mellitus across LatAm has been assessed within individual countries and through multinational studies and ranged between 3 and 36.3% (Fig. 1, Table 1 ). In our review, some national surveys assessed the prevalence of diabetes via population representative samples [33, 36, 38, 40, 42-44, 47, 49, 55, 60, 61, 65, 66, 68, 72, 85-87, 89, 91, 96, 98, 105, 107] and used similar population sampling methods (e.g., multi-stage, clustered, probabilistic sampling), whereas other studies focused on specific geographic regions or communities [34, 35, 37, 45, 46, 48-54, 56-58, 63, 67, 73-75, 77, 82-84, 92-95, 102, 110-112] , recruited participants from clinical settings [51, 59, 62, 69, 95] , or focused on specific age groups [37, 42, 56-58, 75, 109, 112] . Also, the age range of the population surveyed-and consequently, age-adjustment estimates-varied among surveys. Most of the studies (especially national surveys) reported the overall prevalence of diabetes without differentiating between type 1 and type 2 diabetes mellitus and many estimated the prevalence of the disease based on selfreport (being aware of having diabetes and/or taking antihyperglycemic medications) only. Some national surveys and independent studies estimated the prevalence based on the sum of self-report and identifying individuals without history of diabetes but hyperglycemia within the diabetes range [26, 115] . The latter group was considered to have "suspected," "undiagnosed," or "unknown" diabetes. Hyperglycemia within the diabetes range was assessed by measuring fasting blood or plasma glucose (FBG or FPG) only, FBG/FPG and 2-h oral glucose tolerance test (OGTT), FBG/FPG and hemoglobin A1c (HbA1c), HbA1c only, or the combination of FBG/FPG, OGTT, and HbA1c, or glucose levels in urine. Some studies measured capillary blood glucose (CBG), while most studies measured venous blood or plasma glucose. While multiple studies used the ADA/ALAD-recommended glucose/HbA1c cut points for the diagnosis of diabetes [26, 115] , some studies used different thresholds (e.g., fasting glucose ≥ 100 mg/dL (per CBG), random blood glucose ≥ 140 mg/dL, or random blood glucose ≥ 200 mg/dL). Although the differences in the methodology described above limit the ability to perform cross-sectional or trend comparisons among countries, we note several commonalities. During 2005-2020, some countries reported an increase in the prevalence of diabetes [33, 36, 38-40, 66, 70-72, 79, 85, 86] , consistent with previously published reviews [5, 15, 32, [116] [117] [118] [119] [120] [121] [122] [123] . Compared with the rest of the region, and as previously reported [5, 15, 32, 124, 125] , diabetes prevalence varies across the region, with higher prevalence in Mexico (13.7%), Haiti (14.1% in women and 8.2% in men), and Puerto Rico (12.5-12.7% in the population aged 18 ≥ years and 26.8% in the population aged ≥ 45 years), and lower in Colombia (3.0% in the population aged 18 ≥ years, but 11.2% in age group ≥ 60 years), Dominican Republic (3.5%), Ecuador (2.7%), Peru (3.7%), and Uruguay (5.5-6.0%) (Fig. 1, Table 1 ). Multiple studies reported a greater prevalence of diabetes among women [36, 38, 40, 42, 44, 47, 49-52, 57, 60, 62, 63, 65, 70, 72, 75, 78, 79, 83-86, 90, 95, 96, 110, 113] , and with increasing age, especially over age 60 years [33, 36, 44, 47, 50, 55, 69-72, 78, 80, 81, 86, 91, 93, 110] . Some studies reported an inverse relationship between diabetes and socioeconomic status (SES) [33, 79, 103] or educational attainment [33, 44, 62, 63, 70, 72, 73, 75, 76, 78, 79, 86, 101] . Other studies reported a direct relationship between having health insurance and self-reported diabetes [42, 70, 97, 100] , implying that persons who have health insurance-proxy of access to health care services-would be aware of their health issues and report them accordingly. This interaction also poses questions about not only the access to health care but also the timeliness and quality of the care, and health literacy (or the lack of) that persons in the lowest SES-and at the highest risk of diabetes-would experience. Some studies reported a lower prevalence of diabetes among indigenous populations [35, 48, 74] , with one study proposing that exposure to urbanicity was associated with an increased prevalence of diabetes among some indigenous communities [83] . Indeed, rural to urban migration (or living in rural compared with urban areas) has been associated with increased prevalence or risk of developing diabetes in Peru [126, 127] , and multiple countries reported a lower diabetes prevalence in rural compared with urban settings [33, 39, 47, 60, 65, 89-91, 99, 103] . The number of epidemiological studies published since 2005 indicates greater public health awareness about diabetes mellitus across LatAm. Multiple countries have performed at least one national survey on chronic non-communicable diseases in which self-reported diabetes mellitus and/or elevated glycemia has been included (Table 1) . Some surveys have also included at least one laboratory test (i.e., fasting or random blood glucose measurement or HbA1c), which could identify individuals at risk of developing diabetes or those who may have it and are not aware of it. Because hyperglycemia may be mediated by at least two mechanisms of disease-increased hepatic glucose output manifested as fasting hyperglycemia and uncoupled postprandial insulin secretion manifested as postprandial hyperglycemia [115, 128] -a single blood test or measurement may not identify all or most of individuals affected by the disease [115] . Therefore, the actual prevalence of diabetes may still be underestimated in many countries, as highlighted in previous reviews [5, 15, 124] . The etiologies of diabetes mellitus are complex. Thus, the increasing prevalence of diabetes experienced across LatAm may reflect the convergence or interaction of multiple factors [18, 125, 129] . For instance, the increasing prevalence of overweight and obesity documented across LatAm has paralleled the increasing prevalence of diabetes in the region [84, 125, 130, 131] . In addition to increased adiposity, type 2 diabetes mellitus and insulin resistance have also been linked to malnutrition (at different life stages) in some LMICs [130, [132] [133] [134] . Stress associated with chronic poverty, intergenerational poverty, natural disasters, and other adverse events [1, 129, 132, 135] has been linked to chronic systemic inflammation and epigenetic changes, potential common denominators of multiple NCDs [136, 137] . Many LatAm major cities may be epicenters where a fragile built environment and infrastructure and changes in lifestyle and nutrition intersect increasing the cumulative risk of developing diabetes in low-income communities [30, 126, 127, 129, 135, 138, 139] . Increased life expectancy has been associated with increased diabetes prevalence [4, 16, 30, 125, 140] , whereas higher educational attainment, increased access to health care, and higher health literacy level are associated with increased awareness of the disease [117] . These are all factors to consider upon designing comprehensive diabetes prevention and treatment strategies across LatAm countries. In addition, the growing prevalence of diabetes mellitus across LatAm and the complexity of the disease suggest opportunities to create or strengthen collaborations towards its prevention and early detection [141] [142] [143] [144] . For example, multinational and multidisciplinary researchpublic health-health care policy-clinical care partnerships which already exist in formal or informal platforms may be well-positioned to evaluate the impact of nutrition, health insurance, housing, and other public policies [79, 141, 143, [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] on health outcomes and assess their potential translation into preventive strategies at the public health and clinical care levels. At the same time, the eventual implementation of such strategies will be strengthened by local governments' commitment to prioritize the prevention and treatment of NCDs, in this case, diabetes, as previously voiced by experts and advocates in the region [79, 141, [155] [156] [157] [158] . Diabetes Awareness, Treatment, and Control Although fewer than studies focused on prevalence, a considerable number of reports centered on diabetes awareness, treatment, and control across LatAm were published between 2005 and 2020 ( 185, 189] . Most studies did not use the term "diabetes awareness," but equated it (or more appropriately, diabetes unawareness) to "suspected," "undiagnosed," "unknown," or "new" diabetes or "elevated glycemia." "Undiagnosed" diabetes-a proxy for lack of diabetes awareness-ranged widely from 10.3 to 50% across studies and countries ( Table 2 ). The prevalence of undiagnosed diabetes was higher in Guatemala (48.8%), Uruguay (48.7%), Puerto Rico (37.7-50%), Honduras (31.9-53.7% range), Mexico (29.9-50% range), and Nicaragua (43.3%) and lower in Colombia (Bogota) (23.5%), the southernmost countries of South America (20.2%), and Costa Rica (10.3-28.4%). Irazola et al. [189] described that diabetes awareness slightly increased with educational attainment. However, associations between undiagnosed diabetes with age, sex, educational attainment, SES, or geographic location were not published by most studies. The observed range of undiagnosed diabetes suggests that the actual prevalence of diabetes across LatAm could exceed previous estimates [6, 124] and that a potentially significant proportion of persons with diabetes for whom both macroand microvascular complications may be present but not assessed and treated. Therefore, current estimates of the prevalence of diabetes across continents may not fully account for the necessary resources to provide adequate health care for Latin Americans with diabetes [7, 8, 190, 191] . Considering the workforce and resources needed to screen the millions of persons across the region who are at risk of diabetes or have the disease and are not aware, experts have proposed diabetes predictive models requiring specific easily obtained clinical data points that could be readily used in primary care settings [192] [193] [194] . Also, the Finnish Diabetes Risk Score (FINDRISC) has been proposed, tested, or modified to screen and identify individuals at high risk of developing diabetes in Latin America [195] [196] [197] [198] [199] . Point-of-care tests for HbA1c and urine microalbumin have also been proposed as alternatives to identify persons with "undiagnosed diabetes" and/or those at risk of chronic kidney disease (CKD) in low-resource and remote settings in LatAm [200] [201] [202] [203] . The standardization, reliability, and repeatability of some of these tests, as well as the clinical and public health benefit derived from their integration into the health care systems, may need to be determined [204] . However, these and other emerging diagnostic technologies [205, 206] are promising alternatives that could be incorporated to assess the prevalence of diabetes and implement timely interventions. The percent of persons with diabetes following any treatment for diabetes ranged from 52.6 to 99% across studies ( Table 2 ). Prescription and/or use of antihyperglycemic medications was mostly assessed via interviews, although a few studies evaluated medical records. Most individuals reported taking oral antihyperglycemic medications either as monotherapy or as a combination of oral medications, while a smaller percent reported using insulin alone or in combination with oral medications. Five (5%) to 12.9% only followed diet/exercise prescription [161, 163, 167, 176, 179, 186] , and 3.2 to 10.1% were not taking any medications [41, 104, 168, 169, 175] . Receiving or adhering to pharmacological treatment was positively associated with having health insurance [71], and receiving medical care in private rather than public health care settings [71, 187] . At least one study observed better pharmacologic treatment adherence with female sex [185] . Achievement of ADA/ALAD-recommended glycemic goals [23, 207] was assessed by multiple studies. The percentage of persons attaining HbA1c < 7% ranged from 3.5 to 54%. However, some studies defined glycemic control based on fasting or random blood glucose thresholds and reported attainment of glycemic control in the 31.4 to 61.4% range. Attainment of glycemic control was associated with higher socioeconomic status (SES) [160] , having health insurance [160] , and better access and services [208] . Not attaining glycemic control was associated with longer duration of diabetes [163, 187, 209] , taking insulin (alone or in combination with oral antihyperglycemic medications) [176] , forgetfulness (e.g., taking multiple medication for more than one condition) [185] , complex therapeutic regimes [209] , inadequate access to health care services [22] , and availability or health insurance coverage of medications [187] , among other factors. In addition to glycemic control, a smaller number of studies examined the attainment of ADA/ALADrecommended blood pressure and LDL-C-blood pressure < 130/80 mmHg and LDL-C < 100 mg/dL-for patients with diabetes [24, 207] . The percentage achieving blood pressure goals ranged from 25 to 67%, and the percent achieving LDL-C goals ranged from 12 to 52.6% Table 2 ). The percent achieving optimal glycemic, blood pressure, and LDL-C levels altogether was reported by a handful of studies and up to 9.9% ( Table 2) . The findings described above denote critical aspects of the state of diabetes care in Latin America. The achievement of glycemic goals reported by the studies included in our review is similar to previously published studies [164, 179, 180, 187, 210] . This implies seriously chronic and inadequate glycemic control at the population level across the region. The inclusion of questions on treatment for glycemic control, medical, and self-care in some national surveys increases our understanding of health-seeking behaviors, both patients' and clinicians' adherence to recommended guidelines of care, and challenges related to the utilization of health care services and availability of medications. The smaller number of studies reporting on the attainment of blood pressure and LDL-C goals and the proportion of patients achieving those goals also poses questions about the prevention of macrovascular complications in persons with diabetes in Latin America, considering the raising prevalence of CVD in the region [16, 211] . Of note, most national surveys report prevalence and treatment and/or control of diabetes, hypertension, and blood cholesterol and the prevalence of tobacco use individually. Since diabetes involves multiple organs and deserves a holistic care approach, reporting on the co-existence of other CV risk factors with diabetes would enhance critical understanding of CV risk and health care needs. Also, some surveys collected biospecimens, but the test results were not included in the reports. It is possible that they are analyzed and published later. Yet including test results in the surveys would offer a more comprehensive picture of the status of diabetes prevention and care needs [180, 212, 213] to plan interventions accordingly. Various studies included in our review reported on participants' receiving or following ADA/ALAD-recommended guidelines of care [25] for early detection and prevention of microvascular disease-annual fundoscopic exam, examination for peripheral neuropathy and comprehensive foot examination, annual function/urine albumin excretion testing, and HbA1c tested at least 3 times per years [38-40, 72, 96, 159, 160, 165, 166, 168, 169, 171, 172, 175, 176, 180, 182, 186, 214] (Table 3) . Some studies assessed the completion of several guidelines, whereas most studies focused on a few. The completion of the selected ADA guidelines varied, ranging from 14.7 to 97.5% for the foot exam, from 8.6 to 92% for the fundoscopic exam, and from 1.1 to 51.1% for the urine albumin excretion test. Most studies (especially national surveys) inquired about having HbA1c checked within the previous 12 months. The affirmative response ranged from 3.7 to 90.0%. In addition to inquiring about HbA1c testing, some surveys asked whether the participant's blood glucose had been tested (by a health care professional). Having private health insurance was associated with a greater number of affirmative responses to the latter [70, 71, 91] . Despite the smaller number of studies evaluating the completion of the ADA guidelines for foot care and prevention of microvascular disease, and the varied guideline completion rates previously described (Table 3) , the prevalence of long-term microvascular complications associated with diabetes has been documented across LatAm. For instance, in the studies included on our review and others published during the same time frame, the rate of foot ulcers ranged from 1.2 to 14.8% [40, [214] [215] [216] , and nontraumatic lower extremity amputations attributable to diabetes ranges from 1.2 to 7.3% [40, 184, 214, 215, [217] [218] [219] [220] [221] , and the prevalence of diabetic retinopathy ranged from 11.2 to 48% [40, 184, 214, 222, 223] . CKD has become a major public health concern across Central America [224] [225] [226] , and the increasing prevalence of diabetes could exacerbate the incidence of CKD-and eventually end-stage renal disease and its associated health complications-in the region [227] [228] [229] . The findings described above underline not just the urgent need to prevent diabetes but also to prevent complications among those with established disease, and the potentially underestimated burden on patients, societies, and health care systems across LatAm. In this regard, several innovative models of health care for patients with diabetes have been proposed and tested throughout LatAm. Combining care of diabetes and other chronic conditions would be expected to maximize time and resources and improve health outcome. Although combining diabetes and chronic pulmonary disease care did not demonstrate a difference in outcomes [230] , this model could be revisited. Also, interventions at the health care system element of the chronic care model might need to be adapted to the local health care system [231] or synchronized with interventions at other levels. Improvement of health care system structure and processes [232] would assure timely access to patient information and enhance clinician decisionmaking. Integrating social determinants of health into diabetes care demonstrated objective improvements in patient knowledge and cardiometabolic parameters [233] . Enhancing medical continuing education [234] , an intervention combining diabetes prevention and self-management [235] , co-creating interventions with community stakeholders and other countries [141, 144] are other examples of alternatives to improve diabetes care throughout the region. Another major regional example of efforts to implement better care for patients with [147] , telehealth, mobile clinics, and other non-traditional health care delivery models. In addition, a non-exhaustive list of examples of past or current interventions, policies, and initiatives is provided in Table 4 [184, 186, 234, [236] [237] [238] [239] [240] [241] [242] [243] [244] [245] [246] [247] [248] [249] [250] [251] [252] . Interventions in the list include tele-ophthalmology [249, 250, 253, 254] , teambased foot self-care education [236] , diabetic retinopathy education and screening at a community pharmacy [255] , rapid assessment/diagnostic tools to screen for or detect retinopathy, nephropathy, and risk of developing foot ulcers [201, [256] [257] [258] [259] [260] [261] [262] and are examples of clinical research and/or implementation activities designed to strengthen the prevention and early detection of diabetes-associated complications and improve health outcomes throughout LatAm. Many interventions on diabetes care have focused on patients and/or clinicians as the primary recipients or enablers of the interventions. Because of the complex nature of the disease and the multiple factors that mediate treatment effectiveness, interventions involving other levels or elements within the health care organization or system [155, 157, 232, [263] [264] [265] or the health care workforce [158, 263, 266] could be considered. Interventions involving other sectors (e.g., housing, infrastructure, national or local policies) could uncover very valuable and needed strategies to enhance