Features of adipose tissue function against the background of androgen deficiency in men with type 2 diabetes mellitus

The prevalence of hypogonadism in men with type 2 diabetes mellitus (T2DM) is higher than in population. Though, the function of adipose tissue in men with hypogonadism and T2DM is still unclear. Aim: To study the function of adipose tissue in men with T2DM and functional hypogonadism. Materials and Methods: We examined 272 men with T2DM (mean age 53.8±2.7 years). Randomization: 1 group - 148 men with hypogonadism, according to the European Association of Urology criteria 2015; 2 group - 124 patients, not having hypogonadism. The groups were comparable by age and treatment of diabetes. Patients underwent clinical examination, analysis of carbohydrate metabolism and markers of adipose tissue function, such as resistin, leptin, adiponectin. Statistical analysis was carried out using the Mann Whitney U-test. Results: The analysis demonstrated that hypogonadal patients had a significantly higher body mass index, waist and hip circumferences. Levels of fasting glucose and HbA1c weren’t statistically different in two groups. At the same time, patients with hypogonadism had more pronounced hyperinsulinemia (16,2 [10,5; 30,2] vs. 12,7 [8,4; 21] μU/ml, p=0,002) and insulin resistance, calculated as HOMA-IR (6,2 [3,8; 11,0] vs. 4,6 [2,8; 7,0], p<0,001), compared to eugonadal men. The analysis revealed an increase in leptin (10,8 [7,2; 17,5] vs. 9,2 [5,8; 14,9] ng/ml, p=0,03) and resistin levels (7,5 [2,9; 13,3] vs. 3,8 [1,8; 6,5] ng/ml, p<0,001) in the 1st group compared to the 2nd. Contrary, levels of adiponectin (2,8 [0,5; 5,7] vs. 4,7 [0,8; 7,9] μg/ml, p=0.006) were higher in group 2 compared to the 1st one. Thus, despite the equal fasting glucose and HbA1c levels, men with T deficiency have more pronounced adipose tissue dysfunction compared to eugonadal men having T2DM. Conclusion: T deficiency leads to adipose tissue dysfunction in men with T2DM. Disclosure I.A. Khripun: None. S.V. Vorobyev: None. E.V. Bova: None. Funding Russian Science Foundation (14-25-00052)

The prevalence of type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) has increased in the United States over the past 40years. These conditions, long linked with many cardiovascular complications, have recently been linked with androgen or testosterone deficiency in men. Several pathophysiologic hypotheses exist regarding this association, with the most widely reported a relationship to obesity and insulin resistance. Several randomized trials have confirmed that when testosterone replacement therapy is given to patients with T2DM, MetS, or both, metabolic parameters such as waist circumference, hemoglobin A1c , and systolic blood pressure are significantly reduced by up to 11cm, 1.9%, and 23mmHg, respectively. This has not, however, resulted in improved cardiovascular outcomes, as evidenced in studies that found increased rates of cardiovascular events following testosterone replacement therapy. In this review, we summarize the relevant literature regarding the pathophysiology and management of androgen deficiency in men with T2DM, MetS, or both.

Prevalence of and risk factors for androgen deficiency in middle-aged men in Hong Kong

Prevalence of Androgen Deficiency in Men with Erectile Dysfunction

Obesity and androgen deficiency in men – MOSCOW STUDY

Background: The common pathogenetic relations of type 2 diabetes mellitus (T2DM), testosterone (T) deficiency and non-alcoholic fatty liver disease (NAFLD) have indicated a new direction in the study of their mutual influence. It was found that NAFLD is more pronounced in men with T2DM and hypogonadism than in eugonadal patients and associated with hyperinsulinemia, insulin resistance, impaired lipid metabolism and adipose tissue dysfunction. However, the effects of testosterone replacement therapy (TRT) on the severity of NAFLD in men with hypogonadism have not been studied. Aims: To study the effect of TRT on the severity of NAFLD in men with T2DM and hypogonadism. MATERIALS AND METHODS: Anthropometric data, biochemical parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltranspeptidase (GGTP), glucose, immunoreactive insulin, HOMA index, glycosylated hemoglobin, lipidogram), ELISA analysis (total T, LH, sex hormone binding globulin, resistin, adiponectin, leptin), as well as magnetic resonance imaging with determination of the liver fat fraction were examined. Results: The study included 60 men with T2DM and hypogonadism (mean age 54 [49; 57] years), who were randomized into 2 groups: 1 (n=30) - patients who received 1% transdermal T gel (50 mg/day) in addition to standard hypoglycemictherapy; 2 (n=30) - patients who received standard hypoglycemic therapy. The follow-up period was 6 months. T therapy was associated with a decrease in liver enzyme levels: AST by 31%, ALT by 21%, and GGTP by 15.9% (p<0.05) and the hepatic fat fraction by 1.7 times, which reflect the regress of liver inflammation, and, consequently, a decrease in the severity of NAFLD. Moreover, TRT has improved the function of adipose tissue - reduced the concentration of leptin by 1.4 times and resistin by 1.5 times, which was accompanied by an increase in adiponectin level by 1.3 times (p<0.01). The use of TRT was associated with decrease in the severity of visceral obesity, hyperinsulinemia by 1.5 times, an insulin resistance index HOMA by 2.2 times, fasting glycaemia and HbA1c levels, despite constant hypoglycemic therapy. Statistically significant decrease in the levels of total cholesterol and triglycerides was observed in men receiving TRT. Thus, a decrease in adipose tissue dysfunction and insulin resistance in men receiving TRT can be considered as a pathogenetic mechanism responsible for improving liver function and reducing the severity of NAFLD. Conclusions: TRT in men with T2DM and hypogonadism is accompanied by regress of inflammatory activity in liver and intensity of hepatocytes steatosis, reflected by decrease in liver enzymes levels and liver fat fraction.

