Stesura Seveso Archivio Italiano di Urologia e Andrologia 2022; 94, 4464 ORIGINAL PAPER No conflict of interest declared. comorbidities such as chronic fatigue, loss of libido, erec- tile dysfunction, low haematocrit level, cardiovascular events, and decreased bone density (3). Several studies consistently show significant relationships between serum testosterone and T2DM (4). Many studies reported that 25% to 50% of type 2 diabetic males have lowered testosterone levels (5). Hence, testosterone defi- ciency in T2DM has high clinical importance. Although male hypogonadism (MHG) in T2DM has been investi- gated in many researches, the mechanism underlying the pathogenesis of testosterone deficiency in diabetes is still not fully understood yet (6). The majority of previous studies have assessed testosterone levels in elderly, obese males with T2DM (7). On other hand, it is well established that obesity is a major risk factor for type 2 diabetes and cardiovascular disease (8). Several studies have linked male hypogo- nadism with being overweight or obese (9). Large popu- lation-based studies have confirmed that obesity is the single most important factor associated with low testos- terone, overriding the effects of age and comorbidities (10). Therefore, it is unclear whether this is ascribable to the diabetic state per se, or because of other factors, such as obesity or age. Hence, the role of the diabetic state in relation to the effects of obesity and comorbidities on testosterone levels in diabetic men is debatable (11). In this study, we tried to limit the confounding factor that affects the testosterone levels in diabetic males such as obesity. Therefore, we aimed to investigate the prevalence and identify the predictors for testosterone deficiency among non-obese type 2 male diabetic patients. PATIENTS AND METHODS Study population This cross-sectional study was conducted at Mansoura University's Endocrinology, Diabetes, and Metabolism Unit, Specialized Medical Hospital, between March 2021 and August 2021. The Mansoura Faculty of Medicine's Institutional Research Board approved the study design. All study participants provided written informed consent. We enrolled 95 patients aged 25 to 65 who had been diagnosed with T2DM using the American Diabetes Association's diabetes diagnosis criteria. Inclusion criteria were set as follows: males with type 2 Background and aims: it is unclear whether male hypogonadism is ascribable to the dia- betic state per se, or because of other factors, such as obesity or age. We aimed to investigate the prevalence and identify the predictors for testosterone deficiency among non-obese type 2 diabetic males. Methods: This cross-sectional study was conducted on 95 non- obese type 2 diabetic males with BMI below 30. We evaluated the total testosterone (TT) levels to determine prevalence and risk factors of testosterone deficiency. Serum TT ≤ 300 ng/dl defined testosterone deficiency. Results: The prevalence of testosterone deficiency was 29.1%. Testosterone deficient patients had statistically significantly higher visceral adiposity index (VAI), waist, and triglyceride in comparison with normal testosterone patients. TT level correlat- ed with VAI, waist, BMI, LH, and age. VAI was the only signifi- cant predictor of TT levels even after adjustment for age and BMI in regression analysis. Furthermore, VAI was a statistically significant risk factor for testosterone deficiency in binary logis- tic analysis. Conclusions: testosterone deficient non-obese type 2 diabetic male patients had elevated VAI, waist, and triglyceride. Moreover, elevated VAI was a risk factor for testosterone defi- ciency. VAI could be an easily applicable and reliable index for the evaluation and prediction in type 2 non-obese diabetic males. Key WORDS: Non-obese; T2DM; Visceral obesity; Testosterone; VAI; Males. Submitted 5 March 2022; Accepted 2 April 2022 INTRODUCTION Diabetes mellitus (DM) is a major cause of health concern due to its increasing prevalence rate worldwide. By the turn of the last decade, the International Diabetes Federation (IDF) estimated that 404.7 million people worldwide had type 2 diabetes mellitus (T2DM), with the total number