treatment effectiveness and potentially reduce health care costs in the long-term. The feasibility and sustainability of such research efforts-and subsequent policies-would need to be demonstrated and supported locally [143] . Multiple studies in our review reported a higher prevalence of diabetes among women [36, 38, 40, 42, 44, 47, 49-52, 57, 60, 62, 63, 65, 70, 72, 75, 78, 79, 83-86, 90, 95, 96, 110, 113] . While the mediating factors for this sex difference need further study (e.g., history of GDM, which was outside of the scope of this review), the increased prevalence of diabetes among women in some LatAm countries would be expected to have implications for health and health care, and potentially future generations [267] [268] [269] . Since diabetes may increase women's risk for CVD, including stroke [270] , cognitive decline [271, 272] , or some cancers [273, 274] , timely and comprehensive preventive care for women of all ages would need to be prioritized. Due to the epidemiologic transition already experienced by some countries throughout LatAm, the population pyramid is also shifting towards a greater proportion of older adults. Studies included in our review consistently reported an increased prevalence of diabetes with age. Diabetes care challenges specific to this age group include risk of obesity or undernutrition [42, 56] , increased risk for disability [57] , economic barriers to appropriate access to health care [42] , disruption in funding of health insurance [275] , disparate completion of diabetes care guidelines based on health insurance coverage [276] , inequalities in access to and utilization of health care services [277] [278] [279] , complex medical care needs and frailty [280] , cultural beliefs, mental health, and lack of family or social support [281] , among others. Prevention of diabetes and its complications and reliable continuity of care and social support [282] need to be especially tailored for this population across the region. A few studies in our review reported a low prevalence of diabetes among some indigenous populations in LatAm [55, 74, 82] , in parallel to some previous reports [283] [284] [285] [286] about other indigenous groups in the region and in contrast with the higher prevalence of diabetes among American Indians in the USA [287] and the First Nations in Canada [288] . However, other studies in our review and in the current literature have documented elevated diabetes prevalence or risk among indigenous and other socioeconomically disadvantaged ethnic groups [48, 50, 73, 76, 77, 83, 90, 91, 166, [289] [290] [291] [292] [293] . Some of the diabetes prevalence studies included in our review focused on or mentioned participants from indigenous groups [35, 48, 50, 74, 83] and other underrepresented groups (e.g., Garifuna, Afro-Panamanian, Afro-Peruvian, Afro-Ecuadorian) [55, 76, 90, 91, 166] . However, a few studies have evaluated diabetes care, prevalence, and/or prevention of macro-or microvascular complications, diabetes management interventions, other health care needs and access to health care among indigenous populations [241, 244, 246, [294] [295] [296] [297] [298] [299] [300] [301] [302] , and none on the other groups (that we could identify through our search). Understanding the protective mechanisms (e.g., biochemical, immune, epigenetic) against diabetes experienced by some indigenous populations would be relevant to millions at high risk of developing diabetes. At the same time, the increased prevalence of the metabolic syndrome and diabetes experienced by some indigenous groups and other ethnic groups may increase their risk not only for CVD and other diabetes long-term complications but also for re-emerging [239] 2 0 0 9 -2011 Mexico, Honduras Interactive Voice Response (IVR) support calls for chronic disease management for Spanish speakers-The investigators report cumulative findings in Honduras, Mexico, and Spanish-speakers in the U.S. Involvement of caregivers enhanced engagement. By self-report, there was improved medication adherence and self-management was similar across sites. Piette, 2011 [240] 2010 Honduras Cloud-Computing Model -The investigators tested a mobile phone-based intervention of weekly VoIP calls and IVR with patients with diabetes and automated emails to clinicians and voicemail reports to family caregivers for six weeks. Improved self-care and diabetes management and significant improvement in glycemic control were reported. Piette, 2016 [241] 2013 Bolivia Structured caregiver feedback -The investigators assessed whether automated telephone feedback to caregivers ("CarePartners") increased engagement in mobile-health support among patients with diabetes and hypertension in Bolivia. Significantly greater engagement was observed. Patients who spoke indigenous languages at home were more than 3X as likely to complete the IVR calls. Piette, 2014 [242] 2013 Bolivia Mobile health program for chronic disease self-management in Bolivia -Assessment and implementation of IVR for 12 weeks. It was associated with improved medication adherence, self-reported health status, and satisfaction. Prestes, 2017 [243] 2 0 1 6 -2017 Argentina DIAPREMintegrated diabetes care program including systemic changes education, registry and disease management Flood, 2016 [244] 2010 Guatemala Implementation and outcomes of a comprehensive type 2 diabetes program in rural Guatemala through a non-government organization and involving nurse-directed care Flood, 2017 [245] 2012 Rural Guatemala Implementation of a multi-level quality improvement program for ambulatory diabetes care based on input from patients and other stakeholders Flood, 2017 [246] 2 0 1 4 -2016 Rural Guatemala Home-based type 2 diabetes self-managementintervention delivered by diabetes educator at home and synchronized with clinic follow-up. Mayan communities Tapia-Conyer, 2016 [247] Gallardo-Rincón, 2017 [234] 2012 to present Mexico CASALUD Model -is a comprehensive primary health care model implemented in Mexico that enables proactive prevention and disease management using innovative technologies and a patient-centered approach. The program was pilot tested in 2009 and implemented nationwide in 2012. infectious diseases, like tuberculosis [303] [304] [305] . Therefore, disease prevention and health care models that account and reach these populations need to be considered. Through this review, we have highlighted the most current reports on prevalence, awareness, treatment, control, and adherence to recommended guidelines of care for diabetes mellitus across LatAm published from 2000 to 2020. During that time frame, a considerable number of surveys assessing the prevalence of the disease and an increasing body of reports on the achievement of treatment and care goals were identified. Such reports demonstrate the imperative need to garner a more comprehensive understanding of the extent of diabetes across countries, and both past and ongoing efforts to establish effective and sustainable models of prevention and high-quality care able to reach and serve all peoples across the region. During the writing of this manuscript, Latin America had been recognized as the new epicenter of the SARS-CoV-2 (COVID-19) pandemic [306] . The effects of the disease in persons with diabetes in the region are beginning to be uncovered [307] [308] [309] , while some solutions are proposed [310, 311] . The magnitude of the impact of the pandemic on the health and health care needs of persons with diabetes mellitus and other NCDs-let alone on the health care systems infrastructures-in the region are yet to be known. 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c0: cord-309795-2kozsv4z
c1: Dewidar, Bedair
c2: Metabolic liver disease in diabetes – from mechanisms to clinical trials
c3: 2020-06-20
c6: 8655
c7: 306
c8: 28
c9: cord-309795-2kozsv4z.txt
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c4:
  The Liver The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD) Role of diet and lifestyle changes in nonalcoholic fatty liver disease Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance The integrative biology of type 2 diabetes Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance Anti-inflammatory effects of excessive weight loss: potent suppression of adipose interleukin 6 and tumour necrosis factor alpha expression Potential Nexus of Non-alcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: Insulin Resistance Between Hepatic and Peripheral Tissues Insulin resistance causes inflammation in adipose tissue Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling Serum adiponectin levels in different types of non alcoholic liver disease. 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.

c5:
  diabetes; disease; fatty; fibrosis; hepatic; insulin; liver; nafld; nash; non; nonalcoholic; patients; resistance; steatohepatitis; steatosis; treatment; type

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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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Behavior therapy for nonalcoholic fatty liver disease: The need for a multidisciplinary approach Association of Pharmacological Treatments for Obesity With Weight Loss and Adverse Events: A Systematic Review and Meta-analysis Efficacy of orlistat in non-alcoholic fatty liver disease: A systematic review and meta-analysis Effect of Weight Loss Medications on Hepatic Steatosis and Steatohepatitis: A Systematic Review Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study Bariatric Surgery Reduces Features of Nonalcoholic Steatohepatitis in Morbidly Obese Patients Bariatric surgery: a systematic review and meta-analysis Bariatric surgery in patients with non-alcoholic fatty liver disease -from pathophysiology to clinical effects DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery Dynamic changes of muscle insulin sensitivity after metabolic surgery The mechanisms of action of metformin Metformin Use and Clinical Outcomes Among Patients With Diabetes Mellitus With or Without Heart Failure or Kidney Dysfunction: Observations From the SAVOR-TIMI 53 Trial 10-year follow-up of intensive glucose control in type 2 diabetes Metformin in patients with non-alcoholic fatty liver disease: a randomized, controlled trial A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease Metformin in non-alcoholic fatty liver disease: A systematic review and meta-analysis Type 2 diabetes mellitus and risk of hepatocellular carcinoma: spotlight on nonalcoholic fatty liver disease Pleiotropic mechanisms for the glucose-lowering action of DPP-4 inhibitors Cardiovascular outcome trials of glucose-lowering medications: an update Sitagliptin vs. placebo for non-alcoholic fatty liver disease: A randomized controlled trial Sitagliptin in patients with non-alcoholic steatohepatitis: A randomized, placebo-controlled trial Effect of Vildagliptin on Hepatic Steatosis Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus Sitagliptin, and Insulin Glargine Added to Metformin: The Effect on Body Weight and Intrahepatic Lipid in Patients With Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease Effect of Liraglutide Therapy on Liver Fat Content in Patients With Inadequately Controlled Type 2 Diabetes: The Lira-NAFLD Study Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation The anti-diabetic drug exenatide, a glucagon-like peptide-1 receptor agonist, counteracts hepatocarcinogenesis through cAMP-PKA-EGFR-STAT3 axis LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans Effects of Novel Dual GIP and GLP-1 Receptor Agonist Tirzepatide on Biomarkers of Nonalcoholic Steatohepatitis in Patients With Type 2 Diabetes SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial The SGLT2 Inhibitor Dapagliflozin Reduces Liver Fat but Does Not Affect Tissue Insulin Sensitivity: A Randomized, Double-Blind, Placebo-Controlled Study With 8-Week Treatment in Type 2 Diabetes Patients Effect of canagliflozin treatment on hepatic triglyceride content and glucose metabolism in patients with type 2 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 nonalcoholic fatty liver disease: Interim analysis of a 12-week, randomized, placebo-controlled, Phase 2a study n PPARγ signaling and metabolism: the good, the bad and the future Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis Randomized, placebocontrolled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis Pioglitazone for the Primary and Secondary Prevention of Cardiovascular and Renal Outcomes in Patients with or at High Risk of Type 2 Diabetes Mellitus: A Meta-Analysis Targeting Metabolism, Insulin Resistance, and Diabetes to Treat Nonalcoholic Steatohepatitis Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug 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 lipoprotein profile in patients with non-alcoholic steatohepatitis Discovery of Tropifexor (LJN452), a Highly Potent Non-bile Acid FXR Agonist for the Treatment of Cholestatic Liver Diseases and Nonalcoholic Steatohepatitis (NASH) Randomised clinical trial: the efficacy and safety of oltipraz, a liver X receptor alpha-inhibitory dithiolethione in patients with nonalcoholic fatty liver disease Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis Cenicriviroc Treatment for Adults with Nonalcoholic Steatohepatitis and Fibrosis: Final Analysis of the Phase 2b CENTAUR Study Statin Use and Risk of Cirrhosis and Related Complications in Patients With Chronic Liver Diseases: A Systematic Review and Meta-analysis Prescription of statins in suspected non-alcoholic fatty liver dise ase and high cardiovascular risk, a population-based study Ezetimibe 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 


c0: cord-314500-89ovdnxl
c1: Dunachie, Susanna
c2: The double burden of diabetes and global infection in low and middle-income countries
c3: 2018-12-04
c6: 5812
c7: 201
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c9: cord-314500-89ovdnxl.txt
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  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. 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).

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  chronic; dengue; diabetes; disease; infection; mellitus; patients; people; risk; studies; study; type

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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. Classification and Diagnosis of Diabetes International Diabetes Federation: a consensus on Type 2 diabetes prevention Influence of diabetes and hyperglycaemia on infectious disease hospitalisation and outcome Increased Risk of Common Infections in Patients with Type 1 and Type 2 Diabetes Mellitus Impact of diabetes mellitus on treatment outcomes of patients with active tuberculosis The global burden of tuberculosis: results from the Global Burden of Disease Study Geneva: World Health Organization Stress Hyperglycemia in Patients with Tuberculosis Disease: Epidemiology and Clinical Implications Addressing diabetes mellitus as part of the strategy for ending TB Diabetic status in leprosy Diabetic status of patients with leprosy in Kuwait T-Cell Responses Are Associated with Survival in Acute Melioidosis Patients Activities of Daily Living Associated with Acquisition of Melioidosis in Northeast Thailand: A Matched Case-Control Study Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis Bacteremia in diabetic patients: comparison of incidence and mortality with nondiabetic patients Risk factors and mortality of healthcare-associated and community-acquired Staphylococcus aureus bacteraemia Tropical pyomyositis (myositis tropicans): current perspective Case report: diabetes mellitus as a predisposing factor in the development of pyomyositis Bacterial pyomyositis in the United States Primary pyomyositis in North India: a clinical, microbiological, and outcome study Salmonella infections: a retrospective 10-year analysis of 134 cases in a regional hospital in Taiwan Diabetes mellitus-a newly described risk factor for infection from Salmonella enteritidis Bacteremia in adult diabetic patients Comparison of pyogenic liver abscess caused by non-Klebsiella pneumoniae and Klebsiella pneumoniae Distribution of common pathogens in patients with pyogenic liver abscess in China: a meta-analysis Review article: Unresolved problems related to scrub typhus: A seriously neglected life-threatening disease A Systematic Review of Mortality from Untreated Scrub Typhus (Orientia tsutsugamushi) Severity predictors in eschar-positive scrub typhus and role of serum osteopontin Diabetes and Other Risk Factors for Multi-drug Resistant Tuberculosis in a Mexican Population with Pulmonary Tuberculosis: Case Control Study The effect size of type 2 diabetes mellitus on tuberculosis drug resistance and adverse treatment outcomes Epidemiology of Carbapenem-Resistant Enterobacteriaceae in 7 US Communities The Example of Dengue Fever Is diabetes a risk factor for a severe clinical presentation of dengue?-review and meta-analysis Clinico-laboratory spectrum of dengue viral infection and risk factors associated with dengue hemorrhagic fever: a retrospective study Analysis of clinical characteristic of 158 inpatients with dengue fever Relevance of Non-communicable Comorbidities for the Development of the Severe Forms of Dengue: A Systematic Literature Review Prevalence of chronic comorbidities in dengue fever and West Nile virus: A systematic review and meta-analysis Medical risk factors for severe West Nile Virus disease Chikungunya Virus Infection and Diabetes Mellitus: A Double Negative Impact Influenza Virus and Glycemic Variability in Diabetes: A Killer Combination? Front Microbiol Populations at risk for severe or complicated influenza illness: systematic review and meta-analysis World Health Organisation. WHO Hepatitis B Fact Sheet Hepatitis B virus infection as a neglected tropical disease Serological and molecular analysis on the relationships between type 2 diabetes mellitus and hepatitis B virus infection The prevalence of occult hepatitis B virus infection in type 2 diabetes mellitus patients Increased risk of acute hepatitis B among adults with diagnosed diabetes mellitus Hepatitis B and C virus infection and diabetes mellitus: A cohort study Prevalence of hepatitis B virus in patients with diabetes mellitus: a comparative cross sectional study at Woldiya General Hospital, Ethiopia Prevalence of serological markers of chronic hepatitis B virus infection in diabetics in the Lagos University Teaching Hospital Diabetes mellitus as a risk factor of liver cirrhosis in patients with chronic hepatitis B virus infection Increased risk of cirrhosis and its decompensation in chronic hepatitis B patients with newly diagnosed diabetes: a nationwide cohort study Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with new onset diabetes: a nationwide cohort study Hepatitis C virus infection and type 1 and type 2 diabetes mellitus Risk Factors for Herpes Zoster: A Systematic Review and Meta-analysis Diabetes as a Risk Factor for Herpes Zoster Infection: Results of a Population-Based Study in Israel MERS transmission and risk factors: a systematic review A comparison of factors associated with prevalent diabetes mellitus among HIV-Infected antiretroviralnaive individuals versus individuals in the National Health and Nutritional Examination Survey cohort What We Know From Low-and Middle-Income Countries Risk factors for incident diabetes mellitus among HIV-infected patients receiving combination antiretroviral therapy in Taiwan: a case-control study New-onset diabetes in HIV-treated adults: predictors, long-term renal and cardiovascular outcomes Changes in blood pressure, glucose levels, insulin secretion and anthropometry after long term exposure to antiretroviral therapy in South African women Glucose Metabolism Disorders, HIV and Antiretroviral Therapy among Tanzanian Adults Type 2 diabetes mellitus and increased risk for malaria infection Epidemiology of Plasmodium vivax Malaria in India Risk factors for anthroponotic cutaneous leishmaniasis in unresponsive and responsive patients in a major focus, southeast of Iran Reinfestation in cutaneous leishmaniasis: a new look at predisposing conditions Visceral leishmaniasis: a threat to immunocompromised patients in non-endemic areas? Freqüência de diabetes mellitus e hiperglicemia em mulheres chagásicas e não-chagásicas The global diabetes epidemic: what does it mean for infectious diseases in tropical countries? 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. 