Background: The common pathogenetic relations of type 2 diabetes mellitus (T2DM), testosterone (T) deficiency and non-alcoholic fatty liver disease (NAFLD) have indicated a new direction in the study of their mutual influence. It was found that NAFLD is more pronounced in men with T2DM and hypogonadism than in eugonadal patients and associated with hyperinsulinemia, insulin resistance, impaired lipid metabolism and adipose tissue dysfunction. However, the effects of testosterone replacement therapy (TRT) on the severity of NAFLD in men with hypogonadism have not been studied.Aims: To study the effect of TRT on the severity of NAFLD in men with T2DM and hypogonadism.MATERIALS AND METHODS: Anthropometric data, biochemical parameters (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltranspeptidase (GGTP), glucose, immunoreactive insulin, HOMA index, glycosylated hemoglobin, lipidogram), ELISA analysis (total T, LH, sex hormone binding globulin, resistin, adiponectin, leptin), as well as magnetic resonance imaging with determination of the liver fat fraction were examined.Results: The study included 60 men with T2DM and hypogonadism (mean age 54 [49; 57] years), who were randomized into 2 groups: 1 (n=30) - patients who received 1% transdermal T gel (50 mg/day) in addition to standard hypoglycemictherapy; 2 (n=30) - patients who received standard hypoglycemic therapy. The follow-up period was 6 months. T therapy was associated with a decrease in liver enzyme levels: AST by 31%, ALT by 21%, and GGTP by 15.9% (p&lt;0.05) and the hepatic fat fraction by 1.7 times, which reflect the regress of liver inflammation, and, consequently, a decrease in the severity of NAFLD. Moreover, TRT has improved the function of adipose tissue - reduced the concentration of leptin by 1.4 times and resistin by 1.5 times, which was accompanied by an increase in adiponectin level by 1.3 times (p&lt;0.01). The use of TRT was associated with decrease in the severity of visceral obesity, hyperinsulinemia by 1.5 times, an insulin resistance index HOMA by 2.2 times, fasting glycaemia and HbA1c levels, despite constant hypoglycemic therapy. Statistically significant decrease in the levels of total cholesterol and triglycerides was observed in men receiving TRT. Thus, a decrease in adipose tissue dysfunction and insulin resistance in men receiving TRT can be considered as a pathogenetic mechanism responsible for improving liver function and reducing the severity of NAFLD.Conclusions: TRT in men with T2DM and hypogonadism is accompanied by regress of inflammatory activity in liver and intensity of hepatocytes steatosis, reflected by decrease in liver enzymes levels and liver fat fraction.

The prevalence of androgen deficiency in men increases with aging. Two common instruments, the Aging Male Symptoms (AMS) scale and the Androgen Deficiency in the Aging Male (ADAM) questionnaire, are often used to screen for androgen deficiency in clinical practice. The aim of this study is to compare the capability of the AMS scale and the ADAM questionnaire to detect androgen deficiency in middle-aged Taiwanese men. In April 2008, a free health screening was conducted by Kaohsiung Medical University Hospital. All participants completed a health questionnaire and had blood samples drawn between 8:00 am and noon. Serum total testosterone (TT), albumin, and sex hormone-binding globulin levels were measured. The level of free testosterone (FT) was calculated. Clinical symptoms associated with androgen deficiency were screened by using the AMS scale and ADAM questionnaire. Androgen deficiency was defined as TT < 300 ng/dL or both TT < 300 ng/dL and FT< 5 ng/dL. In total, 339 men were included in the final analysis, with the mean age of 54.6 ± 4.9 years (range, 47-65 years). Androgen deficiency was found in 75 men (22.1%) based on the criteria of TT < 300 ng/dL, and in 54 men (15.9%) based on the criteria of TT < 300 ng/dL and FT < 5 ng/dL. When detecting participants with both TT < 300 ng/dL and FT < 5 ng/dL, the sensitivity and specificity of the AMS scale were 57.4% and 48.1%, compared with 66.7% and 25.6% for the ADAM questionnaire. In a sample of middle-aged Taiwanese men, neither the AMS scale nor the ADAM questionnaire had sufficient sensitivity and specificity to detect androgen deficiency. In addition to using those 2 screening instruments, a thorough physical and biochemical workup should still be conducted in patients at risk or suspected of androgen deficiency.