of diabetic patients expected to rise to 679.7 million by 2045 (1). One complication of type 2 diabetes (T2DM) is hypo- thalamic-pituitary-testicular axis (HPT axis) dysfunction. The hallmark of HPT axis dysfunction is characterized by subnormal testosterone levels in association with non-ele- vated luteinizing hormone concentrations. These abnor- malities were not affected by the duration or severity of dia- betes (2). Testosterone deficiency is associated with many Testosterone deficiency in non-obese type 2 diabetic male patients Sherihan I. Gouda 1, Mohamed M. Aboelnaga 1, Ahmed M.G. Elbeltagy 2, Amro Elbaz 1 1 Endocrinology and Diabetes Unit, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 2 Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt. DOI: 10.4081/aiua.2022.4.464 Summary 465Archivio Italiano di Urologia e Andrologia 2022; 94, 4 Testosterone deficiency in non-obese type 2 diabetic male patients diabetes; body mass index below 30; history of normal pubertal development; a normal sense of smell for exclu- sion of Kallman syndrome; age between 18 and 65. In contrast, patients were excluded from this study in case of: female sex; abnormal renal function; abnormal albu- min levels; diabetes with macro albuminuria; liver disor- ders; heart failure; usea of drugs that may affect testos- terone levels, such as replacement therapy and anabolic steroids; patients with known causes of hypogonadism; history of malignancy; autoimmune diseases; diseases of the endocrine system other than Type 2 DM, including Type 1 DM, pituitary disorders, and abnormal thyroid functions. All patients were divided into either a low testosterone group (TT ≤ 300 ng/dl) or a normal testos- terone group (TT > 300 ng/dl). Clinical assessment and anthropometric measurements All subjects underwent a comprehensive medical evalua- tion including medical history with special emphasis on diabetes duration, medication, smoking history, and dia- betic complications history; physical examination and measurement of anthropometric parameters. The patient's height and weight were measured while they were dressed casually and were not wearing shoes. BMI was calculated by dividing weight (kg) by height square (m2). Waist circumference (WC) was measured halfway between the inferior border of the last rib and the crest of the ilium at the end of expiration. Following standard procedure, blood pressure was measured with a sphygmomanome- ter. VAI was calculated for all participants using the fol- lowing formula for males (12): VAI: WC / [39:68 + (1.88 × BMI)] × TG/1:03 × 1:31/HDL. Biochemical parameters After a 12-hour overnight fast, venous blood samples were collected from all patients between 8 A.M. and 10 A.M. including: complete blood count (CBC), fasting lipid profile that included triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL); serum creatinine; glycosylated haemo- globin (HbA1C); fasting blood sugar; albumin; luteinizing hormone (LH); serum total testosterone. LDL-cholesterol was estimated according to the Friedewald formula (TC minus HDL-cholesterol minus TGs/5 in mg/dl). Visceral adiposity index (VAI) was calculated for women and men according to the formulas. Definition Diabetes was defined as a fasting plasma glucose of 100 mg/dl or higher, HbA1c of 6.5% or higher, or a previous diagnosis of type 2 diabetes. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, current use of the antihypertensive drug. Overweight was defined by a body mass index of at least 25 kg/m2. Testosterone deficiency was defined as serum TT less than 300 ng/dl that is the lower limit of the normal range according to the American urological asso- ciation guidelines (13). LH level above 9.4 IU/L was defined as hyperg- onadotropic hypogonadism, while LH levels below 9.4 IU/L were defined as hypogonadotropic hypogonadism (14). Statistical analysis The Statistical Package for the Social Sciences (SPSS), Version 23 was used to analyze the statistical data. Continuous vari- ables were presented as the mean ±standard deviation, and categorical variables were expressed as a proportion (%) whereas non-normally distributed data are expressed as the median (interquartile range). Differences