c0: cord-334773-yw2qgv13
c1: Lisco, Giuseppe
c3: 2020-08-10
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c7: 284
c8: 27
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  Hypothesized mechanisms explaining poor prognosis in type 2 diabetes patients with COVID-19: a review

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  Unfortunately, inconclusive deductions are currently available for considering concomitant medications favourable (as well as detrimental) factors in COVID-19 patients with T2D. Despite some putative mechanisms have been identified and some speculative hypothesis have also been formulated indicating that some anti-diabetes medications may improve clinical course in COVID-19 (pioglitazone, gliflozins, DPP-IV inhibitors, GLP-1RA), further studies are needed to clarify the issue. Considering that pancreatic islets express ACE 2 , glucose impairment in COVID-19 diabetic patients could be attributable to a partial insulin deficiency

c5:
  cardiovascular; coronavirus; cov-2; covid-19; diabetes; disease; glucose; immune; infection; obesity; patients; prognosis; response; risk; sars; t2d

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   key: cord-334773-yw2qgv13 authors: Lisco, Giuseppe; De Tullio, Anna; Giagulli, Vito Angelo; Guastamacchia, Edoardo; De Pergola, Giovanni; Triggiani, Vincenzo title: Hypothesized mechanisms explaining poor prognosis in type 2 diabetes patients with COVID-19: a review date: 2020-08-10 journal: Endocrine DOI: 10.1007/s12020-020-02444-9 sha: doc_id: 334773 cord_uid: yw2qgv13 PURPOSE: Epidemiological data suggest that comorbid patients, mostly those with type 2 diabetes (T2D), are predisposed to poor prognosis in Coronavirus disease 2019 (COVID-19), leading to serious healthcare concerns. The aim of the present manuscript is to review the main relevant mechanisms possibly contributing to worsen the clinical course of COVID-19 in T2D. RESULTS: Poor glucose control, high glycaemic variability and diabetes-related comorbidities at baseline, particularly cardiovascular diseases and obesity, contribute in worsening the prognosis in the above-mentioned cluster of patients. Moreover, both a lower efficient innate immune system response and cytokine dysregulation predispose patients with T2D to impaired viral clearance and more serious pulmonary and systemic inflammation once the SARS-CoV-2 infection occurred. Inconclusive data are currently available for specifically indicate or contraindicate concurrent medications for managing T2D and its comorbidities in infected patients. CONCLUSIONS: T2D individuals should be considered as more vulnerable to COVID-19 than general population, and thus require adequate advices about hygienic tips to protect themselves during the pandemic. A careful management of glucose levels and diabetes-related comorbidities remains essential for avoiding further complications, and patient monitoring during the pandemic should be performed also at distance by means of telemedicine. Further studies are needed to clarify whether medications normally used for managing T2D and its associated comorbidities could have a protective or detrimental effect on COVID-19 clinical course. Background Firstly identified and characterized as 2019-nCOV [1] , human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported as a novel infective agent arisen at the end of the 2019 [2] . SARS-CoV-2 is a positivesense, single strand, enveloped RNA virus belonging to the family of Coronaviridae, and is the 7th beta-coronavirus recognized to infect humans [3] . First metagenomic RNA sequencing of SARS-CoV-2 showed the single-strand RNA consisted of 29,906 nucleotides, and was closely related to a group of bat SARS-like coronaviruses (89,1%) [4] . Further observations confirmed that SARS-CoV-2 was closely related (88%) with two bat SARS-like coronavirus (bat-SL-CoVZC45 and bat-SL-CoVZXC21), but was distant from other two human coronaviruses responsible for severe infective pneumonia: SARS-CoV (79%) and Middle East respiratory syndrome coronavirus (MERS-CoV) (50%) [5] . A high grade of homology between genomic sequences of SARS-CoV-2 form different patients (99.98%) has also been reported, thus confirming a human-to-human transmission of the novel infective agent [5] . Phylogenetic analysis suggested that SARS-CoV-2 progenitors circulated in animal host including bats [6] , snakes, Malayan pangolins, civets, mouse [7, 8] , and underwent to a naturally occurred selection before the zoonotic spillover finally adapting to persistently infect the new host [9] . Official epidemiological report declared that the early cases of infections were detected in December 2019, and involved people who worked or visited the Hua Nan South China Seafood Market [10] , in Wuhan capital city (Hubei province; People's Republic of China). However, it remains still debated whether the zoonotic spillover might have been occurred in other places [11] , particularly in Southeast Asia [12] , and consequently SARS-CoV-2 infection might have been imported to Wuhan. Epidemiological analysis showed a marked widespread of the infection within community places due to a large human-to-human transmission [13] and Wuhan rapidly became the hub of a new pneumonia outbreak [14] . Due to a consistent widespread of detected cases among several countries, the World Health Organization declared the state of pandemic on March 11, 2020 when confirmed cases raised up to 118,000, and SARS-CoV-2 spread into 114 countries [15] . Clinical manifestations of the novel coronavirus disease 2019 (COVID- 19) include fever (87%), cough (58%), dyspnoea (38%), muscle soreness (35%), chest distress (31%) in a context of bilateral pneumonia (76%) with ground glass opacification (70%) at CT scan due to lung interstitial involvement [16] . Autoptic studies described macroscopic features of pleuro-pericarditis, lung consolidation, oedema with overall increased pulmonary weight; while microscopic hallmarks are characterized by pneumocyte hyperplasia, lymphocytic and multinucleated giant cells infiltration, hyaline membranes [17] [18] [19] . Other signs and symptoms of COVID-19 include acute conjunctivitis [20, 21] ; diarrhoea, abdominal pain/discomfort and vomiting [22] [23] [24] ; convulsion, headache, muscle soreness [25] ; diffuse erythematous rush and widespread urticaria [26] ; acute kidney injury [27, 28] ; pharyngodynia, nasal congestion with rhinorrhoea and smell/taste impairment [29] . SARS-CoV-2 may directly affect myocardial tissue, and significantly complicate the prognosis of underlying cardiovascular diseases [30, 31] . SARS-CoV-2 infection usually occurs asymptomatically or mildly symptomatic form of the disease but in predis posed patients with specific clinical conditions, a serious clinical course could be observed thus leading to worse prognosis or death [12] . Worldwide reported case-fatality rate for COVID-19 differs considerably among geographical areas [32] , and could be attributable to several variables, such as testing strategies for screen suspected cases and identification of infectious patients (statistical); accessibility to intensive care according to restricted national healthcare system capacities (organization); baseline patient age and comorbidities (medical) [33, 34] . From the latter point of view, a poor prognosis is usually observed in elderly patients [35] and worldwide age-specific case-fatality rate occurred very high among patients with one or more underlying chronic diseases including cardiocirculatory, renal, pulmonary, central nervous system and mental illness, diabetes mellitus (DM) and malignancies [36, 37] . According to the data shared by the Italian National Institute of Health, patients who died while tested positive for SARS-CoV-2 exhibited an elevated mean age (78.5 years old), mostly men (70%) and with one or more pre-existent chronic diseases (2.7 in mean) [38] . Of these, blood arterial hypertension (78%) and DM (34%) were the most commonly reported clinical comorbidities, followed by ischaemic heart disease (30%) and atrial fibrillation (22%). The leading cause of deaths was attributable to acute respiratory distress (97%) [38] . The global estimated prevalence of T2D accounts for more than 450 millions affected patients corresponding to 9.3% of the worldwide population [39] . Therefore, the number of patients with T2D who will contract SARS-CoV-2 infection is expected to be considerable, and should increase over time. T2D per se does not increase the risk of contracting SARS-CoV-2 infection but could exacerbate the clinical course of COVID-19 leading to a detrimental prognosis [40] . Indeed, the frequency of diabetes in patients with COVID-19 has been reported to 9-12% [41] [42] [43] , raising up to 16-20% in hospitalized patients including those who required intensive care for severe disease [44, 45] . More recently, data collected from nine hospitals from Seattlearea in the United States demonstrated that 58% of patients who required hospitalization for respiratory symptoms attributable to COVID-19 had T2D [46] . In severely ill patients with COVID-19 a pre-existent T2D was observed in about 35% of the cases and, according to the results of an univariate analysis, the presence of T2D resulted a significant risk factor for poor prognosis in this clinical setting (OR 8.14; p < 0.0001) [47] . DM has also been reported as the main clinical condition observed in non-survived patients with COVID-19 (22%) [48] , thus resulting one of the most frequently associated comorbidity in COVID-19 deceased patients [33] . This concern has been further confirmed by the results of a cohort study among 85 fatal cases of COVID-19 in Wuhan, hence defining DM as a potentially harmful comorbidity predisposing to worse clinical course or death once SARS-CoV-2 infection occurred [49] . Different hypothesis should be considered for explaining this clinical phenomenon, including glucose control at baseline and during the infection course, pathophysiology and immune system response in SARS-CoV-2 infected patients with T2D, diabetes-related comorbidities and concomitant medications. Herein, a point-to-point discussion about these putative mechanisms has been carried out. Epidemiological data showed that T2D represents a risk factor for infectious diseases, mostly with bacterial aetiology, particularly at the level of skin and soft tissue, genitourinary, gastrointestinal and respiratory systems [50] . Moreover, life expectancy in individuals with T2D may be affected due to infectious diseases and in certain clusters of patients, such as in elderly with T2D, the leading cause of mortality is attributable to severe pulmonary infections rather than other highly prevalent comorbidities, including cardiovascular diseases and malignancies [51] . On the other hand, DM increases the cumulative risk of medical consultation, hospital admission, intensive care requirement and poor prognosis because of pandemic influenza [52] . Further data reported that airways and pulmonary infections with different aetiologies, including SARS and MERS, were more frequently diagnosed in T2D patients, also showing a severe clinical course [53] [54] [55] [56] . In DM, hyperglycaemia is considered one of the most important factor in determining this burden [57] . Indeed, osteomyelitis, soft tissues infections, endocarditis, tuberculosis and sepsis are most commonly observed in diabetic patients with poor glycaemic control compared to those who achieve better glucose management, and a worse glucose control contributes to increase the rate of hospitalization and mortality, too [57] . Both hyperglycaemia and high glucose variability may consistently complicate the clinical course also in case of influenza A [58] . More recently, a retrospective observational study recruiting more than 7000 cases of COVID-19 from Hubei province (China) and including 952 patients with a pre-existent T2D displayed a higher mortality rate (HR 1.49), more prevalence of multiorgan damage and a greater requirement of medications (antibiotics, systemic corticosteroids, vasoactive substances, oxygen inhalation and either non-invasive or invasive mechanical ventilation) in patients with DM than in nondiabetics [59] . Interestingly, authors also found that, among T2D patients, those with better glucose control (glucose levels between 70 and 180 mg/dl) respective to those with worse glucose control (>180 mg/dl) during hospitalization exhibited a significantly lower rate of mortality (HR 0.14; p < 0.008), and a fewer risk of progression to acute respiratory distress syndrome (HR 0.47; p < 0.009), acute kidney (HR 0.12; p < 0.046) and myocardial (HR 0.24; p < 0.01) injury [59] . Similar results were found by another observation in which worse glucose control (glucose levels >110 mg/dl) at the admission and during hospitalization was found to be an independent risk factor for progression to critical ill or death among T2D patients with confirmed COVID-19 [60] . Therefore, hyperglycaemia represents a relevant matter in patients with COVID-19 fostering poor prognosis once the infection occurred. In addition, recent evidences suggest that SARS-CoV-2 may induce beta-cells damage thus leading to insulin secretion impairment. This phenomenon, in addition to a pre-existent hyperglycaemia and considering that systemic inflammation due to the infection exacerbates the insulin-resistance, is thought to play a significative role to further worsen glucose control and complicate the clinical course of COVID-19 [61] . In conclusion, epidemiological data suggested that DM, particularly T2D, is a frequently observed comorbidity in patients with SARS-CoV-2 infection who require hospitalization, more intensive treatment and exhibit poor prognosis or death. Poor baseline and ongoing glucose control in hospitalized patients rather than the presence of T2D per se seems to facilitate COVID-19 progression [62] . Hence, an optimal and timely blood glucose management during pandemic should be considered as an effective strategy to reduce the probability of hospitalization requirement of infected patients, and for improving the clinical course of those hospitalized for receiving either non-intensive or intensive care. Innate and adaptive immune responses play a crucial role against viral infections [63] . Immune response against coronaviruses has been reviewed elsewhere, highlighting the role of both innate and adaptive systems to promptly contrast virus replication, facilitate virus clearance, stimulate tissue repair and develop persistent defence [64] . Immune response in COVID-19 is not still completely understood making necessary further investigation to better control the pandemic evolution [65] . However, seriously ill COVID-19 patients exhibit an exaggerate response of neutrophils and alveolar macrophages, and a relevant peripheral lymphocytes dysfunction [66] , which lead to an uncontrolled viral shedding, consequent viremia and further systemic immune-mediated damage, thus triggering a harmful vicious circle [66] . Glucose levels may significantly influence immune response as observed in patients with DM. Natural killer (NK) cells activity is weakened in case of hyperglycaemia, and is inversely related with fasting plasma glucose, 2-h postprandial glycaemia and HbA1c levels [67] . Macrophage activation and phagocytosis are both decreased in patients with poor glucose control, but should be restored after an adequate optimization of metabolic control [68] . Neutrophil activation and phagocytosis are both impaired by hyperglycaemia as demonstrated in animal models and humans, thus suggesting a relevant impairment of innate immune response in patients with chronic hyperglycaemia [69] . In an animal model, obese and hyperglycaemic mice experienced higher rate of respiratory infection due to influenza and bacterial pneumonia and that was related to a lower efficient alveolar macrophage response against infections. In addition, a defective Toll-like receptor 4 signalling has been recognized in neutrophils exposed to the gram-negative lipopolysaccharide, leading to a blunted release of chemokines and cytokine, and decreased myeloperoxidase activity [69]. Moreover, T-cells function is significantly dysregulated in T2D and CD4 + lymphocytes preferentially differentiate in Thelper 1 and T-helper 17 instead of T-helper 2 with a consequent imbalance between pro-inflammatory and antiinflammatory activities [70] . On the other hand, the levels of interferon gamma-which normally stimulates CD4 + T cells maturation in sense of T-helper 1 rather than T-helper 2-were found to be lower in T2D patients sera, and can contribute in a blunted T-cell response in T2D [71] . Nevertheless, lower levels of interleukin (IL)-10 have also been described in T2D patients. Considering that IL-10 is capable to suppress the release of pro-inflammatory cytokines, lower levels of IL-10 could be related with higher IL-6-to-IFN gamma and TNF-alpha-to-IFN gamma ratios hence suggesting an enhanced activation of circulating monocytes [71] . High levels of IL-6 have been detected in diabetic patients respective to those with euglycemia, suggesting that hyperglycaemia play a crucial role in determining this immunological effect [72, 73] . In animal models, hyperglycaemia and insulin-resistance increase the level of circulating proinflammatory cytokines and oxidative stress at baseline [74] . Since this pro-inflammatory background usually results reversible after an effective treatment of hyperglycaemia, a low dose endotoxemia consistently enhances systemic inflammation in a animal model [75] . Therefore, hyperglycaemia may predispose to an exaggerate immune response even in case of a mild-to-moderate viral load. As known, a hyperinflammatory syndrome with cytokine dysregulation has been well recognized in seriously ill patients [76] , thus highlighting its crucial role in serious manifestations of COVID-19 [77] . Specific interleukins and chemokines (IL-2, IL-7, IL-6, TNF-alpha, interferon gamma induced protein 10, granulocyte-colony stimulating factor) are upregulated in patients who exhibited a worsen prognosis [78] and particularly high levels