Testosterone (T) deficiency is more prevalent in men with type 2 diabetes mellitus (T2DM) than in population. However, there are no data on the effect of hypogonadism on the severity of T2DM complications. Aim: To study the effect of T deficiency on the severity of T2DM complications in men. Materials and Methods: A retrospective analysis of 487 case histories of men with T2DM was performed (mean age 54.4±5.7 years). The patients were divided into 2 groups: 1-217 men with hypogonadism, according to the EAU criteria 2015; 2-270 patients, not having hypogonadism. The groups were matched by age, duration and treatment of diabetes, HbA1c and fasting glucose levels. Clinical, anamnestic data, laboratory parameters of carbohydrate and lipid metabolism were analyzed. Statistical analysis was performed using the Mann Whitney U-test and a chi-square test. Results: The prevalence of hypogonadism in men with T2DM was 44.6%. The analysis revealed an increase in systolic (140 [130; 160] vs. 136 [128; 149] mm Hg) and diastolic blood pressure (87 [80; 96] vs. 83 [80; 90] mm Hg) in the 1stgroup compared to the 2nd (p=0.01). Levels of total cholesterol (5.4 [4.6; 6.4] vs. 5.1 [4.5; 6.0] mmol/l, p=0.04), triglycerides (2.0 [1.4; 3.0] vs. 1.7 [1.2; 2.2] mmol/l) and very low density lipoproteins (1.0 [0.7, 1; 6] vs. 0.8 [0.6; 1.0] mmol/l) (p=0.001); low density lipoproteins (3.1 [2.4; 4.1] vs. 2.9 [2.4; 3.6] mmol/l) (p=0.03) were higher in group 1 compared to 2. Diabetic retinopathy (70.5% vs. 32.6%), nephropathy (92.1% vs. 58.9%) and polyneuropathy (82.9% vs. 65.6%) were more prevalent in patients of group 1 (p&amp;lt;0.01). All diabetes complications were more severe in men with hypogonadism, despite comparable duration of T2DM and parameters of carbohydrate metabolism. Conclusion: The prevalence of hypogonadism in men with T2DM was 44.6%. The presence of T deficiency in men with T2DM contributes to the progression of micro-and macro-vascular complications of diabetes, and also impairs lipid metabolism. Disclosure I.A. Khripun: None. E.V. Bova: None. S.V. Vorobyev: None. Funding Russian Science Foundation (14-25-00052)

Although androgen deficiency in men has been linked with obesity and the metabolic syndrome, whether it predisposes to, or is a consequence of, type 2 diabetes mellitus (T2DM) is still unclear. To determine the relationship between plasma androgen levels, obesity, metabolic status and T2DM in men of 70 years or older. A sample of 195 men from the Australian Longitudinal Study of Ageing with a mean age of 76.2 +/- 0.3 years were followed up for 8 years. Total testosterone (TT), fasting plasma glucose (FPG), urate, serum creatinine, total cholesterol (TC), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), triglycerides (TG), blood pressure (BP), body mass index (BMI), waist circumference (WC) and diabetic status were assessed at baseline. Self-reported diabetic status was obtained after 8 years. Metabolic syndrome was diagnosed based on the Third National Cholesterol Education Program Adult Treatment Panel clinical criteria. TT levels were lower in diabetic men compared with non-diabetic men (12.1 +/- 0.7 vs. 14.2 +/- 0.4 nmol/l, p = 0.026). TT levels in healthy, non-diabetic men over 80 years of age were lower (11.9 +/- 0.8 vs. 15.0 +/- 0.5 nmol/l, p = 0.002) than TT levels in those aged 70-79 years, inversely related to BMI (r = -0.26, p = 0.001), WC (r = -0.30, p < 0.001) and TG (r = -0.22, p = 0.005) and positively related to LDL-C (r = 0.25, p = 0.002). Men with the metabolic syndrome had significantly lower levels of TT and HDL-C, and higher values of BP, FPG, TG, BMI and WC, compared with those without. However, no significant difference in plasma TT levels was noted between men with incident T2Dm and healthy men. Stepwise linear regression analysis revealed that only LDL-C and WC related significantly to the variance of TT. Multiple logistic regression revealed FPG to be the only independent predictor of incident diabetes (odds ratio = 60.2, p = 0.003). Testosterone levels continue to decline even in healthy men over the age of 80 years. Although TT levels were inversely related to visceral obesity and several components of the metabolic syndrome, our data do not support a predictive or causative role for decreasing TT levels in the development of incident T2Dm. Androgen deficiency is consequent upon, rather than a cause of, poor metabolic status.