between groups of patients were compared by the Mann-Whitney U or Student T-test for continuous variables and the Chi-square test for categorical variables. The relationship between testosterone (the dependent variable) and other statistically significant correlated parameters in Pearson correlation (the independent variables) was investigated using linear regres- sion. The risk factors associated with Testosterone deficien- cy were assessed using binary logistic regression, and the odds ratio (OR) and 95 per cent confidence interval (CI) were calculated. P values less than 0.05 were considered statisti- cally significant. RESULTS We enrolled ninety-six non-obese patients with type 2 DM in this cross-sectional study. Among those diabetic patients, 27 (28.4%) were of normal weight, while 68 (71.6%) were overweight. Their age ranged between 34 and 65 years. We observed that the prevalence of testos- terone deficiency was 29.1% (28 patients). We observed high abnormal level of LH in 14 patients with low testos- terone levels. The prevalence of hypergonadotropic hypog- onadism was 50% of testosterone deficient patients. Other clinical, anthropometric, and laboratory details of the patient were presented in Table 1. Table 1. General characteristics of the study population. N = 96 Age (year) 51.41 ± 7.17 Diabetic duration(year) 9.59 ± 4.18 Smoker ratio 66 (47.1% ) Insulin therapy 52 (37.1% ) Body weight (kg) 86.69 ± 7.96 Height (m) 1.78 ± .058 BMI (Kg/m2) 28.245 (3.05) Waist circumference(cm) 99.48 ± 9.68 Systolic BP (mmHg) 135.00 (15) Diastolic BP (mmHg) 85.00 (15) Total cholesterol mg/dl 248.54 ± 43.29 LDL-C mg/dl 155.88 ± 47.98 HDL-C mg/dl 43.83 ± 6.85 Triglycerides mg/dl 244.14±74.48 UACR mg/gm 28 (62) Retinopathy 29 (30.2% ) Hba1c % 8.5 ± 1.613 Total testosterone ng/dl 405.71 ± 133.78 Testosterone deficiency 28 (29.1%) LH mIU/L 7.44 ± 2.67 VAI 3.25 (1.58) Data expressed as mean (interquartile range) according normality of distribution, Data expressed as mean ± standard deviation or Data expressed in parenthesis are percentage. BM: Body mass index; WC: Waist circumference; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; uACR: Urinary albumin creatinine ratio; Hba1c: Glycated hemoglobin; LH: luteinizing hormone; VAI: Visceral adiposity index. Archivio Italiano di Urologia e Andrologia 2022; 94, 4 S.I. Gouda, M.M. Aboelnaga, A.M.G. Elbeltagy, A. Elbaz 466 In the comparison between 28 patients in the low testos- terone group (TT ≤ 300 ng/dl) and 68 patients in the nor- mal testosterone group (TT > 300 ng/dl), we found that the low testosterone group had a statistically significant higher mean or median of VAI, WC, and triglyceride in comparison with normal testosterone group. Moreover, a higher percentage of patients complicated with retinopa- thy was observed in low testosterone groups. Other dif- ferences between the two groups were shown in Table 2. According to Pearson correlations, TT was negatively cor- related with VAI (log), WC, BMI (log), and LH. On the other hand, TT was positively correlated to age. However, TT was not correlated with duration of diabetes, Hba1c, or lipid parameters. We conducted a regression analysis to determine predictors of total testosterone levels as the dependent variable and age, BMI (log), LH, and VAI (log) as the independent variables in our study patients. We observed that VAI was the only significant predictor of TT levels (p-value = 0.41). Furthermore, VAI was a statisti- cally significant predictor of TT levels even after adjust- ment for age and BMI as shown in Tables 3, 4. The binary logistic regression was performed with hypog- onadism as the dependent variable and age, overweight (defined by BMI more than 30), WC, LH, retinopathy, and VAI (log) as the independent variables. We observed that the Visceral adiposity index was a statistically signifi- cant risk factor for testosterone deficiency among non- obese type 2 diabetic males (p-value = 0.46). More data are available in Table 5. DISCUSSION Despite the high prevalence of male hypogonadism in type 2 diabetic, regardless of diabetic control status, the underlying mechanisms of hypogonadism pathogenesis in type 2 diabetes mellitus have not been fully clarified