of IL-6 have been detected in case of serious pulmonary involvement or in patients requiring intensive care [79] . These findings are also more evident in elderly patients who display less vigorous immune response against viral shedding, greater susceptibility to more serious pulmonary and systemic involvement, and are finally predisposed to COVID-19 progression [80] . Both the number and function of T cells (both CD4 + and CD8 + ) [81, 82] , B cells depletion, and hypercoagulability have also been observed in seriously ill cases and the greater the magnitude of these haematological and biochemical alterations then the greater the severity of the prognosis [83, 84] . In conclusion, diabetic patients especially elderly individuals and those with worse baseline glucose control may exhibit immune system dysregulation that predispose them to a less effective response against SARS-CoV-2 and to a dysfunctional inflammation that requires to be carefully monitored in confirmed cases of COVID-19, for preventing or avoiding a harmful progression of the disease. Angiotensin-converting enzyme 2 (ACE 2 ) is a carboxypeptidase normally involved in the cleavage of angiotensin I and angiotensin II, and is the main receptor for SARS-CoV-2 playing a determinant role in viral entry into the host, and clearly explaining both the transmissibility and severity of COVID-19 among humans [85] . ACE 2 is expressed at the level of several tissues (transmembrane and soluble forms), such as lung [86] , oral mucosa [87] , intestine [88] , brain [89] , pancreatic islets [90] , testis [91] and kidney [92] . Differentiated type 2 pneumocytes normally express ACE 2 , which is essential to regulate pulmonary homoeostasis and protects against pulmonary injury [93] . Indeed, low levels of ACE 2 have been described in severe acute and chronic pulmonary diseases thus predisposing to poor prognosis [94] . However, ACE 2 is overexpressed in chronic diseases, including T2D, and this phenomenon could be also related with chronical exposure to several medications [94, 95] . This biochemical condition is believed to facilitate the internalization of SARS-CoV-2 into pneumocytes, thus contributing to worse prognosis in COVID-19 [94, 95] . However, the role of ACE 2 overexpression in worsening the prognosis is an emergent issue, and remains currently debated [96] . Cardiovascular diseases, including coronary and cerebrovascular artery disease and heart failure, are frequently observed in T2D patients and it has been estimated that about a third of them displayed these kind of complications over time [97] . Cardiovascular system is the main extrapulmonary compartment extensively involved in COVID-19, as suggested by a frequent myocardial involvement in affected patients especially in those having hypertension, T2D and cardiovascular diseases at baseline [98] . Vascular inflammation and endothelial dysfunction [99] , myocardial injury and cardiac arrhythmias are not-infrequently observed in COVID-19 confirmed cases, significantly influencing the risk of poor prognosis or death in this cluster of patients [100] [101] [102] . Overweight-obesity syndrome is a multifactorial disease which significantly predispose to cardiometabolic risk, and is strictly associated with insulin-resistance, glucose metabolism impairment and T2D [103] [104] [105] . Despite obesity is usually associated with decreased risk of death in patients with severe acute respiratory distress (obesity paradox), currently available data suggest that an elevated body mass index should be considered as an independent risk factor predisposing to poor prognosis [106] and death in COVID-19 [107] [108] [109] [110] . Indeed, the prevalence rate of obesity in this cluster of patients has been reported in 42% of the cases [111] and a BMI greater than 35 kg/m 2 has been usually observed in patients requiring hospitalization and invasive mechanical ventilation [112] also in younger patients (<60 years) [113] . Pathophysiological mechanisms possibly related with poor prognosis in obese patients are not completely understood but may be attributable to a greater inflammatory background as similarly found in DM due to hyperglycaemia and insulin resistance [70] . Obesity is usually associated to other severe comorbidities with high impact on cardio-metabolic health, such as fatty liver disease, vascular inflammation, cardiovascular atherosclerotic diseases and heart failure [114] that might be related with a higher burden of lethal complications, especially in hospitalized patients with COVID-19 [115] . In addition to cardiometabolic risk factors, obese patients are more prone to have a decreased pulmonary ventilation or obstructive sleep apnoea, which predispose them to low levels of blood oxygenation at baseline and consequently to worse respiratory outcomes in case of acute infective respiratory diseases [116, 117] . Nutritional patterns usually exhibited by obese patients are frequently characterized by an elevated dietary consumption of processed food rich in saturated fat, cholesterol, sugar and a low consumption of fibres and micronutrients, such as vitamin D [118] . These dietary patterns may affect physiological microbiome composition, weaken the immune response against microbial agent and foster immune system dysfunction [115] . In addition, vitamin D deficiency/insufficiency and sedentary lifestyle, which are highly prevalent among obese patients, should be considered as predisposing factors for worse prognosis in response to acute infections, including COVID-19 [119] . Abdominal obesity usually leads to a low cardiorespiratory reserve and systemic inflammatory dysfunction which predispose to a worse prognosis in COVID-19 [120] . Conversely, regular physical exercise, which is normally lacking in an obesogenic lifestyle, is associated to higher levels of cardiorespiratory fitness, and is believed to improve the innate immune response and attenuate cytokine dysregulation often experienced by high risk patients with the so called cytokine storm [121] . Visceral obesity is also a risk factor for both the development and progression of cardiovascular diseases [114] considering that it fosters higher level of pro-thrombotic circulating factors and predisposes to thrombotic events [122] . Furthermore, visceral obesity is more prevalent in men than women and this biological phenomenon has been hypothesized to have a putative role in driven poor prognosis of COVID-19 especially in men. From this point of view, male obesity is usually associated with a functional hypogonadism and these clinical conditions are both associated with one other [123] , according to a complex and multifactorial pathogenesis [124] that fosters higher baseline levels of inflammation and endothelial dysfunction [125] . Aromatase gene expression is enhanced by prostaglandin E 2 , whose levels were found to be higher in visceral adipose tissue of obese men [126] . An enhanced aromatase activity at the level of adipose tissue increases local levels of estradiol that is thought to be a defensive mechanism against local inflammation and insulin resistance [127] . Whether augmented aromatase levels (and activity) at the level of adipose tissue in men may be responsible for a systemic testosterone-tooestrogen imbalance remains questionable. However, obese men are usually affected by this biochemical condition and body mass index is inversely correlated to testosterone-to-oestrogen ratio [128] . A low testosterone-to-estradiol ratio contributes to increase the cardiovascular risk particularly in elderly [129] and in those with previous cardiovascular diseases [130] [131] [132] . In addition, hormonal pattern associated with visceral obesity may play a relevant role in reducing the efficacy of immune response against infectious agents, predisposing to cytokine dysregulation, endothelial dysfunction, thrombosis, finally driving patients, particularly men, to poor prognosis or death [133] . Moreover, ACE 2 is also expressed on adipose cells [134] and a larger extension of adipose tissue in obese patients may significantly increase the number of available receptors for SARS-CoV-2, thus leading to a much greater viral shedding once the infection occurs [135] . In conclusion, multiple diabetes-associated chronic comorbidities, particularly obesity, have been found to worsen the prognosis in COVID-19 affected patients by acting as independent risk factors. Careful management and prompt interventions are thus required for improve clinical outcome predominantly in type 2 diabetic patients. Pathogenetic mechanisms basically involved in SARS-CoV-2 infection may be exacerbated by the use of concomitant medications for the management of T2D. Of note, an exaggerate pulmonary and systemic expression of ACE 2 facilitates SARS-CoV-2 replication and may be responsible for worse clinical course and poor prognosis [94, 95] . In animal model, pioglitazone has demonstrated to increase ACE 2 expression particularly at the level of hepatic and adipose tissue [136, 137] . On the other hand, the analysis of potential therapeutic targets for SARS-CoV-2 assessed by a computational model found pioglitazone to have a potential for inhibiting 3CLpro, an essential target for viral replication [138] . These findings did not provide conclusive assumption and diabetologists can safely prescribe pioglitazone taking into account general concerns including fluid retention and heart failure [139] . Gliflozins prescription is increasing over time, also considering a long-term beneficial cardiovascular and renal protection [140, 141] . Many mechanisms of cardiovascular and renal protection have been proposed, including an enhanced induction of ACE 2 expression at the level of heart and kidney but it is unclear whether this effect may negatively influence clinical course in COVID-19 [142] . Moreover, despite gliflozins reduce inflammatory injury and endothelial dysfunction, none conclusive data are currently available to confirm their potential beneficial effect in diabetics with COVID-19 [143] . Concerns about gliflozins use in COVID-19 are attributable to volume contraction, renal insufficiency and increased risk of ketoacidosis that may be supposed to occur particularly in hospitalized patients, including those severely ills. Dipeptidyl peptidase IV (DPP-IV or CD26) is a transmembrane and soluble ectopeptidase largely expressed in human tissues, including airways, lung and leucocytes [144] . Particularly, DPP-IV is specifically involved in MERS pathogenesis given that it mediate MERS-CoV-2 internalization in host cells [145] . No data actually support the role of DPP-IV in the internalization of SARS-CoV-2 and further study are needed to verify this aspect, and for demonstrating clear protective effects [146] . However, DPP-IV inhibitors have shown to potentiate immune response by increasing T-cells survival, consequently enhance immune response [147] , and possibly playing a relevant role in reducing the onset or progression of acute pulmonary manifestations in COVID-19 [145] . Glucagon-like peptide 1 receptor agonists (GLP-1RAs) belong to an effective class of medications approved for the treatment of T2D and for preventing diabetes-related cardiovascular and renal complications over time [148] [149] [150] [151] . Immune response and systemic inflammation play a crucial role in SARS-CoV-2 infection, particularly in case of severe clinical course of the disease. In this clinical scenario, it is speculated that the use of GLP-1RAs could provide both a better glucose control and anti-inflammatory effects with consequent improvement of outcomes in COVID-19 affected patients [143] . In patients with pulmonary inflammation, mononuclear circulating cells express lower level of GLP-1 receptors than controls and this condition is associated with a blunted production of interferon gamma by T cells and NK cells. In addition, the expression of programmed death cell protein 1, which mediates T-cell apoptosis, is enhanced on T-cell surface and consequently the efficiency of cell-mediated immune response is weaken. Liraglutide, a once-daily administered long-acting GLP-1RA, demonstrated to restore the expression of GLP-1 receptors on macrophage surface, and potentiate immunemediated response [152] . In addition, both DPP-IV pharmacological inhibition (linagliptin) and GLP-1RA (liraglutide) were found to contrast pulmonary injury, reduce platelet activation, microvascular thrombosis, and oxidative stress in mice model of endotoxemia [153] . Moreover, GLP-1RAs have been found to reduce the expression of pulmonary IL-33, thus playing an interesting role in contrasting a IL-33 mediated damage in immune-allergic diseases and viral infections [154] . Considering that pancreatic islets express ACE 2 , glucose impairment in COVID-19 diabetic patients could be attributable to a partial insulin deficiency [56] . However, glucose impairment could also be attributable to SARS-CoV-2 infection-induced stress or as the consequence of some medications or treatment protocols, including high-dose glucocorticoids, particularly used in hospitalized patients [155] . Insulin therapy is recommended in hospitalized patients [156] , including those with COVID-19, and a basal-bolus respective to a sliding scale regimen should be preferred in infected patients for avoiding glycaemic excursion and greater glucose variability [157, 158] . Hypertension is frequently observed in T2D patients leading to a consistent increase in the risk of atherosclerotic cardiovascular and renal diseases [159] . ACE inhibitors and angiotensin receptor blockers compared to other antihypertensive medications demonstrated to be more effective to prevent or delay the onset of cardiovascular and renal complications in people with T2D, and are currently used as the first-line treatment in these patients [160, 161] . Evidence from animal models suggested that ACE inhibitors are able to increase the expression of ACE 2 at the level of lung, thus leading to initial clinical concerns about the management of arterial hypertension in diabetic patients [162] . First suggestions advised to replace these medications with calciumchannel blockers in order to avoid undesirable detrimental effects of COVID-19 clinical course [95] . Nevertheless, no sufficient data supported the hypothesis that the use of renin-angiotensin system blockers may interfere with the internalization of SARS-CoV-2 in respiratory cells hence increasing its virulence [163] . In addition, ACE inhibitors and angiotensin receptor blockers protect lung, heart and kidney against inflammation, thus playing a potential beneficial role also in T2D patients with COVID-19 [164] . Statins are usually prescribed especially in T2D patients to protect against cardiovascular complications [165] . The role of statins in COVID-19 is not clearly established, however, some observation should be done. First, COVID-19 is associated with higher cardiovascular mortality specifically in patients with more risk factors, including hypertension and T2D, and statins could be useful to maintain or optimize lipid management and improve endothelial dysfunction in this clinical setting [166] . In animal models, statins inhibit the myeloid differentiation primary response 88 (MYD88) [167] . MYD88 is a protein adaptor for inflammatory signalling pathways downstream of members of Toll-like receptors and IL-1 receptor families, and plays a critical function in the activation and amplification of innate immune response [168] . The inhibition of MYD88 seems to reduce pulmonary inflammatory damage, and to improve survival in SARS-CoV and MERS-CoV infected mice [167] . Patients with established cardiovascular disease, and those at higher risk of atherosclerotic cardiovascular disease including T2D (also in primary prevention) should be advised to maintain current statin treatment also in case of confirmed COVID-19. In patient with active COVID-19, an increased risk of muscular damage has been described and statin therapy could be interrupted for a short period of time in order to favour muscular recovery [169] . T2D should be considered as a risk factor for poor prognosis in COVID-19 due to several reasons, including poor baseline glucose control and high glycaemic variability, diabetes-related immune dysfunction and concurrent comorbidities, also proven to act as independent risk factors for poor prognosis in this clinical setting. Considering that respiratory system remains essentially the leading way for SARS-CoV-2 entering in host, and given that immune barriers are weaken in T2D patients, including resident pulmonary macrophages, neutrophils and T cells [70] , diabetologists could improve clinical outcomes in COVID-19 simply by the use of such a medication with potential for positive immune-modulation and anti-inflammatory effects. Unfortunately, inconclusive deductions are currently available for considering concomitant medications favourable (as well as detrimental) factors in COVID-19 patients with T2D. Despite some putative mechanisms have been identified and some speculative hypothesis have also been formulated indicating that some anti-diabetes medications may improve clinical course in COVID-19 (pioglitazone, gliflozins, DPP-IV inhibitors, GLP-1RA), further studies are needed to clarify the issue. A timely glucose control should be obtained in diabetic patients during pandemic for the purpose to avoid potentially harmful outcomes in case of SARS-CoV-2 infection [170] . Anti-diabetic medications should be used with caution, also considering their impact on patient safety in case of complications related with COVID-19 infection (renal failure, cardio-respiratory burden, ketoacidosis, etc). Oral and non-insulin injectable medications (GLP-1RAs) should be considered to maintain or intensify household glucose control, while insulin treatment is currently known to be safer in case of hospitalized and seriously ill patients [171] . Given this consideration, in seriously ill patients, immune response should be adequately monitored in order to carefully predict or precociously diagnose a severe disease [172] and cytokines, including IL-6, may be considered as a goal for novel and more specific target therapies particularly in T2D individuals [173] [174] [175] . Beyond the risks strictly related with COVID-19 infections in diabetic patients, further concerns should be taken into account. Social distancing and lockdown have been proposed as the most effective action to prevent and reduce spread of SARS-CoV-2 infection [176] . Consequently, more time has been spent in household and access to public and private services has been consistently reduced. Thus, several barriers exist for diabetic patients to maintain an adequate fitness status and weight management as well as access to ambulatory care for obtaining adequate treatment adjustments [177] . In the last few months, home confinement led to physical inactivity and low exposure to sunlight, with possible detrimental effects particularly in diabetic and obese patients [119] . Physical exercise should be encouraged also at home or outdoor, even respecting social distancing rules, since it promotes weight loss, and improves cardiorespiratory fitness [121] ; reduces levels of cortisol thus reinforcing immune response against infections; induces T-cell differentiation and maturation [178] . Importantly, patients should be advised about risks and supported regarding pandemic-related concerns. Particularly, they should be elucidated about general hygienic tips to protect themselves and others from SARS-CoV-2 spread; promptly recognize COVID-19 signs and symptoms; access orderly to approved testing if exposed; furthermore, it is important to avoid unnecessary routine appointment in person especially for elderly patients [179] . Closely monitoring of glucose control should be recommended at home and glucose reports should be periodically sent to the diabetologist for proper therapy adjustments [180] . The hard lesson form Lombardy disaster probably teaches to change prospective in the conception of patients care during the present and in case of further pandemic. Implementation of community-centred care system (home care and mobile clinics) may result in a prompt detection and better management of infected patients particularly for frail individuals. Moreover, it might contain an unnecessary hospital workload, letting hospital activities to focus mainly on acute cares and limiting contagion risks among inpatients and healthcare personnel. Finally, it could provide at home special cares for elderly and comorbid patients [181] . In this historical moment, the use of technologies appears certainly appropriated to better manage chronic clinical conditions, including DM [182] [183] [184] . 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c1: Daryabor, Gholamreza