67 - Surgical Management of Male Infertility

Despite recognition that androgen deficiency in men should be defined according to biochemical and clinical criteria, most prevalence estimates are based on low testosterone levels alone. The objective of this study was to examine the association between symptoms of androgen deficiency and low total and calculated free testosterone levels and estimate the prevalence of symptomatic androgen deficiency in men. This study was a population-based, observational survey. A total of 1,475 Black, Hispanic, and white men, between the ages of 30-79 yr, with complete data on testosterone, SHBG, and symptoms of androgen deficiency, and who are not taking medications that impact sex steroid levels were randomly selected from the Boston Area Community Health Survey. Outcomes were measured as symptomatic androgen deficiency, defined as low total (<300 ng/dl) and free (<5 ng/dl) testosterone plus presence of low libido, erectile dysfunction, osteoporosis or fracture, or two or more of following symptoms: sleep disturbance, depressed mood, lethargy, or diminished physical performance. Mean age of the sample was 47.3 +/- 12.5 yr. Approximately 24% of subjects had total testosterone less than 300 ng/dl, and 11% of subjects had free testosterone less than 5 ng/dl. Prevalence of symptoms were as follows: low libido (12%), erectile dysfunction (16%), osteoporosis/fracture (1%), and two or more of the nonspecific symptoms (20%). Low testosterone levels were associated with symptoms, but many men with low testosterone levels were asymptomatic (e.g. in men 50+ yr, 47.6%). Crude prevalence of symptomatic androgen deficiency was 5.6% (95% confidence interval: 3.6%, 8.6%), and was not significantly related to race and ethnic group. Prevalence was low in men less than 70 yr (3.1-7.0%) and increased markedly with age to 18.4% among 70 yr olds. Projection of these estimates to the year 2025 suggests that there will be as many as 6.5 million American men ages 30-79 yr with symptomatic androgen deficiency, an increase of 38% from 2000 population estimates. Prevalence of symptomatic androgen deficiency in men 30 and 79 yr of age is 5.6% and increases substantially with age. The aging of the U.S. male population will cause a large increase in the burden of symptomatic androgen deficiency. Future work should address the clinical significance of low testosterone levels in asymptomatic men.