yet (15). In the same consent, the contribution of the dia- betic status or hyperglycaemia on androgen levels in males is still debated. The strong association between type 2 diabetes with obesity, insulin resistance status, and aging may be the significant contributory factor in testos- terone deficiency in type 2 DM patients rather than dia- betes itself (16). The main result in this cross-sectional study is that vis- ceral adiposity functional activity evaluated by VAI is the main risk factor in type 2 diabetic males with BMI below 30. Moreover, VAI was the only predictor for testosterone levels in non-obese type 2 diabetic males even after adjustment for age and BMI, although testosterone levels Table 2. Comparison of clinical and laboratory characteristics of male type 2 DM patients with TT > 300 VS ng/dl those with TT ≤ 300 ng/dl. TT > 300 ng/dl (n = 68) TT ≤ 300 ng/dl (n = 28) P value Age (year) 52.1 ± 7.29 49.71 ± 6.69 0.139 DM duration (year) 9.34 ± 4.27 10.21 ± 3.98 0.354 Smoker ratio 30 (44.1%) 11 (39.2%) 0.821 Height (m) 1.78 ± .06 1.7675 ± .05 0.290 Body weight (kg) 86.54 ± 8.39 87.04 ± 6.96 0.785 BMI (Kg/m2) 27.75 (3.44) 28.73 (2.13) 0.197 WC (cm) 98.24 ± 9.35 102.50 ± 9.95 0.049 Systolic BP (mmHg) 135.00 (15) 137.50 (14) 0.218 Diastolic BP (mmHg) 85 (15) 85 (13) 0.09 microalbumiric 24 (35.5%) 12 (42.8%) 0.497 Retinopathy ratio 16 (23.5%) 13 (46.4%) 0.049 TV mg/dl 249.96 ± 41.94 245.11 ± 47.02 0.620 LDL-c mg/dl 158.51 ± 45.48 149.49 ± 53.93 0.405 HDL-c mg/dl 44.56 ± 7.53 42.07 ± 4.44 0106 TG mg/dl 234.43 ± 76 267.71 ± 66.14 0.046 Hba1c % 8.36 ± 1.53 8.93 ± 1.7 0.111 LH mIU/L 7.2 ± 1.85 8.02 ± 4.01 0.173 UACR mg/gm 28 (62.53) 28 (74) 0.812 VAI 3.03 (1.54) 3.86 (1.77) 0.006 Data are presented as the mean ± SD. median (IQ range) or the number of patients in each group with percentages. BM: Body mass index; WC: Waist circumference; SBP: Systolic blood pressure; DBP: Diastolic blood pressure; LDL: Low-density lipoprotein; HDL: High-density lipoprotein; TG: Triglyceride;; Hba1c: Glycated hemoglobin; LH: Luteinizing hormone; uACR: Urinary albumin creatinine ratio; VAI: Visceral adiposity index. Table 3. Pearson correlation and stepwise multiple regression analysis between total testosterone levels with other statistically significant correlated independent factor. r P value B β P value Age .218 .033 2.723 .146 .145 Log BMI .213 .037 25.488 .040 .760 WC -.255 .012 -1.723 -.125 .352 LH -.222 .030 -8.630 -.172 .082 Log VAI -.278 .006 -164.284 -.208 .041 BM: Body mass index; WC: Waist circumference; LH: Luteinizing hormone; VAI: Visceral adiposity index. Table 4. Association between total testosterone levels and other statistically significant correlated independent factors in regression analysis after adjustment for BMI and age. Model 1 Model 2 B β P value B β P value Age 2.723 .146 .145 2.721 .146 .147 WC -1.723 -.125 .352 -1.638 .118 .397 BMI (log) 25.488 -.208 .760 4.984 .008 974 LH -8.630 -.172 .082 -8.654 -.173 .083 VAI (log) -164.284 040 .041 -165.076 -.209 .041 Model 1 adjusted for age and model 2 adjusted for BMI and age. BM: Body mass index; WC: Waist circumference; LH: Luteinizing hormone; VAI: Visceral adiposity index. Table 5. Logistic regression analysis for risk factor of testosterone deficiency. B S.E Wald P value OR 95% C.I. for Odds ratio Lower Upper Age -.046 .037 1.563 .218 .956 .891 1.027 Overweight -.802 .878 .834 .367 2.373 .363 15.536 Waist .045 .033 1.891 .207 .344 .066 1.806 Log VAI 3.629 1.629 4.965 .046 1.436 1.007 2.048 Retinopathy -1.138 .514 4.901 .060 .382 .140 1.043 LH .049 0.84 .308 .579 1.050 .883 1.249 B: Estimated coefficient; S.E: Standard error; CI: Confidence interval; WC, waist circumference; VAI: Visceral adiposity index; LH: Luteinizing hormone. 