c2: The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System
c3: 2020-07-22
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c7: 438
c8: 25
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  The endocrine part is made of different cell types, including α, β, δ, and ε cells that secrete glucagon, insulin, somatostatin, and ghrelin hormones, respectively. A humanin analog decreases oxidative stress and preserves mitochondrial integrity in cardiac myoblasts Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2 Novel clearance mechanisms of platelets Flow cytometric analysis of platelets type 2 diabetes mellitus reveals 'angry' platelets Platelet activity and hypercoagulation in type 2 diabetes Increased circulating resistin is associated with insulin resistance, oxidative stress and platelet activation in type 2 diabetes mellitus Increased levels of soluble adhesion molecules in type 2 (non-insulin dependent) diabetes mellitus are independent of glycaemic control Molecular mechanisms underpinning microparticle-mediated cellular injury in cardiovascular complications associated with diabetes Association between mean platelet volume in the pathogenesis of type 2 diabetes mellitus and diabetic macrovascular complications in Japanese patients Increased erythrocyte-and platelet-derived microvesicles in newly diagnosed type 2 diabetes mellitus Type 2 diabetes and cardiovascular disease: have all risk factors the same strength? Advanced glycation end products induce a prothrombotic phenotype in mice via interaction with platelet CD36 Central role of the P2Y12 receptor in platelet activation Long non-coding RNA metallothionein 1 pseudogene 3 promotes p2y12 expression by sponging miR-126 to activate platelet in diabetic animal model Introduction to the human gut microbiota Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection Faecalibacterium prausnitzii-derived microbial anti-inflammatory molecule regulates intestinal integrity in diabetes mellitus mice via modulating tight junction protein expression Considering gut microbiota in treatment of type 2 diabetes mellitus Metformin effect on gut microbiota: insights for HIV-related inflammation The bacterium Akkermansia muciniphila: a sentinel for gut permeability and its relevance to HIV-related inflammation High glucose decreases intracellular glutathione concentrations and upregulates inducible nitric oxide synthase gene expression in intestinal epithelial cells The role of iron in diabetes and its complications Hyperglycemia promotes microvillus membrane expression of DMT1 in intestinal epithelial cells in a PKCalpha-dependent manner Betacell deficit and increased beta-cell apoptosis in humans with type 2 diabetes Fatty acid-induced lipotoxicity in pancreatic beta-cells during development of type 2 diabetes Mesenchymal stem cell therapy in type 2 diabetes mellitus Establishment of insulin-producing cells from human embryonic stem cells underhypoxic condition for cell based therapy Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction A simple method for the generation of insulin producing cells from bone marrow mesenchymal stem cells Secretagogin affects insulin secretion in pancreatic beta-cells by regulating actin dynamics and focal adhesion Secretagogin regulates insulin signaling by direct insulin binding.

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  cells; diabetes; diabetes mellitus; disease; dm patients; dysfunction; endothelial; et al; expression; glucose; human; immune; individuals; infections; inflammation; insulin; levels; macrophages; mellitus; mice; patients; resistance; risk; role; t2 dm; type

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   key: cord-336201-fl606l3b authors: Daryabor, Gholamreza; Atashzar, Mohamad Reza; Kabelitz, Dieter; Meri, Seppo; Kalantar, Kurosh title: The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System date: 2020-07-22 journal: Front Immunol DOI: 10.3389/fimmu.2020.01582 sha: doc_id: 336201 cord_uid: fl606l3b Metabolic abnormalities such as dyslipidemia, hyperinsulinemia, or insulin resistance and obesity play key roles in the induction and progression of type 2 diabetes mellitus (T2DM). The field of immunometabolism implies a bidirectional link between the immune system and metabolism, in which inflammation plays an essential role in the promotion of metabolic abnormalities (e.g., obesity and T2DM), and metabolic factors, in turn, regulate immune cell functions. Obesity as the main inducer of a systemic low-level inflammation is a main susceptibility factor for T2DM. Obesity-related immune cell infiltration, inflammation, and increased oxidative stress promote metabolic impairments in the insulin-sensitive tissues and finally, insulin resistance, organ failure, and premature aging occur. Hyperglycemia and the subsequent inflammation are the main causes of micro- and macroangiopathies in the circulatory system. They also promote the gut microbiota dysbiosis, increased intestinal permeability, and fatty liver disease. The impaired immune system together with metabolic imbalance also increases the susceptibility of patients to several pathogenic agents such as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, the need for a proper immunization protocol among such patients is granted. The focus of the current review is to explore metabolic and immunological abnormalities affecting several organs of T2DM patients and explain the mechanisms, whereby diabetic patients become more susceptible to infectious diseases. The metabolic syndrome is defined by the presence of metabolic abnormalities such as obesity, dyslipidemia, insulin resistance, and subsequent hyperinsulinemia in an individual (1) . Dyslipidemia, the main characteristic of metabolic syndrome, is defined by decreased serum levels of high-density lipoproteins (HDLs) but increased levels of cholesterol, free fatty acids (FFAs), triglycerides (TG), VLDL, small dense LDL (sdLDL), and oxidized LDL (ox-LDL) ( Table 1 ) (2) . Individuals with the metabolic syndrome are much more likely to develop type 2 diabetes mellitus (T2DM), cardiovascular diseases (CVDs), and fatty liver disease (2) (3) (4) . T2DM, the most common form of diabetes (∼90%), is characterized by a systemic inflammatory disease accompanied by insulin resistance (IR) or decreased metabolic response to insulin in several tissues, including the adipose tissue, liver, and skeletal muscle, as well as by reduced insulin synthesis by pancreatic beta cells (4, 5) . Studies on immunometabolism have indicated that the metabolic states and immunological processes are inherently interconnected (6) . In this scenario, metabolites derived from the host or microbiota regulate immunological responses during health and disease (6) . Accordingly, in obese individuals, expanded adipose tissue at different locations, by initiating and perpetuating the inflammation, induces a chronic low-level inflammatory state that promotes IR (4). Every organ system in human body can be affected by diabetes, but the extent of organ involvement depends largely on the severity and duration of the disease (Figure 1 and Table 1 ). During the progression of diabetes, hyperglycemia promotes mitochondrial dysfunction and induces the formation of reactive oxygen species (ROS) that cause oxidative stress in several tissues such as blood vessels and pancreatic beta cells (7) (8) (9) . Accumulating damage to the mitochondria, as well as several macromolecules, including proteins, lipids, and nucleic acids by ROS promotes the process of aging (10) . As a result, pancreatic β cells that require functional mitochondria to maintain insulin synthesis fail to generate high enough levels of insulin (11, 12) . In the absence of compensatory mechanisms, stress-responsive intracellular signaling molecules are activated and cellular damage occurs. Elevated intracellular levels of ROS and subsequent oxidative stress play an important role in the pro-atherosclerotic consequences of diabetes and the development vascular complications (9, 13) . Moreover, the non-enzymatic covalent attachment of glucose and its toxic derivatives [e.g., glyoxal, methylglyoxal (MGO), and 3deoxyglucosone] to the biological macromolecules such as nucleic acids, lipids, and proteins leads to the formation of advanced glycation end products (AGEs) (14, 15) . Accumulated AGEs block the insulin signaling pathway and promote inflammation (16, 17) . In addition, the attachment of AGEs to their receptors [e.g., CD36, galectin-3, scavenger receptors types I (SR-A1), and II (SR-A2)] on the surfaces of immune cells in the circulation and tissues activates the expression of pro-inflammatory cytokines and increases free radical generation (18) . Furthermore, due to the chronic exposure of cells to high glucose levels in untreated T2DM patients, glucose toxicity might occur in several organs. This will FIGURE 1 | Effects of T2DM on body organs. T2DM is an inflammatory state that affects circulatory system, gastrointestinal tract, pancreatic beta cells, liver, and skeletal muscles and makes them dysfunctional. NFALD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ER, endoplasmic reticulum. eventually lead to nephropathy, cardiomyopathy, neuropathy, and retinopathy. Gut microbiome dysbiosis is another important factor that can facilitate the induction and progression of metabolic diseases such as T2DM (19) . The gut microbiome dysbiosis, by altering the barrier functions of intestine and the host metabolic status, promotes the insulin resistance in diabetic patients (19) . Diabetes also impairs the immune system and increases the susceptibility of patients to serious and prolonged infections (20) . This is likely to be the case with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as well (21, 22) . In the current paper we will review recent research to explore the impairment of body organs in T2DM patients and explain how diabetic patients become more susceptible to certain infectious diseases. Vascular homeostasis is an important function of the endothelium. Under homeostatic conditions, the ECs maintain the integrity of blood vessels, modulate blood flow, deliver nutrients to the underlying tissues, regulate fibrinolysis and coagulation, control platelet adherence and patrol the trafficking of leukocytes (Figure 2A ) (23) . Normal ECs also internalize high-density lipoproteins (HDLs) and its main protein part apolipoprotein A-I (apoA-I) in a receptor-mediated manner to activate endothelial cell nitric oxide (eNOS) synthase and promote anti-inflammatory and antiapoptotic mechanisms ( Figure 2B ) (24) . HDL receptors on the surfaces of ECs include: the ATP-binding cassette (ABC) transporters A1 and G1, the scavenger receptor (SR)-B1 and the ecto-F1-ATPase (24) . According to the epidemiological studies, diabetes mellitus is considered as one of the main risk factors for CVD (Figure 1 ) (25) . From the beginning of T2DM, the functions of ECs are impaired, which is the main cause of disease-related side-effects (26) . ECs can initiate and perpetuate the inflammatory milieu during the pathogenesis of diabetes. Due to the negative impacts of hyperglycemia and subsequent oxidative stress, CVDs are more common among diabetic patients (27) . It has been observed that incubation of human aortal endothelial cells (HAECs) with a medium containing high glucose concentrations (HG, 20 mM) increases the intracellular levels of MGO and glycated proteins that in turn activate the unfolded protein response (UPR) and trigger inflammatory and prothrombotic pathways (28) . Glycated apoA-I, which is formed during hyperglycemia, modifies its structure, decreases its lipid-binding ability, prevents cholesterol efflux from macrophages and impairs its anti-inflammatory function (29, 30) . Vaisar et al. have shown that HDLs from diabetic patients have a reduced capacity to trigger eNOS production and suppress tumor necrosis factor-α (TNF-α)mediated inflammatory responses within ECs (31) . Diseases such as T2DM that induce high levels of vascular injury are accompanied by an elevated number of circulating endothelial cells (CECs) (32) . T2DM-related risk factors such as dyslipidemia, hyperglycemia, and hyperinsulinemia as well as other conditions (e.g., inadequate physical activity, smoking, and high blood pressure) facilitate the formation of atherosclerotic plaques/lesions (33) . Dyslipidemia, due to the elevated flux of FFA from insulin-resistant tissues and spillover from entry (C) Blood vessels in T2DM patients. During the progression of the disease, red blood cells become glycated, while activated ECs synthesize elevated levels of adhesion molecules and chemokines that facilitate monocytes recruitment, adhesion, and transmigration across the endothelium toward the subendothelial region. Monocytes are then differentiated into macrophages and eventually, by excess lipid uptake, generate foam cells. Subsequently, further immune cell infiltration into the atherosclerotic lesion occurs, where their inflammatory cytokines promote platelet activation, EC apoptosis, and increased generation of ROS and Ox-LDL. (D) interactions between oxLDL and its receptor aggravate ROS generation, NF-κB activation and inflammation. EC, endothelial cell; RBC, red blood cell; PLT, platelet; HDL, high-density lipoprotein; Ox-LDL, Oxidized low-density lipoprotein; ROS, reactive oxygen species; eNOS, endothelial nitric oxide synthase; NO, Nitric oxide; LOX-1, lectin-type oxidized LDL receptor 1. into adipocytes, is considered as an important risk factor for developing CVD among diabetic patients. This is because dyslipidemia promotes inflammation, endothelial dysfunction, and platelet hyperactivation (34, 35) . During the progression of atherosclerosis, lipids, immune cells, and extracellular matrix accumulate in the arterial intima or subendothelial regions ( Figure 2C ) (33) . Advanced plaques can impede blood flow and cause tissue ischemia or might become disrupted and generate a thrombus that stops the blood flow of important organs. Vascular complications of diabetes engage either tiny or large blood vessels (micro-and macroangiopathy, respectively). Microangiopathies, which can be seen in the kidneys, vasa nervorum and eye tissues, cause nephropathy, neuropathy, and retinopathy. Macroangiopathies, by inducing atherosclerosis in the coronary, carotid, and peripheral arteries, increase the risk of myocardial infarction (MI), stroke and peripheral artery disease (PAD). Macrovascular complications due to EC dysfunction are considered as an important cause of mortality and morbidity among diabetic patients (36) . Oxidative stress has an essential role in the induction of vascular complications during the course of diabetes (8) . EC dysfunction (e.g., delayed replication, dysregulated cell cycling, and apoptosis), as well as enhanced ox-LDL formation are some consequences of oxidative stress. It has been well-established that sdLDL and ox-LDL have an enhanced atherogenic ability and are more useful biomarkers than total LDL for predicting CVD (37, 38) . sdLDL particles have a smaller size than other LDL particles. Thus, sdLDL particles are more easily oxidized, and their atherogenic potential is enhanced. During oxidative stress, levels of ox-LDL increase by the excess action of reactive oxygen species (ROS) (13) . Subsequently, ox-LDL interaction with scavenger receptors, including CD36, SR-A1/CD204, SR-B1, and lectin-like ox-LDL receptor-1 (LOX-1) on the surface of ECs