Type 2 diabetes mellitus (T2DM) in children and adolescents is becoming an increasingly important public health concern throughout the world (1–17). Because of the relatively recent recognition of the problem in this age group, many children with new onset T2DM may be misclassified as having T1DM. Conversely, as the population becomes heavier, overweight adolescents with autoimmune diabetes may be misdiagnosed as having T2DM. T2DM is often associated with risk factors for cardiovascular disease that may already be present at the time of diagnosis, making normalization of blood glucose levels and diagnosis and treatment of hypertension and dyslipidemia important (18). T2DM occurs when insulin secretion is inadequate to meet the increased demand posed by insulin resistance (19). Thus, T2DM is commonly associated with other features of the insulin resistance syndrome [hyperlipidemia, hypertension, acanthosis nigricans, ovarian hyperandrogenism, non-alcoholic fatty liver disease (NAFLD)] (20). Insulin secretion depends on disease status and duration, and can vary from delayed but markedly elevated in response to a glucose challenge, to absolutely diminished (19). Adults with symptoms have 50% reduction at the time of diagnosis, and may become insulin dependent within a few years (21). T2DM occurs: in youth most often during the second decade of life, with a mean age of diagnosis of ∼13.5 years. This coincides with the peak of physiologic pubertal insulin resistance, which may lead to onset of overt diabetes in previously compensated adolescents. in all races, but at a much greater prevalence in those of non-white European descent, e.g. those of black African descent, native North American, Hispanic (especially Mexican)-American, Asian, South Asian (Indian Peninsula), and Native Pacific islanders. The SEARCH for Diabetes in Youth population-based study found the proportion of physician diagnosed T2DM among 10–19-year-olds to vary greatly by ethnicity in the US: 6% for non-Hispanic whites, 22% for Hispanics, 33% for blacks, 40% for Asians/Pacific Islanders, and 76% for Native Americans (8). In Hong Kong > 90% of young onset diabetes is T2DM (10), in Taiwan 50% (11) and nearly 60% in Japan (Ogawa et al. personal communication). in > 75% of cases in youth in the USA there is a first or second-degree relative with T2DM. in youth in the USA and Europe with body mass index (BMI) above 85th percentile for age and sex. In Japan, however, ∼30% of T2DM are not obese (17), in Asian Indian urban children, half of those with T2DM had normal weight (< 120% ideal for height) (12), and half of Taiwanese children with T2DM were not obese (11). in some asymptomatic individuals in high-risk populations during medical, school, or sports examinations (22,23). in the presence of ketosis/ketoacidosis, one third or more of newly diagnosed patients (24). This presentation is responsible for misclassification of T2DM patients as T1DM. occasionally with severe dehydration (hyperosmolar hyperglycemic coma, hypokalemia) at presentation, which can be fatal (24,25) with a sex ratio (male:female) that varies from 1: 4–1:6 in native North Americans to 1:1 in Asians and Libyan Arabs without associated HLA specificities. without associated islet cell autoimmunity (see autoimmunity T2DM). The pathophysiology of autoimmune 'T2DM' is unclear. It most likely represents autoimmune T1DM in overweight or obese individuals with underlying insulin resistance. It has been postulated that obesity and insulin resistance may promote an inflammatory response to antigen exposure caused by apoptosis of beta cells (26). Youth and adults in US and Europe who are clinically diagnosed with T2DM are found to have T1DM-associated auto-antibodies in 15–40% of cases, including many who are not receiving insulin one year after diagnosis (27–30). Antibody positive young adult individuals with the T2DM phenotype are significantly less overweight and younger than antibody negative patients (21, 27). Hemoglobin (HbA1c) concentrations are significantly higher in young adults with T2DM who are antibody positive compared with those who are antibody negative (27). ß-cell function is significantly less in antibody positive individuals, the most dramatic difference being reported in younger adult patients (25–34 years), resulting in more rapid development of insulin dependence, usually by 3 years duration (27, 30). The presence of islet cell antibodies (ICA) and glutamic acid decarboxylase antibodies in adults with clinically typical T2DM has been referred to as latent autoimmune diabetes of adults (27, 31). Neither the autoimmunity nor the diabetes is latent, however (26). Atypical diabetes mellitus (ADM) occurs throughout childhood, but rarely begins past age 40. It has only been described in young people of African descent. There is a strong family history in multiple generations with an autosomal dominant pattern of inheritance, but an abnormal sex ratio (M : F = 1 : 3). ADM is not associated with HLA specificities and islet autoimmunity does not occur. Ketosis or ketoacidosis is typical at onset. Insulin secretion is present but diminished and without long-term deterioration of function. Interestingly, insulin is often not required for survival after treatment of acute metabolic deterioration, although diabetes control may be poor and ketoacidosis may recur without insulin, e.g. with illness or pregnancy. ADM is not associated with obesity beyond that in the general population and it is not associated with insulin resistance. Monogenic diabetes (formerly referred to as maturity onset diabetes of the young or MODY) For more in depth information see the ISPAD Clinical Consensus Guidelines for Monogenic Diabetes (34). Identified in families with multigenerational diabetes; including asymptomatic individuals identified through testing of family members. Monogenic diabetes is not associated with obesity beyond that in the general population and it is not associated with insulin resistance The clinician is obliged to weigh the evidence in each individual patient to distinguish between T1DM and T2DM. The reasons for this conundrum are: with increasing obesity in childhood, as many as 15–25% of newly diagnosed T1DM (or monogenic diabetes) patients may be obese. the significant number of pediatric patients with T2DM demonstrating ketonuria or ketoacidosis at diagnosis (2). T2DM is common in the general adult population, with a random family history of ∼15% or greater in minority populations, reducing the specificity of a positive family history. positive family history for T2DM is increased for patients with T1DM as much as threefold over the non-diabetic population and T1DM is more frequent in relatives of patients with T2DM (35, 36). There is considerable overlap in insulin or C-peptide measurements between T1DM, T2DM and MODY at onset of diabetes and over the first year or so. This overlap is due to the recovery phase of autoimmune-mediated T1DM (the honeymoon) and degree of glucotoxicity/lipotoxicity impairing insulin secretion at the time of testing in both T1DM and T2DM. In addition the insulin resistance of obesity raises residual C-peptide levels in obese adolescents with T1DM. Such measurements are thus relatively valueless in the acute phase. [The role of C peptide may be more helpful in established diabetes as persistent elevation of C-peptide above the level of normal would be unusual in T1DM after 12–24 months.] The criteria and classification of diabetes are presented in greater detail in the ISPAD Clinical Practice Consensus Guidelines: Definition, Epidemiology, Diagnosis and Classification of Diabetes (37) Diagnostic criteria for diabetes are based on BG measurements and the presence or absence of symptoms (E) (38,39). Three ways to diagnose diabetes are possible and each, in the absence of unequivocal hyperglycemia, must be confirmed, on a subsequent day, by any one of the three methods given below. Diabetes is diagnosed when: A fasting plasma glucose (FPG) is ≥ 7.0 mmol/l (126 mg/dl) or The post challenge plasma glucose is > 11.1 mmol/l (200 mg.dl) performed as described by the World Health Organization (39), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. or Symptoms of diabetes and a casual plasma glucose ≥ 200 mg/dl (11.1 mmol/L). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. Diabetes in children, including T2DM, usually presents with characteristic symptoms such as polyuria, polydipsia, blurring of vision, and weight loss, in association with glycosuria and, in some cases, ketonuria. In its most severe form, ketoacidosis or hyperglycemic hyperosmolar state may develop and lead to stupor, coma, and in absence of effective treatment, death. The diagnosis is usually confirmed quickly in symptomatic individuals by measurement of a marked elevation of the blood glucose level. In this situation, if ketones are present in the blood or urine, treatment is urgent. Waiting another day to confirm the hyperglycemia may be dangerous in allowing ketoacidosis or hyperosmolarity to evolve. In the absence of symptoms or presence of mild symptoms of diabetes, hyperglycemia detected incidentally or under conditions of acute infective, traumatic, circulatory, or other stress may be transitory and should not in itself be regarded as diagnostic of diabetes. The diagnosis of diabetes, in the absence of symptoms, should not be based on a single plasma glucose concentration. Diagnosis may require continued observation with fasting and/or 2-h postprandial BG levels and/or an oral glucose tolerance test (OGTT). An OGTT should not be performed if diabetes can be diagnosed using fasting, random, or postprandial criteria, as excessive hyperglycemia can result using a fasting OGTT in these circumstances. (E). If doubt remains, periodic re-testing should be undertaken until the diagnosis is established or refuted. There are individuals whose glucose levels do not meet the criteria for diabetes, but are too high to be considered normal. Impaired glucose tolerance (IGT) and impaired fasting glycaemia (IFG) are intermediate stages in the natural history of disordered carbohydrate metabolism between normal glucose homeostasis and diabetes (E). IFG and IGT are not interchangeable and represent different abnormalities of glucose regulation. IFG is a measure of disturbed carbohydrate metabolism in the basal state, while IGT is a dynamic measure of carbohydrate intolerance after a standardized glucose load. Patients with IFG and/or IGT are now referred to as having 'pre-diabetes', indicating the relatively high risk for development of diabetes in these patients (38). IFG and IGT may be associated with the metabolic syndrome (MS), which includes obesity (especially abdominal or visceral obesity), dyslipidemia of the high-triglyceride and/or low-high density lipoprotein type, and hypertension. Individuals who meet the criteria for IGT or IFG may be euglycemic in their daily lives as shown by normal or near-normal glycated hemoglobin levels, and those with IGT may manifest hyperglycemia only when challenged with an OGTT. FPG < 5.6 mmol/L (100 mg/dL)= normal fasting glucose. FPG 5.6–6.9 mmol/L (100–125 mg/dL)= IFG. FPG ≥ 7.0 mmol/L (126 mg/dL)= provisional diagnosis of diabetes (the diagnosis must be confirmed, as described above under 'Diagnostic criteria for type 2 diabetes'). The corresponding categories for IGT when the OGTT is used are as follows: 2-h postload glucose < 7.8 mmol/l (140 mg/dl)= normal glucose tolerance. 