467Archivio Italiano di Urologia e Andrologia 2022; 94, 4 Testosterone deficiency in non-obese type 2 diabetic male patients in our study correlated with anthropometric parameters such as BMI and waist circumference. VAI as a index for visceral fat dysfunction is more reliable than other obesi- ty parameters in predicting testosterone deficiency. Low TT levels were strongly associated with increased VAI in our cross-sectional study regardless of age, or diabetes status control. Although many studies evaluated hypogonadism in diabet- ic patients, only a few studies evaluated obesity by VAI. A recent population-based study among diabetic and non- diabetic observed that VAI was the best predictor of male hypogonadism among different obesity indices (17, 18). Likewise, VAI is more reliable than other metabolic or anthropometric parameters in the evaluation of visceral adiposity effect on erectile dysfunction (19, 20). In this cross-sectional study, the prevalence of testos- terone deficiency was 29.1 per cent. This prevalence of testosterone deficiency in type 2 diabetic males was lower than that reported in previous studies in Egypt (21) and the Middle East region (22). The difference is expected by the selection of our patients with BMI below 30. Surprisingly, we have a high prevalence of hyperg- onadotropic hypogonadism. We observed high abnormal level of LH in 14 patients (50%) with low testosterone levels. In our study, we observed that other obesity parameters such as BMI or waist diameters correlated with testosterone levels in Pearson correlation. However, BMI and WC were not a significant predictor for testos- terone levels in regression analysis. Several studies con- sistently reported a negative impact for obesity on testos- terone levels (18, 19, 23). These results in non-obese type 2 diabetic male patients could point to the role of abdom- inal obesity in the pathogenesis of male hypogonadism in T2DM. The results in this study may indicate that adipose fat function may be important than fat mass. In this study, age correlated with testosterone levels. This result was in concordance with many previous studies that observed decreased levels of testosterone with aging in diabetic patients (11, 24, 25) and the general popula- tion (26). However few studies did not observe this link in type 2 diabetic patients (27, 28). In this study, we observed significantly higher triglyc- eride levels in testosterone deficient diabetics. However, HDLc levels were insignificantly different between the two groups. This may be attributed to the effect of patients’ selection and lifestyle such as exercise and diet that could affect HDL levels. Many studies linked hypog- onadism and dyslipidaemia (21, 22, 27). Moreover, con- trolled trials on testosterone replacement observed favourable effects for testosterone on lipid profile in dia- betics (29). However, the effect of dyslipidaemias on testosterone levels is still unexplored. VAI includes anthropometric and metabolic parameters as TG or HDL- c. Hence, the correlation between testosterone and TG or HDL-c cannot be excluded. Surprisingly, testosterone deficiency was not related to diabetic status. Testosterone deficiency in this study did not correlate with glycated haemoglobin or the duration of diabetes. These results are in agreement with many studies in diabetics in general (28). However, our find- ings contradict another large study which correlated testosterone levels with diabetic status control (30). In this study, we found that non-obese diabetics with testosterone deficiency had higher significant retinopathy prevalence. However, we found non-significant different urinary albumin excretion between both groups. The effect of nephropathy was not assessed in this study as we excluded macro-albuminuria patients. Micro-vascular complications were reported in many studies to correlate with low testosterone levels in males (21, 22, 31). Although the pathophysiological mechanism of testos- terone deficiency in Type 2 DM is still not fully revealed, few mechanisms have been hypothesized. The role of inflammatory mediators such as tumour necrosis factor- alpha and Interleukin-1 beta was postulated. Obesity is considered as a state of chronic inflammation (33). These mediators have been reported to suppress hypothalamic gonadotropin-releasing hormone (GnRH) at the hypothala- mic level (34). Insulin resistance is another mechanism that could be involved in hypogonadism pathogenesis. Insulin resistance and brain insulin resistance, which was defined as impaired insulin action in the neuron (34). Normal insulin response is required for the HPG axis's functional integrity