activates the NADPH oxidase that in turn increases the expression of ROS and activates the transcription factor NF-αB (39) . Afterwards, the expression of LOX-1, adhesion molecules (e.g., selectins and integrins) and the secretion of pro-inflammatory cytokines and chemokines are increased, while NO synthesis is decreased in ECs ( Figure 2D ) (39) (40) (41) . EC-derived chemokines bind to their cognate receptors on the surfaces of monocytes and recruit them toward the inflamed endothelium. Following this, selectin-based rolling and integrin-based attachment of monocytes to the ECs cause their migration toward the subendothelial region, where they develop into lipid-laden macrophages or foam cells later on (42) . The scavenger receptor LOX-1 plays an important role in the uptake of ox-LDL during atherogenesis. It is strongly expressed on the surfaces of ECs, but has an inducible pattern of expression on the surface of macrophages and smooth muscle cells (43) . The accelerated uptake of ox-LDL by macrophages accounts for their transformation into foam cells, the initial hallmark of atherosclerosis (41, 43) . Besides, diabetes leads to both quantitative and qualitative defects in circulating angiogenic progenitor cells (CAPCs) that take part in the repair of injured endothelium (44) . It has been shown that humans or mice with decreased numbers of CD31 + CD34 + CD133 + CD45 dim Sca-1 + Flk-1 + CAPCs have an increased prevalence of T2DM, elevated HbA1c levels and aggravated CVD risk scores (44, 45) . In diabetic patients, despite elevated serum levels of proangiogenic molecules, like angiopoietin-1/2, EPO, and VEGF-A, angiogenesis is impaired. This is mainly due to the decreased expression levels of VEGFR2 and CXCR4 on the surfaces of CAPCs, which makes them unresponsive to the angiogenic factors (44, 46) . It has also been shown that circulating proangiogenic granulocytes composed of eosinophils and neutrophils are also impaired in diabetic patients (47) . Besides, elevated levels of AGEs in T2DM cause EC dysfunction and vascular inflammation (48) . Ren et al. have shown that incubation of human coronary artery endothelial cells (HCAECs) with AGEs causes decreased expression (at both mRNA and protein levels) and enzymatic activity of eNOS, increased levels of ROS, diminished mitochondrial membrane potential and declined activity of catalase and superoxide dismutase in treated cells (49) . Another study by Lan et al. has shown that AGEs in the pancreas decrease EC viability and induce their apoptosis in an NFκB signaling-related manner (50) . However, apigenin (4 ′ ,5,7trihydroxyflavone) can protect ECs against oxidative stress and subsequent inflammatory reactions mediated by AGEs (51) . Apigenin binds to methylglyoxal (MGO) and forms a complex that inhibits AGE formation. Chettab et al. have shown that the expression of ICAM-1 as well as the production of IL-8, are significantly increased in HUVECs cultured in HG medium compared to cells cultured in normal glucose (NG, 5.5 mM) conditions (52). Bammert et al. found out that incubation of HUVECs with HG media promotes the generation of endothelial microparticles (EMPs) that, when added to normally cultured HUVECs, downregulate the expression of anti-apoptotic microRNA miR-Let7a, but enhance the synthesis of active caspase-3 and cause cell apoptosis (53) . Several microRNAs, including miR-21, miR-26a, miR-30, miR-92a, miR-126, miR-139, miR-199a, miR-222, and miR-let7d, regulate vascular homeostasis. It has been shown that the expressions of miR-26a and miR-126 are significantly reduced in circulating MPs isolated from diabetic patients compared with normal individuals. This could be involved in making diabetic individuals more susceptible to coronary heart disease (54) . Moreover, HG media upregulate the expression of NADPH oxidase that will induce the generation of ROS. This leads to subsequent apoptosis of the HUVECs through a ROS-dependent caspase-3 pathway (55). Su et al. have demonstrated that argirein medication, by inactivating NADPH oxidase, can prevent endothelial cell apoptosis in a rat model of T2DM and hence attenuate vascular dysfunction (56) . HG further increases the permeability of the HUVECs in a protein kinase C (PKC)-dependent manner (57, 58) . Hassanpour et al. showed that incubation of endothelial progenitor cells with the serum of T2DM patients inhibits their migration toward bFGF, increases their expression of VEGFR-2, but reduces their expression of VEGFR-1 and induces their apoptosis (59) . However, humanin (HN), a mitochondriumderived peptide, is cytoprotective against apoptosis during pathological conditions, such as diabetes mellitus (60) . It has been demonstrated that simultaneous incubation of H9C2 cells, a line of rat cardiac myoblasts, with H 2 O 2 and HN decreases the intracellular levels of ROS, preserve mitochondrial function/structure and decline cellular apoptosis (61) . Wang et al. have indicated that the treatment of HUVECs with HN before their incubation with HG medium increases the expression of eNOS, while decreasing the expression of endothelin 1 (ET-1), VCAM-1, TNF-α, IL-1β, and E-selectin in a krüppellike factor 2 (KLF2)-dependent manner. Such changes in the expression of integrins prevent the attachment of monocytes to HUVECs (62) . Accordingly, HN might be used to prevent the development of hyperglycemia-associated EC dysfunction in T2DM. EC activation and expression of adhesion molecules also facilitate activation and adhesion of platelets. This will increase the risk of thrombosis and promote the development of thrombotic angiopathy, typical for diabetic patients. Platelets are tiny anucleated cellular fragments generated from megakaryocytes in the bone marrow. They circulate in the blood for ∼5-9 days and play essential roles in hemostasis and in controlling vascular integrity (63) . Circulating inactive platelets move in the proximity of vessel walls (Figure 2A ) and rapidly get activated in response to vascular injury. At the end of their life, platelets are cleared from circulation with the action of the liver and spleen-resident macrophages. Platelets have an essential role in the initiation and progression of inflammation. Platelet hyperactivation that occurs during inflammatory states (e.g., T2DM) facilitates the pathogenesis of CVDs ( Figure 2C ) (64, 65) . It has been shown that elevated levels of resistin, an adipokine, in diabetic patients enhances oxidative stress, promotes endothelial dysfunction and facilitates platelet activation (66) . Activated platelets with an increased mean volume [mean platelet volume (MPV)] secrete microparticles (MPs) and soluble adhesion molecules (e.g., sP-selectin and sCD40L) that in turn activate endothelial and immune cells (67) (68) (69) . Higher levels of platelet-derived MPs, which correlate positively with fasting blood sugar and glycated hemoglobin, have been shown in newly diagnosed T2DM patients compared to healthy individuals (70) . In T2DM patients thrombotic microangiopathies can lead to the development of CVDs (71) . Platelets in the patients adhere to ECs and aggregate more rapidly than in healthy individuals thereby increasing the risk of thrombosis. In a mouse model of T2DM, Zhu et al. have shown that AGEs interact with CD36, a member of the type 2 scavenger receptor family, on the surfaces of murine platelets to activate them and induce a prothrombotic state (72) . Elevated levels of the P2Y12 receptor on the surface of platelets in T2DM expose diabetic patients to a prothrombotic condition. This receptor has an essential role in platelet activation (73) . Zhou et al. have shown that long non-coding RNA (lncRNA) metallothionein 1 pseudogene 3 (MT1P3), which is markedly upregulated in megakaryocytes of T2DM patients, enhances the expression of p2y12 receptor in platelets (74) . They indicated that this is due to the inhibitory action of MT1P3 on miR-126. Virtually all parts of the human digestive system, including the gastrointestinal tract, pancreas, and the liver are affected by diabetes. The GIT is populated with a myriad of microorganisms, including principally bacteria but also archaea, viruses, fungi, and protozoans that dynamically influence the health status and homeostasis of the host. The physiological functions of the GIT resident microbes improve gut integrity, protect against microbial pathogens and regulate immune responses (75) . Mucosal barriers, such as intestinal epithelial cells (IECs) and the mucus layer, spatially isolate the host immune system and gut microbiota to prevent unnecessary immune activation and intestinal inflammation. They also facilitate the uptake of nutrients through receptors and transporters. However, hyperglycemia, in a GLUT2-dependent manner, can influence the mucus and alter the integrity of adherence and tight junctions between intestinal epithelial cells of diabetic mice. This will enhance the permeability of the intestinal barrier leading to so called "leaky gut." Subsequently, hyperglycemia may facilitate the dispersal of an enteric infection into a systemic infection (Figure 1 ) (76) . Interestingly, the reversal of hyperglycemia, conditional deletion of GLUT2 from the IECs and inhibition of glucose metabolism will fix the barrier dysfunction and prevent the spread of bacteria (76). Xu et al. have shown that Faecalibacterium prausnitzii, one of the most frequent commensal bacteria in normal individuals with essential roles in gut homeostasis, generates anti-inflammatory molecules that enhance the expression of tight junctions and improve intestinal integrity during diabetes (77) . However, in some cases, gut microbiota dysbiosis or altered microbial composition of the intestines could induce T2DM and lead to its progression (78) . Of interest, the widely used antidiabetic drug metformin can improve barrier integrity and restore the healthy microbiota composition of the gut in diabetic patients (79) . The intestinal commensal bacterium Akkermansia muciniphila can also act as a sentinel to reduce microbial translocation across the gut and prevent the subsequent inflammation in patients with T2DM (80) . Hyperglycemia can further decrease the intracellular levels of glutathione (GSH) but increase iNOS activity and NO production in the IECs (81). Zhao et al. have found out that hyperglycemia in a PKCα-dependent manner inhibits the ubiquitination, internalization and degradation of the divalent metal transporter 1 (DMT1) present on the microvillar membranes of IECs. Subsequently, intestinal iron uptake is enhanced and accumulated iron ions aggravate diabetes-related complications and increase mortality (82, 83) . The pancreas consists of the exocrine and endocrine compartments. The endocrine part is made of different cell types, including α, β, δ, and ε cells that secrete glucagon, insulin, somatostatin, and ghrelin hormones, respectively. These cells are aggregated into specialized structures called islets of Langerhans, which play an important role in controlling blood glucose levels through the secretion of insulin and glucagon. In T2DM, despite normal levels of β-cell replication and islet formation, β-cell apoptosis is increased so that the number of cells declines by ∼50% (Figure 1 ) (84) . During the progression of T2DM, the insulin-resistant state forces β-cells to compensate for the lack of insulin by elevating its synthesis to restore the normal blood glucose level. However, in severe diabetic patients, β-cell exhaustion, and subsequent persistent hyperglycemia occur (7) . Furthermore, chronic elevated serum levels of free fatty acids, seen in obesity and T2DM, induce lipotoxicity in beta-cells and suppress their insulin secretion ability (85) . To alleviate chronic inflammation, overcome insulin resistance (IR) and to prevent β-cell apoptosis, stem cells or stem cell derivatives such as insulin-producing cells (IPCs) and exosomes have been suggested (86) (87) (88) (89) . Their effects are believed to be mainly due to their anti-inflammatory activities. Secretagogin (SCGN) is predominantly expressed by pancreatic β-cells protecting their normal functions. SCGN also acts as an insulin binding protein to make it more stable, avoid its aggregation, improve its functions and enhance its secretion (90, 91) . In T2DM patients, due to the islet cell dysfunction and endoplasmic reticulum (ER) stress, serum levels of SCGN are elevated reflecting stress and dysfunctional islet cells (92) . Moreover, in patients with T2DM, islet amyloid polypeptide (IAPP or amylin), a peptide hormone and one of the main secretory products of pancreatic β-cells, tends to deposit in the islets of Langerhans, form insoluble fibrils and impair secretory functions of β-cells (93) . IAPP is costored with insulin in the secretory granules of pancreatic β cells. In steady-state conditions it regulates food intake, insulin secretion, and glucose metabolism (94). Ribeiro et al. have noted that pancreatic extracellular vesicles (EVs) from healthy individuals, but not from T2DM patients, directly bind to IAPPs and prevent amyloid formation within the pancreatic islets (95) . The authors showed that the altered protein-lipid composition of the EVs is the main reason for this discrepancy (95) . However, Chatterjee et al. have shown that β-cells from T2DM patients have a dysfunctional proteasome complex that fails to degrade pancreatic IAPP, whereby amyloid formation is induced (96) . Furthermore, in T2DM patients, lipids accelerate the formation of fibrillary IAPP, which aggravates islet cell damage (97) . Dhar et al. have demonstrated that chronic use of MGO in Sprague-Dawley rats increases the expression of NF-αB, MGO-derived AGEs and their receptors in pancreatic β cells. MGO can also induce apoptosis of islet β cells, increase fasting plasma glucose levels and impair glucose tolerance (98) . In T2DM patients the plasma level of MGO directly correlates with fasting blood sugar and HbA1c levels (99) . Bo et al. further showed that MGO in a dose-based manner impairs insulin secretion of pancreatic β-cell lines MIN6 and INS-1 through increased generation of ROS and by induction of mitochondrial dysfunction (100). Robertson et al. have found out that elevated levels of ROS in pancreatic β-cells inhibit the pancreas duodenum homeobox-1 (PDX-1) transcription factor that is needed for insulin synthesis (7) . It has been shown that chronic use of MGO in animals could induce T2DM, while simultaneous use of alagebrium, which breaks AGE compounds, attenuates the disease (98) . It has also been reported that during the course of diabetes dedifferentiation and conversion of β-cells into αand δ-"like" cells occurs (101) . In conclusion, the pancreatic β cell function is progressively reduced during the progression of T2DM. The liver is by far the most important metabolic organ with essential roles in regulating homeostasis and mediating glucose and lipid metabolism. Metabolic activities of the tissue are precisely controlled by the actions of metabolic substrates, including free fatty acids (FFAs) and hormones (102) . T2DM patients usually suffer from a chronic liver condition called non-alcoholic fatty liver disease (NAFLD). It is characterized by steatosis that means ectopic fat storage in hepatocytes and subsequent insulin resistance (Figure 1 ) (103) . Lipid accumulation in hepatocytes leads to impaired biogenesis of miR-206 that facilitates insulin signaling and prevents lipogenesis (104) . Several factors such as obesity, increased serum levels of fatty acids, and insulin resistance can increase the risk of fatty liver disease. P2Y2 receptor, through the induction of the c-Jun N-terminal kinase (JNK) and prevention of insulin signaling, can promote insulin resistance in hepatocytes in T2DM (105) . In some cases, NAFLD may progress into an aggressive form of inflammatory fatty liver disease called non-alcoholic steatohepatitis (NASH), which might cause liver cirrhosis and organ failure (106). Dang et al. have indicated that exosomes released from the adipose tissues of obese mice due to the smaller miR-141-3p content can promote insulin resistance in the murine hepatocyte cell line AML12 (alpha mouse liver 12) (107) . The adipokine visfatin that is released from the adipose tissue of obese individuals has also been shown to activate the pro-inflammatory STAT3 signaling pathway and NF-κB in the human liver cell line HepG2 and promote their insulin resistant state (108) . Nevertheless, the hepatocyte growth factor (HGF) can alleviate the insulin resistance of hepatocytes and control their triglyceride and cholesterol contents (109) . Skeletal muscle (SM) is the main tissue that releases glucose after insulin stimulation. Hence, insulin resistance in SM has a pivotal role in the metabolic dysregulation of T2DM. Insulin resistance in SM is the primary defect of T2DM that facilitates the progression of fatty liver disease, deposition of fat in the liver (Figure 1 ) (110) . Skeletal muscle from diabetic patients expresses less genes related to insulin signaling and metabolic pathways, but more apoptosis and immune-related genes (111) . This inflammatory milieu is mainly due to the proinflammatory actions of obesity-related adipose tissue mediators, which are released into the circulation and promote inflammation within the SM (4). Furthermore, obesity causes intermyocellular and perimuscular adipose tissue expansion that acts like adipose tissue depots to enhance SM inflammation (112) . It has been shown that human skeletal muscle cells (hSMC), isolated from diabetic patients, after a 24-h culture generate significantly more TNF-α, IL-6, IL-8, IL-15, monocyte chemotactic protein (MCP)-1, Growth-Related Oncogene (GRO)-α, and follistatin compared to non-diabetic individuals (113) . This altered secretion of myokines (e.g., cytokines secreted by SMs) is an intrinsic feature of SM during the progression of T2DM. In SM, GLUT-4, which is quickly translocated to the cell surface, facilitates glucose uptake in response to insulin hormone as well as muscle contraction. Pinto-Junior et al. have shown that the use of AGE-albumin in rats increases the expression of the inflammatory molecule NF-κB1 