2-h postload glucose 7.8–11.1 mmol/l (140–199 mg/ dl)= IGT. 2-h postload glucose > 11.1 mmol/l (200 mg/dl)= provisional diagnosis of diabetes (the diagnosis must be confirmed with additional testing, as described above). After the diagnosis of diabetes is established, autoantibody testing should be considered when diagnosing and treating T2DM. Diabetes autoantibody testing should be considered in all pediatric patients with the clinical diagnosis of T2DM because of the high frequency of islet cell autoimmunity in otherwise "typical" T2DM. Antibodies will indicate an earlier need for insulin as well as the need to monitor for thyroid autoimmunity and to consider other autoimmune disorders associated with T1DM. (E) Diabetes autoantibody testing also should be considered in overweight/obese children > 13 years of age with a clinical picture of T1DM (weight loss, ketosis/ketoacidosis), some of whom may have T2DM (E) Insulin resistance is an impaired response to the physiologic effects of insulin, including effects on glucose, lipid, and protein metabolism, and on vascular endothelial function. Insulin resistance occurs in most tissues including liver, muscle, and fat tissue and is influenced by sex, age, race/ethnicity, stage of sexual maturation, and total adiposity. While visceral adiposity is important in insulin resistance in adults, the specific contribution of visceral adiposity to insulin resistance in the pediatric population remains uncertain. Several events in development may be associated with increased risk for the insulin resistance syndrome. These include premature adrenarche in girls (pubic hair appearing before the age of 8 years) and being born small for gestational age. Girls with a history of premature adrenarche are at increased risk for ovarian hyperandrogenism and PCOS and thus, insulin resistance (40). Children born small for gestational age are at increased risk for insulin resistance related to decreased intrauterine growth (41) and also at increased risk for premature adrenarche. Diabetes is only one manifestation of the insulin resistance syndrome or the MS (22, 42–50). Other associations include: Obesity: Obesity has deleterious associations with morbidity and cardiovascular risk independent of effects related to insulin resistance and diabetes (51–54). Nephropathy: Albuminuria (either micro- or macro- ) is present at the time of diagnosis in a substantial number of adolescents with T2DM and prevalence increases with duration of diabetes (24). Proteinuria and focal segmental glomerular sclerosis have also been reported in African-American adolescents with severe obesity, in the absence of diabetes (55). Hypertension; Hypertension is estimated to account for 35–75% of diabetes complications, both microvascular and macrovascular (56). Diabetes or impaired glucose tolerance doubles the risk of developing hypertension (57). In addition, there is a possible genetic predisposition to hypertension in T2DM related to the associated angiotensin converting enzyme genotype (58). Hypertension in T2DM is due to volume expansion and increased vascular resistance (59) related to reduced (NO)-mediated vasodilatation and increased activity of the renin-angiotensin system. Dyslipidemia: Hypertriglyceridemia and decreased high-density lipoprotein cholesterol are the hallmarks of T2DM dyslipidemia. Additional findings include elevated very low-density lipoprotein (VLDL), elevated LDL-c, elevated lipoprotein(a), and increased small dense LDL particles. Decreased lipoprotein lipase activity, increased lipoprotein glycation and increased lipoprotein oxidation render the lipoproteins more atherogenic. (60,61) Ovarian hyperandrogenism and premature adrenarche (62): PCOS is being increasingly recognized in adolescents as part of the insulin resistance syndrome. Adolescents with PCOS have ∼40% reduction in insulin-stimulated glucose disposal compared to body composition matched non-hyperandrogenic control subjects (59). Decreasing insulin resistance may improve ovarian function and increase fertility. NAFLD: Hepatic steatosis is present in 25–45% of adolescents with T2DM and more advanced forms of NAFLD, such as non-alcoholic steatohepatitis, are increasingly common and associated with progression to cirrhosis (24, 64). NAFLD now represents the most common cause of cirrhosis in children and the most common reason for liver transplantation in adults in the US. Systemic inflammation: elevated C-reactive protein, inflammatory cytokines and white blood cell counts in obese adolescents have been associated with increased risk for cardiovascular disease in adults (54). Additional health problems related to obesity include Obstructive sleep apnea (OSA) with associated pulmonary hypertension (65), orthopedic problems resulting in diminishing physical activity (66,67), pancreatitis, cholecystitis and pseudotumor cerebri. In adults, there is a strong association between level of hyperglycemia and increased risk of macrovascular disease. Hyperglycemia, dyslipidemia, and hypertension are contributors to the acceleration of atherosclerosis in T2DM, along with oxidative stress, glycation of vascular proteins, and abnormalities of platelet function and coagulation. Defective endothelium dependent vasodilatation is an additional factor accelerating atherosclerosis in T2DM. It is an early sign of increased risk for cardiovascular disease, and predictive of cardiovascular events (68) (B) and occurs in obese children relative to their level of obesity and degree of insulin resistance (69) (B). Co-morbidities characteristic of the insulin resistance syndrome are commonly seen at diagnosis or appear early in the course of T2DM and should be tested for sooner than in T1DM, where these disorders are complications of the diabetes rather than co-morbid conditions (70, 71) (B). A more complete discussion of testing for complications/co-morbidities is presented in the ISPAD Clinical Practice Guidelines for microvascular and macrovascular complications (72). Either micro- or macro-albuminuria, may be present at the time of diagnosis and albuminuria should be evaluated at diagnosis and annually thereafter (55, 72)(E). Likewise, hypertension may be present at, or prior to diagnosis of diabetes and each individual should be evaluated at every visit for hypertension. Dyslipidemia is more common in type 2 diabetes and in family members, (60,61) and should be screened for when metabolic stability is achieved. Evaluation for NAFLD should be done at diagnosis and annually thereafter (24)(E). Inquiries about puberty, menstrual irregularities and obstructive sleep apnea should be made at diagnosis and regularly thereafter (65)(E). Additional information is available in the ISPAD Clinical Practice Guidelines on complications. (72). Dyslipidemia, hypertension and albuminuria are more common in type 2 diabetes compared to type 1 diabetes and may be present at diagnosis and should be assessed after blood glucose control has been optimized. Confirmed hypertension (BP> 95% for age, gender and height) or albuminuria should be treated with an ACE inhibitor or, if not tolerated, an angiotensin receptor blocker (E). Combination therapy may be required if hypertension or albuminuria does not normalize on single agent treatment (E). Side effects are cough, hyperkalemia, headache and impotence (73). In addition, major congenital malformations have been reported with first trimester exposure to ACE inhibitors but not with other antihypertensive agents in non-diabetic women (74). Testing for dyslipidemia should be performed soon after diagnosis when BG control has been achieved and annually thereafter. (60,61) E Goal is LDL-C < 2.6 mmol (100 mg/dl) (68). If LDL-C is borderline (2.6-3.4 mmol;100–129 mg/ dl), or elevated (≥ 3.4 mmol; 130 mg/dl), repeat lipid profile should be performed in 6 months and dietary intervention to decrease total and saturated fat initiated. If LDL-C remains elevated after 3-6 months of attempting to optimize blood glucose control and diet, pharmacotherapy is warranted (72). Statin therapy has been shown to be safe and effective in children as in adults and should be the first pharmacologic intervention (72) although long term safety data are not available. Special attention should be paid to symptoms associated with muscles and connective tissues, as there is an increased risk of rhabdomyolysis The of T2DM in children and adolescents has required that with the of T1DM in children and adolescents the between the treatment of these T1DM is throughout the population to T2DM in North and Europe those with e.g. levels, less less well This has not been described for Asian T2DM. age. T1DM occurs throughout childhood, when is T2DM occurs in when family of families with a with T1DM have family with the disease, while 75% or more of families of the with T2DM have such The of these family to control weight and is with complications in the family and a of and in the treatment In most T1DM, beyond insulin and glucose is only for those individuals who are overweight and In all youth with T2DM, the is on and on glucose and effects of have the of T1DM and blood glucose insulin In in with an that dense increasingly and have to the of T2DM in children and its in of of including hypertension, dyslipidemia, and in the of complications may require more control in insulin T2DM than in T1DM, and attention to as by the Diabetes (21). also the ISPAD Clinical Practice Guidelines for diabetes and family for youth with type 2 diabetes is as important as it is in type 1 diabetes. and for T2DM will on and in insulin therapy and may not be required in T2DM will a greater on dietary and physical activity than is required for T1DM. should be given by with and of the and of youth with T2DM should be in a and age Because the of youth with T2DM are the ISPAD Guidelines for are to the of youth and families with T2DM The family will need to the of treatment of T2DM and to the of the required to T2DM should that the in the diagnosis type 1 type in a minority of patients can be and for the youth and The can be by the of blood glucose metabolism using therapy is to the metabolic of the specific of the of diabetes. is the of treatment of T2DM The family and should the of obesity and T2DM. must have an of the health and of the to an effective should be made in small and with the that these need to be The patient and family should be to monitor the and of and physical in any a and is for The and treatment for T2DM should include a and/or to a with and in of children with is should be to family and should be to all The family should be to dietary with including for weight reduced total and saturated fat increased and increased physical activity specific dietary are given in the ISPAD Guidelines for dietary should include: on and in of these and and for can result in substantial weight and is one of the most important for weight loss. and for the family and for the patient in an age including about dietary and activity related to and activity by of and using for that should be on in one with other activity as a family and should be in a or and not from a or of high density and in the the of and control of positive of or weight reduction in high and for and activity as for of and activity and for and should be for each patient and family that are to family and and should be to all A family or should be identified who is available to in physical activity with the may be to patients and family members. to with the dietary and is important to the of the should include: and an daily is to the of increased at reducing such as the and the time in related may be the most effective activity to be as a This should include daily to be more such as using of or to and to and and (E). for to and physical activity, including increases in daily (E). of blood glucose should be performed of should be and include a of fasting and postprandial glucose have been fasting a and daily post after the are while the within the (E). If the impaired glucose tolerance more frequent testing should be for of acute illness or when symptoms of or patients should more frequent testing and be in with their diabetes for (E). Patients on insulin or need to monitor for asymptomatic (E). should be at a year and if insulin is being used or metabolic control is should be continued in addition to pharmacologic therapy The of pharmacologic therapy is to decrease insulin resistance, increase insulin or to postprandial glucose The first used should be It has the over of reduction in without the risk of weight is decreased or remains and LDL-C and levels decrease during for type 2 diabetes in children and adolescents. of with over 3 months the need to a or insulin or in with a or a inhibitor Patients for should be on the effects of diabetes and oral agents on and oral agent should be used during pregnancy.