to be maintained (35). According to one study, hyperinsulinemia caused by neuronal insulin receptor knockout can result in a 60-90% decrease in LH concentrations (33). Another mechanism could be relat- ed to adipokines such as leptin and adiponectin which have been reported to have a permissive role in the regu- lation of the hypothalamic-pituitary-gonadal (HPG) axis. Leptin resistance in the hypothalamus or other neurons may play a role in the pathogenesis of hypogonadism seen in obesity, insulin resistance, and T2DM (29). Furthermore, leptin directly suppresses the stimulatory action of gonadotropins on the testicular Leydig cells, reducing testosterone formation (28). Furthermore, testosterone has a direct correlation with circulating adiponectin (36). Finally, the aromatase enzyme converts testosterone to oestrogen in adipose tissue, resulting in hypothalamic-pituitary-gonadal axis inhibition and sub- sequent hypogonadism (37). In the light of those postulated mechanisms for male hypogonadism in diabetic patients, VAI could be a valu- able index for predicting male hypogonadism and is linked with these postulated mechanisms. VAI by involv- ing the metabolic parameters could reflect chronic inflammatory status. Decreases in serum HDL and increases in triglycerides were reported to be linked with inflammatory status and mediators (38). Likewise, VAI was reported to be strongly correlated with insulin resist- ance estimated by HOMA-IR and metabolic syndrome (39, 40). Furthermore, among the most commonly used adiposity assessment indices, VAI has the strongest corre- lation with the most well-known adipocytokines in dia- betic patients (41) and non-diabetic (42). Finally, a pop- ulation-based study observed that VAI correlates with estradiol levels in males which reflect aromatase enzyme activity (43). Hence, the VAI value could better reveal the effects of WC, BMI, HDL, and TG on testosterone levels. This cross-sectional study cannot inform whether low testosterone is the cause or the result of visceral obesity. Current evidence, however, suggests that this relation- ship is bidirectional (11). A two-way relationship between low testosterone levels and abdominal obesity Archivio Italiano di Urologia e Andrologia 2022; 94, 4 S.I. Gouda, M.M. Aboelnaga, A.M.G. Elbeltagy, A. Elbaz 468 was reported (44). Weight loss could increase testos- terone levels, indicating that testosterone deficiency is functional (45). Weight loss bariatric surgery-induced resulted in a significant increase in Testosterone levels (46). In contrast, lower testosterone level after androgen deprivation therapy is associated with weight gain (45). In our study, a higher prevalence of hypergonadtropic hypogonadism could point to an increased risk of T2DM with testosterone deficiency. This study is not devoid of some limitations, firstly the cross-sectional design. The second limitation was the rel- atively small case number that might limit the power to detect a difference. Thirdly, because free testosterone lev- els can reflect the extent of testosterone's biological activ- ities, free testosterone concentration should be used to assess hypogonadism. However, free testosterone deter- mination is difficult, so free testosterone is frequently cal- culated with a formula in practical activity. Finally, this study is a single-centre study in a tertiary hospital. Therefore, patient selection bias might exist. This research highlights the value of an easily applicable tool such as the visceral adiposity index in predicting testosterone deficiency in non-obese diabetics. VAI could be more reliable than other parameters in predicting testosterone deficiency in diabetics. In conclusion, the elevated VAI index is associated with higher risks of testosterone deficiency in non-obese dia- betic males. VAI is an easily applicable reliable index for the prediction of male hypogonadism in non-obese type 2 diabetic male patients. REFERENCES 1. Hassan M, Hatata EZ, Al-Arman M, Aboelnaga MM. Urinary cystatin C as a biomarker of early renal dysfunction in type 2 dia- betic patients. Diabetes Metab Syndr. 2021; 15:102152. 2. Gianatti EJ, Grossmann M. Testosterone deficiency in men with Type 2 diabetes: pathophysiology and treatment. Diabet Med. 2020; 37:174-186. 