within the SM. NF-κB1 binds to the promoter of the GLUT-4 gene and suppresses its expression (at both mRNA and protein levels) (114) . Accordingly, GLUT-4 levels on the surfaces of SM decrease and subsequently, whole-body IR develops. The immune system is generally classified into two main arms, innate and adaptive (or acquired) immunity. Adaptive immunity is mediated by B cells, which produce antibodies and T cells, which are classified into CD4 + helper cells and cytotoxic CD8 + cells. A considerable literature has discussed the dysfunctional immune responses in diabetic patients ( Table 2 ) (115) (116) (117) (118) (119) (120) . Abnormal immune cell activation and subsequent inflammatory environment has an essential role in the progression of T2DM (121) . In this regard, chronic inflammation due mainly to the activation of the myeloid cell lineage (e.g., macrophages and neutrophils), is directly related to the induction of IR (4, 122). Their numbers are elevated, are larger and more granular, express diminished levels of antioxidant genes but elevated levels of pro-apoptotic and pro-inflammatory genes. Complement system Attachment of C-type lectin proteins to mannose residues is decreased, lectin pathway is impaired, CD59 activity is reduced, MAC deposition in vascular walls is increased. Dendritic cells (DCs) Their numbers and activity are reduced. Their cholesterol efflux is decreased, generate foam cells, have dysfunctional efferocytosis. Are activated, constitutively release NETs, produce high levels of MPO, ROS, and calprotectin (S100A8/A9), are more susceptible to apoptosis, their migration, phagocytosis and microbial killing are impaired. NK cells Their numbers are increased but are usually dysfunctional, express high levels of GLUT4 but decreased levels of NKG2D and NKp46, have reduced degranulation capacity, are more susceptible to apoptosis. NKT cells Their numbers are increased, produce high levels of IFN-γ, IL-4, and IL-17, express high levels of NKp30, NKG2D, and NKp44 but low levels of NKG2A and 158b. Innate lymphoid cells (ILCs) ILC1s are increased and produce high levels of IFN-γ. Humoral immunity (B cells) Germinal centers are reduced, Ab production and isotype switching is defective, Abs become glycated, Abs fail to activate complement. functions of osteoclasts, which are bone-resident innate immune cells (126) . This may affect bone structure and delay bone healing. Defects in the innate, as well as adaptive immunity, are supposed to be the main cause of diabetic individuals' susceptibility to infections (127) . Furthermore, some microorganisms, especially bacteria, in hyperglycemic conditions are better nourished and become more virulent, while also having a better milieu to cause infections. Complement System The complement system is a first-line defense mechanism against invading microorganisms. It acts via different but interconnected classical, alternative, and lectin pathways (128) . Ilyas et al. have shown that under high glucose conditions, the attachment of Ctype lectin proteins to high-mannose containing glycoproteins is substantially decreased in a dose-dependent manner. These carbohydrate-binding proteins include mannose-binding lectin (MBL), surfactant protein D (SP-D), dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN, CD209), and DC-SIGN-related (DC-SIGNR) protein (129) . Reduced binding of MBL in the presence of high levels of sugar causes a significant reduction in the lectin pathway activity, but does not influence classical or alternative pathway activity (129) . Nevertheless, Barkai et al. did not find significant differences in the function of classical or MBL pathways between T2DM and healthy individuals (130) . However, significantly decreased activity of ficolin-3-mediated lectin and alternative pathways, as well as decreased levels of C4d and soluble complement C5b-9 (sC5b-9) were seen in diabetic patients with Escherichia coli-mediated urinary tract infections (130) . This may be linked to a reduced ability of diabetics to protect themselves against bacterial infections. The lipopolysaccharides of certain Gram-negative bacteria, like Salmonella serotype O6,7 as well as the cell walls of fungi, are rich in mannose. Possibly, because of this, in addition to additional provision of nutrients, an increased prevalence of fungal infections is seen in T2DM patients (131, 132) . Patel et al. found a significantly higher prevalence of oral candida carriage in diabetic patients compared to healthy controls (131) . They found that Candida albicans was the most commonly isolated species followed by C. tropicalis, but uncommon species such as C. lusitaniae and C. lipolytica were also isolated (131) . Another study by Jhugroo et al. showed that C. albicans is the predominant yeast isolated from oral mucosal lesions of diabetic patients, followed by. C. tropicalis and C. krusei Dendritic cells (DCs) are a heterogeneous population of specialized and professional antigen-presenting cells (APCs) that create a crucial link between the innate and adaptive immune responses (136, 137) . Some studies have shown that the numbers of DCs are reduced in both type 1 and 2 diabetes (138, 139). Seifarth et al. have found that T2DM patients with poor metabolic control have decreased numbers of both myeloid and plasmacytoid DCs compared with healthy controls. This could make them more susceptible to opportunistic infections (139) . In the case of good blood glucose control, the reduction in DC numbers was less prominent but still significant, especially for myeloid DC1 (mDC1) cells (139) . Another study by Blank et al. demonstrated that women with T2DM and poor glycemic control (HbA1c ≥ 7%) have fewer numbers of circulating plasmacytoid DCs (pDCs) compared to diabetic women with good glycemic control (HbA1c < 7%) or to healthy women (140). Montani et al. have recently shown that hyperglycemic medium and hyperglycemic sera derived from T2DM patients prevent the maturation of monocytes into effective DCs and their activation in vitro (141) . Interestingly, quercetin, a flavonoid with antiinflammatory and antioxidant characteristics, prevented such effects (141) . Macrophages are important immune cells that play critical roles through all stages of the pathogenesis of T2DMrelated atherosclerosis (41). Swirski et al. have shown a significantly elevated number of pro-inflammatory monocytes in the circulation of ApoE −/− mice, an animal model of atherosclerosis, compared to control mice (142) . Modifications of the lipoproteins in the arterial walls of diabetic individuals make them pro-inflammatory and activate the overlying endothelium. In response, monocytes are recruited into the subendothelial region, differentiate into macrophages and internalize the accumulated lipoproteins. Finally, cholesterol-laden foam cells are generated. They promote inflammation and progression of the disease through the synthesis and secretion of cytokines, chemokines, ROS, and matrix metalloproteinases (MMPs) (Figure 2C ) (42) . Foam cells lose their migratory potential, die by apoptosis and generate a necrotic core within the atherosclerotic plaque (143) . It has been demonstrated that the use of mesenchymal stem cells in ApoE −/− mice reduces the numbers of monocytes/macrophages at the site of inflammation, decreases lipid deposition and diminishes plaque size (144). Ma et al. have studied the effects of long-term hyperglycemia in diabetic mice and found out that compared to non-diabetic control mice, the numbers of F4/80 + macrophages isolated from spleen (SPMs), as well as from peritoneal exudates (PEMs) of diabetic mice are significantly decreased (145) . Subsequently, Sun et al. showed that stimulation of PEMs from diabetic mice in vitro with IFN-γ and lipopolysaccharide (LPS) significantly decreased the expression of intercellular adhesion molecule 1 (ICAM-1 or CD54), CD86, TNF-α, and IL-6, while it increased the production of nitric oxide (NO) (146) . They further showed that stimulation of PEMs isolated from diabetic mice with IL-4 caused an enhanced arginase activity (146) . Kousathana et al. have demonstrated that circulating monocytes isolated from diabetic patients produce higher levels IL-6, while having an impaired activation of the NLRP3 inflammasome and subsequently reduced IL-1β production (147) . However, they showed that proper glycemic control would restore such modifications. Poor inflammatory responses in circulating monocytes, as well as in macrophages, are responsible for elevated susceptibility to infections and their severity in patients with T2DM. Macrophages play a critical role in tissue repair. Early in wound healing, they are pro-inflammatory to clear pathogens and debris but later, they resolve inflammation and promote tissue repair. In pathological conditions, failure to transform from pro-inflammatory to the anti-inflammatory proliferative phase can cause chronic inflammation in the affected tissue (148). have shown that an impaired wound healing process in animals with T2DM is due to high levels of NLRP3 inflammasome activity, which promotes the generation of IL-1β and IL-18 in macrophages (149, 150) . Efficient skin wound healing process is mediated by the up-regulation of the peroxisome proliferatoractivated receptor (PPAR)-γ in macrophages that convert their pro-inflammatory phenotype into healing-related. PPARγ suppresses cytokine production by macrophages and hence is upregulated in inflamed tissue-resident macrophages. However, in T2DM, PPARγ expression is down-regulated in skin-resident macrophages that enhance the activity of NLRP-3 inflammasome and cause chronic inflammation. Using myeloid-specific PPARγ −/− mice, it has been shown that the absence of PPAR-γ in macrophages is sufficient to delay the healing process and extend tissue inflammation (150) . In T2DM patients, chronic hyperglycemia and hyperlipidemia trigger the secretion of a damage-associated S100A8 molecule (calgranulin A) from pancreatic islets that in turn increase macrophage infiltration (151) . Westwell-Roper et al. have shown that IAPP aggregates in T2DM patients polarize islet-resident macrophages toward the M1-like F4/80 + CD11b + CD11c + phenotype that produces pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Furthermore, M1 cells promote islet inflammation, cause β-cell malfunction and apoptosis (152) . In T2DM, excess phagocytosis of apoptotic β-cells by macrophages induces their lysosomal permeabilization, generation of ROS, inflammasome activation, and pro-inflammatory cytokines secretion (153) . Collectively, these observations reveal that the functions and plasticity of macrophages are compromised during the progression of T2DM. Neutrophils are the most prevalent circulating leukocytes and one of the main components of innate immunity. They are recruited to the sites of infection through chemotaxis following complement activation, most importantly by C5a. Activated neutrophils bind via their surface receptors to induced ligands on the surfaces of inflamed endothelial cells to migrate to tissues. There they phagocytose and kill invading microbes with lysosomal enzymes, antimicrobial peptides and by the generation of ROS (154). Neutrophils from patients with T2DM, but not from healthy individuals, are activated and produce elevated levels of ROS. So, it could increase the risk of random organ injury (155) . In diabetic patients, the plasma levels of homocysteine are elevated, which is mainly due to its impaired clearance rate (156) . This will induce neutrophils to constitutively release neutrophil extracellular traps (NETs) that can cause vascular damage and delays in wound healing (157, 158) . It has been shown that the circulating level of hydrogen sulfide (H 2 S) is significantly reduced in fasting blood of patients with T2DM compared with healthy individuals as well as in streptozotocin-induced diabetic rats compared with controls (159) . H 2 S is produced from cysteine by the action of several enzymes. It acts as a regulator of cell signaling and homeostasis (160) . It is essential to maintain balanced levels of antioxidants and protect tissues from oxidative stress (160) . The use of H 2 S or the endogenous L-cysteine in vitro blocks the production of IL-8 and monocyte chemoattractant protein-1 (MCP-1) in the human U937 monocyte cell line incubated in high-glucose medium (159) . Yang et al. have shown that H 2 S treatment decreases NETosis and enhances the healing process of diabetic wounds by preventing ROS-dependent ERK1/2 and p38 activation (161) . It has been shown that the levels of NET components, including histones, elastase and proteinase-3, are elevated in the sera from patients with diabetic foot ulcers (162) . Wang et al. have recently indicated that HG dramatically enhances NADPH oxidasedependent NET generation in diabetic rats and humans. It was proposed that this could have a role in the induction of diabetic retinopathy (163) . Indeed, patients with T2DM have elevated plasma levels of MGO, which can induce the production of proinflammatory cytokines like TNF-α, IL-6, and IL-8 by neutrophils and make them more susceptible to apoptosis (99) . Myeloperoxidase (MPO), which is abundantly produced by neutrophils, but only to a small extent by monocytes and macrophages, might be useful as an early biomarker of inflammation in diabetic individuals (164) . Binding of MPO to endothelial cells increases its half-life. Thereby, more proinflammatory oxidant hypochloric acid (HClO) is generated that extends the damage to blood vessels (165) . In T2DM patients, neutrophil activities, including migration, phagocytosis and microbial killing are impaired. This makes diabetic individuals more susceptible to infections (166) . It has been welldocumented that neutrophils isolated in animal models of T2DM have an impaired TLR4 signaling pathway. This is reflected as a diminished cytokine and chemokine production, possibly as a consequence of reduced phosphorylation of NFκB and IκBα (167) . The half-life of these neutrophils as well as their in vivo migration and myeloperoxidase activity are decreased. During hyperglycemia, neutrophils produce calprotectin (S100A8/A9), which interacts with the receptor for advanced glycation end products (RAGE) on the surface of hepatic Kupffer cells and promotes the synthesis of IL-6 (168). Subsequently, IL-6 stimulates hepatocytes to increase the generation of thrombopoietin that in turn attaches to its receptor on the surfaces of bone marrow precursor cells and megakaryocytes to enhance their proliferation and expansion. This results in reticulated thrombocytosis, which means elevated megakaryocyte activity and thrombopoiesis. Interestingly, diabetes-related thrombocytosis and subsequent atherothrombosis can be reduced by lowering blood glucose, depleting Kupffer cells or neutrophils or by preventing the binding of S100A8/A9 to RAGE using paquinimod (168) . Thom et al. have shown that the incubation of human and murine neutrophils with HG medium would cause their cytoskeletal and membrane instability. This will induce the generation of 0.1 to 1 µm diameter microparticles and activate the NLRP3 inflammasome (169) . Microparticles, which are potently pro-inflammatory, are found in the circulation of healthy individuals, but their generation is increased during cell activation in several diseases, including T2DM and cardiovascular diseases (170, 171) . Furthermore, serum levels of soluble FasL (sFasL) are increased in patients with T2DM thereby activating neutrophils and aggravating the inflammatory milieu (172, 173) . The proinflammatory roles of sFasL are mediated through increased amounts or activity of NFκB, IL-1β, caspase-1, CD11b/CD18, and ROS (173) . Caspase-1 activation prevents the sFasL-dependent apoptosis of neutrophils and inhibits their expression of Fas and caspase-3 (173) . Accordingly, hyperglycemia disturbs the normal functions of neutrophils and increases the susceptibility to infections by pathogenic microorganisms. The expression level of NKG2D is negatively correlated with HbA1c levels implying that chronic hyperglycemia would cause NK cell dysfunction (176) . Also, hyperglycemia increases the expression of unfolded protein response (UPR) genes in NK cells and induces their apoptosis (176) . NKT cells express simultaneously markers of both T cells (TCR and CD3) and NK cells [CD16, CD56, CD314 (NKG2D), and CD337 (NKp30)]. NKT cell subsets produce a broad range of cytokines, including GM-CSF, IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-9, IL-10, IL-13, IL-17, and IL-21 (178) . They recognize lipids and glycolipids presented by CD1d molecules. Phoksawat et al. have shown that the frequency of CD3 + CD4 + CD28 null CD56 + NKG2D hi NKT cells, which produce high levels of IL-17, are increased in diabetic patients and their numbers are directly correlated with HbA1c levels (179, 180) . Lv et al. have recently shown that the numbers of CD3 + CD56 + NKT cells are higher in diabetic patients compared to healthy individuals (181) . They further showed that such cells are mostly CD4 + , produce elevated levels of IFN-γ and IL-4 and express high levels of NKp30, NKG2D, and NKp44 but low levels of inhibitory receptors NKG2A and 158b (181) . The co-culture of these cells with HUVECs significantly decreased their proliferation and migration abilities that were mainly IL-4dependent (181) . Taken together these studies show that diabetic individuals appear to have elevated levels of inflammationpromoting NKT cells. ILCs are critical effectors of innate immunity that produce both regulatory and pro-inflammatory cytokines to promote tissue repair, immunity, and inflammation (182) . Mature ILCs lack the TCRs. Based on their cell surface markers, cytokine production as well as expression of transcription factors the ILCs are classified into types 1, 2, and 3 (183) . These correspond to the different types of CD4+ T helper cells: Th1, Th2, and Th17, respectively. IFN-γ is the cytokine signature of ILC1s, while type 2 cytokines (e.g., IL-5 and IL-13) are mainly produced by ILC2s and the main product of ILC3s are IL-17 and IL-22. Regarding transcription factors, T-bet is mainly