Opioid analgesics are frequently prescribed for the treatment of chronic pain and are a common cause of male androgen deficiency. Despite its high prevalence, this adverse effect of chronic opioid use remains underappreciated by clinicians. As a result, androgen deficiency remains underdiagnosed and likely undertreated. This focused review discusses the expanding literature on opioid-induced androgen deficiency and the efficacy of testosterone therapy, with a particular focus on its anti-nociceptive effects. Original and review articles on opioid-induced male androgen deficiency published from 1950 through June 2024 were retrieved from PubMed using the key terms "opioids," "hypogonadism," "low testosterone," and "testosterone therapy." References within the retrieved publications were also researched. Opioids suppress the gonadal axis mainly by inhibiting GnRH synthesis and secretion. The prevalence of opioid-induced androgen deficiency in men varies between 20% and 80% and is influenced by the type of opioid used, duration of exposure, age of the cohort, and how low testosterone was defined. Limited data from clinical trials suggest that testosterone therapy improves libido, body composition, and certain domains of quality of life. Early evidence also suggests that testosterone has anti-nociceptive properties, confirming findings from preclinical and population studies. Chronic opioid use is a common but underappreciated cause of androgen deficiency in men. There is a need to raise awareness among clinicians regarding this adverse effect of opioid use. Testosterone therapy could be considered in men with unequivocal androgen deficiency after a thorough clinical evaluation. Ongoing clinical trials will shed further light on the efficacy of testosterone therapy, particularly regarding its anti-nociceptive effects.