3. Anupam B, Shivaprasad C, Vijaya S, et al. Prevalence of hypogo- nadism in patients with type 2 diabetes mellitus among the Indian population. Diabetes Metab Syndr. 2020; 14:1299-1304. 4. Gianatti EJ, Grossmann M. Testosterone deficiency in men with Type 2 diabetes: pathophysiology and treatment. Diabet Med. 2020; 37:174-186. 5. Castellano-Castillo D, Royo JL, Martínez-Escribano A, et al. Effects of SHBG rs1799941 polymorphism on free testosterone levels and hypogonadism risk in young non-diabetic obese males. J Clin Med. 2019; 8:1136. 6. Gianatti EJ, Grossmann M. Testosterone deficiency in men with Type 2 diabetes: pathophysiology and treatment. Diabet Med. 2020; 37:174-186. 7. Grossmann M. Low testosterone in men with type 2 diabetes: sig- nificance and treatment. J Clin Endocrinol Metab. 2011; 96:2341- 2353. 8. Mozafar Saadati H, Sabour S, Mansournia MA, et al. Effect mod- ification of general and central obesity by sex and age on cardiovas- cular outcomes: Targeted maximum likelihood estimation in the ath- erosclerosis risk in communities study. Diabetes Metab Syndr. 2021; 15:479-485. 9. Fernandez CJ, Chacko EC, Pappachan JM. Male obesity-related secondary hypogonadism - Pathophysiology, clinical implications and management. Eur Endocrinol. 2019; 15:83-90. 10. Lee DM, O'Neill TW, Pye SR, et al. The European Male Ageing Study (EMAS): design, methods and recruitment. Int J Androl. 2009; 32:11-24. 11. Ng Tang Fui M, Hoermann R, et al. Obesity and age as dominant correlates of low testosterone in men irrespective of diabetes status. Andrology. 2013; 1:906-912. 12. Amato MC, Giordano C, Galia M, et al. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with car- diometabolic risk. Diabetes Care. 2010; 33:920-922. 13. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone thera- py in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010; 95:2536- 2559 (erratum in J Clin Endocrinol Metab. 2021; 106:e2848) 14. Tajar A, Forti G, O'Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010; 95:1810-8. 15. Ganesh HK, Vijaya Sarathi HA, George J, et al. Prevalence of hypogonadism in patients with type 2 diabetes mellitus in an Asian Indian study group. Endocr Pract. 2009; 15:513-520. 16. Al-Goblan AS, Al-Alfi MA, Khan MZ. Mechanism linking diabetes mellitus and obesity. Diabetes Metab Syndr Obes. 2014; 7:587-591. 17. Turan E, Öztekin Ü. Relationship between visceral adiposity index and male infertility. Andrologia. 2020; 52:e13548. 18. Haymana C, Sonmez A, Aydogdu A, et al. Visceral adiposity index and triglyceride/high-density lipoprotein cholesterol ratio in hypogonadism. Arch Endocrinol Metab. 2017; 61:282-287. 19. Akdemir AO, Karabakan M, Aktas BK, et al. Visceral adiposity index is useful for evaluating obesity effect on erectile dysfunction. Andrologia. 2019; 51:e13282. 20. Dursun M, Besiroglu H, Cakir SS, et al. Increased visceral adi- posity index associated with sexual dysfunction in men. Aging Male. 2018; 21:187-192. 21. Ghazi S, Zohdy W, Elkhiat Y, Shamloul R. Serum testosterone levels in diabetic men with and without erectile dysfunction. Andrologia. 2012; 44:373-380. 22. Al Hayek AA, Khader YS, Jafal S, et al. Prevalence of low testos- terone levels in men with type 2 diabetes mellitus: a cross-sectional study. J Family Community Med. 2013; 20:179-186. 23. Fui MN, Dupuis P, Grossmann M. Lowered testosterone in male obesity: mechanisms, morbidity and management. Asian J Androl. 2014; 16:223-231. 24. Anupam B, Shivaprasad C, Vijaya S, et al. Prevalence of hypog- onadism in patients with type 2 diabetes mellitus among the Indian population. Diabetes Metab Syndr. 2020; 14:1299-1304. 25. Tajar A, Forti G, O'Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010; 95:1810-1818. 26. Zheng R, Cao L, Cao W, et al. Risk factors for hypogonadism in male patients with type 2 diabetes. J Diabetes Res. 2016; 2016:5162167. 27. Zheng R, Cao L, Cao W, et al. Risk factors for hypogonadism in male patients with type 2 diabetes. J Diabetes Res. 2016; 2016:5162167. 