expressed by ILC1s, GATA3 and RORα are mostly expressed by ILC2s and RORγt is predominantly expressed by ILC3 (183) . In T2DM, the numbers of circulating as well as adipose tissue-resident ILC1s are increased compared with normal individuals (184, 185) . The frequency of circulating ILC1s is positively correlated with fasting plasma glucose (FPG), HbA1c, homeostasis model assessment for insulin resistance (HOMA-IR), serum-free fatty acids (FFAs) and adipose tissue insulin resistance index (Adipo-IR) (184, 185) . It has also been shown that patients with increased numbers of ILC1 have an elevated risk of developing T2DM (184) . A study by Wang et al. indicated that adipose tissue-resident ILC1s, via the production of IFN-γ, promote tissue fibrosis and induce diabetes in obese individuals (185) . Liu et al. have demonstrated that the numbers of ILC2s as well as serum cytokine levels of IL-4, IL-5, and IL-13 are significantly elevated in diabetic kidney disease patients and have a positive correlation with disease severity (186) . They further demonstrated that ILC2s, through the TGF-β1 signaling pathway, are involved in renal fibrosis seen in diabetic kidney disease (184) . However, Galle-Treger et al. indicated that the engagement of the glucocorticoid-induced tumor necrosis factor receptor (GITR/or TNFRSF18) on the surface of activated ILC2s promotes their secretion of IL-5 and IL-13, ameliorates glucose homeostasis, protects against the onset of and improves established insulin resistance (187) . The protective role of ILC2s during acute metabolic stress has also been well-documented by Dalmas et al. (188) . Humoral Immunity (B Cells) Elevated levels of blood glucose generate covalent sugar adducts with several proteins through non-enzymatic glycation. This can impair humoral immunity in many ways, e.g., by modifying the structure and functions of immunoglobulins (Igs) (189) (190) (191) (192) (193) (194) . Such modifications in the structure of Igs can be determined using matrix-assisted laser desorption ionization (MALDI) mass spectrometry (119, 191) . The molecular mass of Igs in diabetic patients is higher than in normal subjects (189) . This can lead to reduced efficiency of vaccines that stimulate humoral immunity in these patients. It has been shown that immunization with influenza (flu) vaccines in diabetic patients induces normal or even elevated levels of flu-specific antibodies compared with normal individuals (195) (196) (197) (198) . However, the ability of the dysfunctional glycated antibodies to neutralize viruses is impaired, which will increase the susceptibility to infections. Farnsworth et al. have shown that in T2DM, class switch defects in the assembly of antibody genes are also present (199) . In a model system, mice with T2DM have decreased amounts of specific anti-Staphylococcus aureus antibodies (total as well as IgG), which will increase the risk of infection and morbidity of diabetic mice. However, the levels of IgM were elevated, but inefficient in protecting against infection, possibly because of their inability to directly promote phagocytosis. In another study, Farnsworth et al. have demonstrated that defects in humoral immunity, as shown by decreased levels of total IgG and anti-Staphylococcus aureus antibody, aggravate foot infections in a murine model of T2DM (200) . This was due to a reduced germinal center induction and decreased numbers of T and Blymphocytes within the germinal centers. This causes failures in antibody generation and class-switch recombination (200) . Mathews et al. have shown that the protective levels of antibodies against Streptococcus pneumoniae surface protein A are lower in diabetic patients compared to non-diabetic individuals. These antibodies also have a reduced potential to trigger complement activation on the surface of pneumococci, whereby phagocytosis of the bacteria becomes compromised (201) . They showed that hyperglycemia reduces both the antibody titers as well as the ability to deposit complement on the bacteria. The abovementioned changes in the ability to protect against S. aureus and S. pneumoniae are important, because these bacteria belong to the most common infection-causing pathogens in diabetic patients. Another major group is constituted by Gram-negative bacteria that commonly cause e.g., urinary tract infections. Many studies have shown that T-cell functions are impaired in individuals with T2DM (202) (203) (204) (205) . Elevated levels of activated CD4 + CD278 + T helper cells, cytotoxic T-cells, and Th17 cells have been observed in obese diabetic patients compared to nonobese ones (205, 206) . Nevertheless, PBMCs isolated from obese diabetic patients produced smaller amounts of IL-2, IL-6, and TNF-α after stimulation with phytohemagglutinin (PHA) (205) . Martinez et al. indicated that diabetic patients have reduced pathogen-specific memory Th17 responses as well as decreased numbers of CD4+ T cells in response to stimulation with Streptococcus pneumoniae (206) . Th17 cells are critical for the recruitment of neutrophils to the infection site and improve the phagocytosis of invading bacteria and yeast (207) . Moura et al. have shown that diabetic patients, particularly those with foot ulcers, have reduced levels of naive T-cells, but an elevated number of effector T cells and a reduction in the TCR-Vβ repertoire diversity (204) . The observed changes are mainly due to an abnormal amount of inflammatory cytokines (e.g., IFN-γ and TNF-α) produced during infection and to subsequent robust stimulation of T-cells. Leung et al. have reported that ischemic tissues of T2DM patients contain elevated numbers of TNF-α and IFN-γ producing Th1 cells but diminished numbers of regulatory T cells (Tregs), which suppress angiogenesis and decrease vascular density (208) . The high rate of infectious diseases in T2DM patients might also be linked to a reduction in the mitochondrial DNA function that causes downstream lymphocyte dysfunction and subsequently increased susceptibility to infection (209) (210) (211) (212) . In support, we have recently shown that the numbers of IFN-γ producing cells against cytomegalovirus (CMV), Epstein-Barr virus (EBV), and influenza virus are fewer in T2DM patients compared to normal controls (202) . Kumar et al. have also investigated the functions of CD8 + T cells and NK cells in the whole blood of T2DM patients infected with Mycobacterium tuberculosis (M.tb). Compared to controls, the patients exhibited a reduction in cytokine production (IFN-γ, IL-2, IL-17A/F, and TNF-α) and decreased expression of cytotoxic molecules (perforin, granzyme B, and CD107a) (203, 213) . These studies conclude that the functions of both CD4 + and CD8 + T-cell are defective in T2DM patients. T2DM is usually associated with an elevated risk of asymptomatic bacteriuria, urinary tract infections (UTIs), pyelonephritis and non-sexually transmitted genital infections, such as balanitis and vulvovaginal infections (213) (214) (215) . The incidence of infections with a complicated course is significantly higher in diabetic patients compared to healthy controls ( Table 3) . It seems that it is principally defects in the innate immune responses of diabetic individuals that are responsible for the increased susceptibility and prevalence of infections (4, 225 (199, 201) CD8 + Tcells Mycobacterium tuberculosis (203, 213) susceptible to the causative pathogen of Lyme disease, Borrelia burgdorferi (216) . The disease is mainly due to the ability of the bacteria to escape complement opsonization and attack, which leads to an impaired uptake and killing of bacteria by neutrophils (227) . Neutrophil dysfunction also increases the susceptibility of diabetic animals to Staphylococcus aureus (217) (233) . During the progression of T2DM in human subjects, the basal phenotype of macrophages is altered so their capacity to control Mycobacterium tuberculosis is diminished (222) . Martinez et al. have indicated that alveolar macrophages isolated from diabetic mice express decreased levels of macrophage receptor with collagenous structure (MARCO) and CD14 that are engaged in the recognition of trehalose 6,6'-dimycolate, a bacterial cell wall component (223) . Diabetes increases the severity of tuberculosis (TB) and enhances the risk of progression to the active form in latent infections (234, 235) . Diabetic TB patients have elevated frequencies of Th1 and Th17 cells as well as increased serum levels of inflammatory cytokines, including IFN-γ, TNF-α, IL-1β, IL-2, IL-6, IL-17A, and IL-18 but decreased levels of IL-22 compared to non-diabetic TB patients. This can contribute to dysfunctional immune responses and poor immune control of a TB infection (236) . A positive correlation between the serum levels of IFN-γ, TNF-α, IL-2, and IL-17A with Hb-A1c levels was also observed. This indicates an association between impaired control of diabetes and the proinflammatory milieu. Tripathi et al. have demonstrated that serum levels of IL-22 were significantly decreased in TB-infected T2DM mice and humans compared to non-diabetic TB-infected mice and humans (224) . They revealed that the treatment of TB-infected diabetic mice with recombinant IL-22 or ILC3s (cellular source of IL-22) increased the survival of mice, prevented the accumulation of neutrophils near alveoli, diminished the generation of neutrophil elastase 2 (ELA2) and prevented epithelial cell damage (224) . Tan et al. have shown that B. pseudomallei and M. tuberculosisinfected PBMCs of diabetic patients fail to produce IL-12. This leads to a decreased IFN-γ production, poor bacterial killing and elevated intracellular bacterial loads (237) . An impaired IL-12 production is mainly due to decreased intracellular glutathione (GSH) concentrations within the infected cells of diabetic individuals (237) . Such a combination of an inflammatory microenvironment and dysfunctional immune responses enhances the bacterial load and can subsequently amplify lung injury and fibrosis in diabetic TB patients. Chellan et al. have further shown that infections caused by Enterococcus faecalis, Staphylococcus aureus, and Pseudomonas aeruginosa are more prevalent in the wounds of diabetic patients (238) . T2DM patients are more susceptible to UTIs caused by antibioticresistant Escherichia coli, Proteus spp., Klebsiella spp., coagulasenegative staphylococci, Enterobacter spp., and enterococci (215, 239) . Diabetic patients are also more susceptible to Helicobacter pylori (H. pylori) infections (240). Cui et al. have recently reported that T2DM patients have an increased risk of infection with Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8) (241) . They further showed that the viral load and antibody titers are positively correlated with blood glucose levels (241) . Diabetic patients also have been shown to have an increased risk of infection with the severe acute respiratory syndrome coronavirus (SARS-CoV) ( (248) . The influenza virus that usually causes self-limiting infections can induce severe forms of the disease in diabetic patients (249, 250) . Following the 2009 H1N1 influenza pandemic, diabetic individuals suffered from more severe infections compared to non-diabetic people (251, 252) . Diabetic patients have also a higher prevalence of chronic cytomegalovirus (CMV), Herpes simplex virus (especially HSV-1), and varicellazoster virus infections (253) (254) (255) . Accordingly, it seems that the immune response against viruses is impaired in diabetics, and these patients need more care during viral infections. Coronavirus virions are enveloped positive-strand RNA spherical viruses with a diameter of ∼125 nm characterized by spike proteins projecting from their surface and with an unusual large RNA genome (256) . The spike (S) protein of the virus binds to its receptor on the surface of cells by which intracellular proteases are induced (257) (258) (259) . Subsequently, the S protein priming and cleavage occurs that allow viral fusion to the plasma membrane and entrance of viral genome into the cells (259) . SARS-CoV and SARS-CoV-2 use angiotensin-converting enzyme 2 (ACE2) as their receptor while MERS-CoV uses dipeptidyl peptidase-4 (DPP4) to enter the cells (260, 261) . ACE2 is strongly expressed in blood vessels, pancreas, intestine, brain, lungs, heart, and testis (262) . Interestingly, nasal epithelial cells, especially goblet, and ciliated cells express the highest levels of ACE2 and the intracellular protease transmembrane serine protease 2 (TMPRSS2) that facilitates the entrance of the SARS-COV-2 (263) . Furthermore, the expression of ACE2 is significantly up-regulated in diabetic patients and those treated with ACE inhibitors (264) . Coronaviruses cause respiratory, enteric and central nervous system (CNS) diseases in various animal species except rats and mice (264) . Most coronavirus infections are mild, but major outbreaks of deadly pneumonia have been caused by SARS-CoV, MERS-CoV, and SARS-CoV-2 in 2002, 2014, and 2019-2020, respectively (265) . On March 11, 2020, The World Health Organization (WHO) announced the pandemic of SARS-CoV-2, the etiologic agent of coronavirus disease-19 (COVID-19) (265) . The novel coronavirus pandemic, which has emanated from Wuhan, China, promotes symptoms similar to those caused by the SARS-CoV outbreak in 2002. The viral pandemic, which has put the world on alert, has caused over 7.9 × 10 6 confirmed human cases and at least 43 × 10 4 deaths throughout the world (https://www.worldometers.info/coronavirus/) by June 14, 2020. Most of the infected people experience only mild to moderate respiratory disease and recover soon without the need for special treatment. However, aged individuals and those with health problems, including diabetes, obesity, cardiovascular disease (CVD), hypertension, immune deficiency, and chronic respiratory disease are more likely to develop serious illness (https://www.who.int/health-topics/coronavirus#tab= tab_1). Patients death is mainly due to the acute respiratory distress syndrome, disseminated intravascular coagulation, hemorrhage, coagulopathy, acute organ (e.g., kidney, heart, liver) injury, multi-organ failure, and secondary bacterial infections (266) . Elevated levels of adipose-tissue derived adipokines, interferon, and TNF-α in diabetic patients may impair immune-responses against SARS-COV-2 (267, 268) . It has been shown that diabetic patients have impaired clearance of SARS-CoV-2 from their circulation (269) . Accordingly, diabetic patients due to the diminished viral clearance, impaired T cell function, and accompanied cardiovascular disease are more susceptible to the coronaviruses infection and subsequent cytokine release syndrome (CRS) (270, 271) . In support, elevated levels of IL-1β, IL-2, IL-6, IL-7, IL-8, IL-10, IFN-γ, interferon gamma-induced protein 10 (IP-10), granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 1α (MIP1α), serum ferritin, fibrinogen, plasminogen, C-reactive protein (CRP), and D-dimer have been observed in patients with COVID-19 (266, 269, 272, 273) . COVID-19 patients, especially those requiring intensive care unit (ICU) have decreased total lymphocytes (lymphopenia), T cells (both CD4+ and CD8+), B cells, and NK cells (274, 275) . It should be noted that most of the surviving T cells in such patients have an exhausted phenotype (274) . Consequently, disease severity is mainly because of the host immune response to viral infection. Current evidence about the relationship between pathophysiological mechanisms of diabetes and COVID-19 are limited and further research is still needed. Patients with T2DM have an elevated risk of infection with Plasmodium falciparum (276) , Toxoplasma gondii (277), Opisthorchis viverrini (278), Strongyloides stercoralis (279), Cryptosporidium parvum (280), Blastocystis hominis (281), Ascaris lumbricoides (280, 282, 283) , and Giardia lamblia (283) . Interestingly, diabetic patients who were treated with metformin had less P. falciparum infections compared to untreated patients (276) . Omaña-Molina et al. have shown that in a mouse model of T2DM the animals have an increased susceptibility to granulomatous amoebic encephalitis (GAE) caused by trophozoites of Acanthamoeba culbertsoni (284) . The possible reasons for the increased risk of diabetics for parasitic infections are metabolic abnormalities and immune dysregulation. Chellan et al. have shown a higher prevalence of fungal infections in the wounds of diabetic patients (238) . The prevalence correlated with the levels of HbA1c. The most widely observed fungal isolates were C. albicans, Candida parapsilosis, C. tropicalis, Trichosporon asahii, and Aspergillus species. Some of them were resistant to antifungal medications (238) . Al Mubarak et al. have also demonstrated that diabetic patients with periodontitis are more susceptible to infection with C. albicans, C. dubliniensis, C. tropicalis, and C. glabrata (285) . The incidence of candidiasis was significantly increased in patients over the age of 40 with HbA1c > 9 (285). It has also been shown that diabetic patients are more susceptible to UTIs caused by C. albicans (239) . Hyperglycemia impairs the normal functions of the circulatory system, gastrointestinal tract, pancreatic beta cells, liver as well as of skeletal muscles to boost systemic insulin resistance. A hyperglycemic environment also leads to immune cells dysfunction. It increases intestinal permeability, which subsequently enhances the risk of infections in T2DM patients. Accordingly, further research is still needed to find missing links between impaired physiological/immunological mechanisms and increased susceptibility to infections in T2DM patients. The information would be important for better therapy and the design of much more effective vaccination strategies in diabetic patients. GD and KK conceived the study and wrote the manuscript. GD contributed to the final revision of the manuscript. MA participated in preparing the first draft. DK and SM were involved in the final revision of the manuscript. All authors contributed to the article and approved the submitted version. 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