Background To date, the currently available data aboutthe effect of testosterone (T) on the cardiovascular system of men are highly controversial. The particular interest is its effect on the endothelium in men with type 2 diabetes mellitus (T2DM) having a high risk of vascular complications. The purpose of this work was to evaluate the effect of endogenous T on function of endothelium in men with T2DM. Methods The study included 204 men, aged 40–65 years, with T2DM. Patients underwent clinical examinations, analysis of carbohydrate metabolism, evaluation of biochemical parameters of endothelial function such as nitric oxide (NO), endothelial synthase type 3 (eNOS3), VCAM-1, ICAM-1, p- and e-selectins, endothelin. The ultrasound assessment of flow-mediated dilatation of the brachial artery (FMD-BA) and intima-media thickness (IMT) of brachial arteries were performed. Patients were divided into 2 groups: 1 – 93 men with late onset hypogonadism established according to EAU 2015 criteria and 2 – 111 men having normal level of endogenous T and absence of clinical symptoms of hypogonadism. Statistical analysis of the data was carried out using the Mann-Whitney U-test (STATISTICA 10 software package). Results The parameters of carbohydrate metabolism and the duration of T2DM were comparable in two groups. The concentrations of NO (85.0 [60.4; 210.4] vs 137.5 [87.8; 281.5] μmol/l, p=0.001) and eNOS3 (192.2 [109.6; 407.3] vs 293.3 [117.1; 686.2] pg/ml, p=0.03) were lower in the 1st group compared to the 2nd one. There was an increase in the levels of VCAM-1 by 32.6% and ICAM-1 by 43% (p&lt;0.0001), p-selectin by 19.5% (p=0.003) in the 1st group compared to the 2nd group. The endothelium-dependent FMD-BA was less pronounced (9.4 [6.9; 13.0] vs 12.2 [10.0; 16.7] %, p=0.0007) and had a delay in time of dilation by 33.3% in patients with hypogonadism compared to eugonadal men. There was an increase in IMT (1.0 [0.9; 1.2] vs 0.9 [0.7; 1.1] mm, p=0.03) in the 1st group compared to the 2nd. Conclusion T deficiency in men with T2DM leads to endothelial dysfunction, decreasing secretory and vasomotor function of endothelium. This indicates the raise of cardiovascular risk and predicts progression of vascular complications in men with T2DM and late onset hypogonadism. Acknowledgement/Funding Supported by Russian Science Foundation, grant #14-25-00052.