469Archivio Italiano di Urologia e Andrologia 2022; 94, 4 Testosterone deficiency in non-obese type 2 diabetic male patients 28. Cai X, Tian Y, Wu T, et al. Metabolic effects of testosterone replacement therapy on hypogonadal men with type 2 diabetes mel- litus: a systematic review and meta-analysis of randomized con- trolled trials. Asian J Androl. 2014; 16:146-152. 29. Fukui M, Tanaka M, Hasegawa G, et al. Association between serum bioavailable testosterone concentration and the ratio of gly- cated albumin to glycated hemoglobin in men with type 2 diabetes. Diabetes Care. 2008; 31:397-401. 30. Šimoniene D, Platukiene A, Prakapiene E, et al. Insulin resist- ance in type 1 diabetes mellitus and its association with patient's micro- and macrovascular complications, sex hormones, and other clinical data. Diabetes Ther. 2020; 11:161-174. 31. Blaya R, Blaya P, Rhoden L, Rhoden EL. Low testosterone levels and metabolic syndrome in aging male. Curr Pharm Des. 2017; 23:4470-4474. 32. Dandona P, Dhindsa S. Update: Hypogonadotropic hypogo- nadism in type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011; 96:2643-2651. 33. Watanobe H, Hayakawa Y. Hypothalamic interleukin-1 beta and tumor necrosis factor-alpha, but not interleukin-6, mediate the endo- toxin-induced suppression of the reproductive axis in rats. Endocrinology. 2003; 144:4868-4875. 34. Brüning JC, Gautam D, Burks DJ, et al. Role of brain insulin receptor in control of body weight and reproduction. Science. 2000; 289:2122-2125. 35. Elsaied MA, Masallat D, Abdel-Hamid IA. Correlation of adiponectin with testosterone in patients with and without type 2 dia- betes and erectile dysfunction. Am J Mens Health. 2019; 13:1557988318807049. 36. C. Langer, B. Gansz, C. Goepfert et al. Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochemical and Biophysical Research Communications 2002; 296:1051-1057 37. Feingold KR, Grunfeld C. The effect of inflammation and infec- tion on lipids and lipoproteins. In: Feingold KR, Anawalt B, Boyce A, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; January 8, 2019. 38. Ji B, Qu H, Wang H, et al. Association between the visceral adi- posity index and homeostatic model assessment of insulin resistance in participants with normal waist circumference. Angiology. 2017; 68:716-721. 39. Štepánek L, Horáková D, Cibicková L, et al. Can visceral adi- posity index serve as a simple tool for identifying individuals with insulin resistance in daily clinical practice?. Medicina (Kaunas). 2019; 55:545. 40. Amato MC, Pizzolanti G, Torregrossa V, et al. Visceral adiposi- ty index (VAI) is predictive of an altered adipokine profile in patients with type 2 diabetes. PLoS One. 2014; 9:e91969. 41. Al-Daghri NM, Al-Attas OS, Alokail MS, et al. Visceral adiposi- ty index is highly associated with adiponectin values and glycaemic disturbances. Eur J Clin Invest. 2013; 43:183-189. 42. Wang N, Zhai H, Han B, et al. Visceral fat dysfunction is posi- tively associated with hypogonadism in Chinese men. Sci Rep. 2016; 6:19844. 43. Blaya R, Blaya P, Rhoden L, Rhoden EL. Low testosterone levels and metabolic syndrome in aging male. Curr Pharm Des. 2017; 23:4470-4474. 44. Grossmann M, Hamilton EJ, Gilfillan C, et al. Bone and meta- bolic health in patients with non-metastatic prostate cancer who are receiving androgen deprivation therapy. Med J Aust. 2011; 194:301- 306. 45. Pekgor S, Duran C, Berberoglu U, Eryilmaz MA. The role of vis- ceral adiposity index levels in predicting the presence of metabolic syndrome and insulin resistance in overweight and obese patients. Metab Syndr Relat Disord. 2019; 17:296-302. 46. Aboelnaga EM, Aboelnaga MM, Elkalla HM. Metformin addition to androgen deprivation therapy effect on cancer prostate patients with type 2 diabetes Diabetes Metab Syndr. 2021; 15:102251. Correspondence Sherihan I. Gouda, MD Endocrinology and Diabetes Unit, Faculty of Medicine, Mansoura University, Mansoura (Egypt) Mohamed Mosaad Aboelnaga, MD (Corresponding Author) dr.mhd.endocrine@gmail.com Endocrinology and Diabetes Unit, Faculty of Medicine, Mansoura University, 2 El Gomhouria Street, Zip code: 35516, Mansoura (Egypt) Ahmed MG Elbeltagy, MD Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura (Egypt) Amro Elbaz, MD Endocrinology and Diabetes Unit, Faculty of Medicine, Mansoura University, Mansoura (Egypt)