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Objective Obesity in adolescent males is associated with the lowering of total and free testosterone concentrations. Weight loss may increase testosterone concentrations. Design and methods We evaluated the changes in sex hormones following bariatric surgery in 34 males (age range: 14.6–19.8 years) with obesity. These participants were part of a prospective multicenter study, Teen-Longitudinal Assessment of Bariatric Surgery. The participants were followed up for 5 years after surgery. Total testosterone, total estradiol, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, C-reactive protein, insulin and glucose were measured at baseline, 6 months and annually thereafter. Free testosterone, free estradiol and HOMA2-IR were calculated. Results Study participants lost one-third of their body weight after bariatric surgery, with maximum weight loss achieved at 24 months for most participants. Free testosterone increased from 0.17 (95% CI: 0.13 to 0.20) at baseline to 0.34 (95% CI: 0.30 to 0.38) and 0.27 nmol/L (95% CI: 0.23 to 0.32) at 2 and 5 years (P < 0.001 for both), respectively. Total testosterone increased from 6.7 (95% CI: 4.7 to 8.8) at baseline to 17.6 (95% CI: 15.3 to 19.9) and 13.8 (95% CI: 11.0 to 16.5) nmol/L at 2 and 5 years (P < 0.001), respectively. Prior to surgery, 73% of the participants had subnormal free testosterone ( Conclusions Bariatric surgery led to a robust increase in testosterone concentrations in adolescent males with severe obesity. Participants who regained weight had a decline in their testosterone concentrations.

Primary hyperaldosteronism is a major cause of secondary hypertension and carries additional cardiovascular risks beyond that of the elevated blood pressure. Primary hyperaldosteronism is more prevalent in obese people, and weight loss reduces aldosterone levels. It needs to be determined whether obesity related factors directly contribute to the pathogenesis of primary hyperaldosteronism. Here we show that the non-esterified fatty acids (NEFA) palmitic acid, and to a lesser extent, linoleic acid significantly stimulated aldosterone production and steroid enzyme induction in adrenocortical HAC15 cells of human origin. Palmitic acid, linoleic acid, and to a much lesser extent, oleic acid induced the expression of aldosterone synthase. Induction of the Steroidogenic Acute Regulatory Protein (StAR) was modest. Increased aldosterone secretion was independent of fatty acid beta-oxidation in the mitochondria but may involve free fatty acid receptor 1 (FFAR1/GPR40) and endoplasmic reticulum (ER) stress. Palmitic acid and linoleic acid induced the expression of C/EBP Homologous Protein (CHOP), a marker of ER stress, correlating with their ability to induce aldosterone synthase gene expression. Palmitic acid, but not linoleic acid decreased mitochondrial potentials and induced uncoupling protein 2 (UCP2). Palmitic acid enhanced, while docosahexaenoic acid (DHA) suppressed aldosterone response to angiotensin II (Ang-II). Our study provides evidence that NEFAs modulate aldosterone production, and further suggests that hyperaldosteronism shares similar pathogenesis with other obesity-related disorders such as metabolic syndrome.

Objective Diabetes mellitus has been recognized as one of the comorbidities that predict the severity of illness in patients infected with COVID-19. The characteristics of patients presenting with diabetic ketoacidosis (DKA) and COVID-19 infection have not been described. Methods We describe 5 patients with DKA and concomitant COVID-19 admitted to the intensive care unit of an academic medical center. Three patients had type 1 diabetes mellitus, and 2 patients had type 2 diabetes mellitus. Results While DKA with an infectious etiology is a common presentation, we observed that the patients with DKA precipitated by COVID-19 presented with atypical symptoms. COVID-19 infection was revealed during search for an etiology of DKA. Conclusion It is prudent to have a low threshold to screen for COVID-19 infection in patients with DKA.

Objective: Erythropoiesis stimulating agents (ESAs) are required in most of the patients with end-stage renal disease (ESRD) for treatment of anemia. Subnormal testosterone concentrations are very ...

Aims Insulin has anabolic effects on skeletal muscle. However, there is limited understanding of the molecular mechanisms underlying this effect in humans. We evaluated whether the skeletal muscle expression of satellite cell activator fibroblast growth factor 2 (FGF2) and muscle growth and differentiation factors are modulated acutely by insulin during euglycemic–hyperinsulinemic clamp (EHC). Design and methods This is a secondary investigation and analysis of samples obtained from a previously completed trial investigating the effect of testosterone replacement in males with hypogonadotropic hypogonadism and type 2 diabetes. Twenty men with type 2 diabetes underwent quadriceps muscle biopsies before and after 4 h of EHC. Results The infusion of insulin during EHC raised the expression of myogenic growth factors, myogenin (by 72 ± 20%) and myogenin differentiation protein (MyoD; by 81 ± 22%). Insulin reduced the expression of muscle hypertrophy suppressor, myogenic regulatory factor 4 (MRF4) by 34 ± 14%. In addition, there was an increase in expression of FGF receptor 2, but not FGF2, following EHC. The expression of myostatin did not change. Conclusions Insulin has an acute potent effect on expression of genes that can stimulate muscle differentiation and growth.

Male sex is associated with severe COVID-19. It is not known whether the risk of hospitalization differs between men with hypogonadism, men with eugonadism, and those receiving testosterone therapy (TTh).To compare COVID-19 hospitalization rates for men with hypogonadism who were not receiving TTh, men with eugonadism, and men receiving TTh.This cohort study was conducted in 2 large academic health systems in St Louis, Missouri, among 723 men with a history of COVID-19 who had testosterone concentrations measured between January 1, 2017, and December 31, 2021.The primary exposure was gonadal status (hypogonadism, eugonadism, and TTh). Hypogonadism was defined as a total testosterone concentration below the limit of normal provided by the laboratory (which varied from 175 to 300 ng/dL [to convert to nanomoles per liter, multiply by 0.0347]).The primary outcome was rate of hospitalization for COVID-19. Statistical adjustments were made for group differences in age, body mass index, race and ethnicity, immunosuppression, and comorbid conditions.Of the 723 study participants (mean [SD] age, 55 [14] years; mean [SD] body mass index, 33.5 [7.3]), 116 men had hypogonadism, 427 had eugonadism, and 180 were receiving TTh. Men with hypogonadism were more likely than men with eugonadism to be hospitalized with COVID-19 (52 of 116 [45%] vs 53 of 427 [12%]; P .001). After multivariable adjustment, men with hypogonadism had higher odds than men with eugonadism of being hospitalized (odds ratio, 2.4; 95% CI, 1.4-4.4; P .003). Men receiving TTh had a similar risk of hospitalization as men with eugonadism (odds ratio, 1.3; 95% CI, 0.7-2.3; P = .35). Men receiving inadequate TTh (defined as subnormal testosterone concentrations while receiving TTh) had higher odds of hospitalization compared with men who had normal testosterone concentrations while receiving TTh (multivariable adjusted odds ratio, 3.5; 95% CI, 1.5-8.6; P = .003).This study suggests that men with hypogonadism were more likely to be hospitalized after COVID-19 infection compared with those with eugonadism, independent of other known risk factors. This increased risk was not observed among men receiving adequate TTh. Screening and appropriate therapy for hypogonadism need to be evaluated as a strategy to prevent severe COVID-19 outcomes among men.

Hypogonadism as a cause of depression, daytime sleepiness, and flushing is often missed in young males. Our case report highlights the importance of screening for hypogonadotropic hypogonadism and its treatment in symptomatic men with severe obesity, especially if they have depression, excessive sleepiness, and narcolepsy.

Context One-third of men with type 2 diabetes have subnormal free testosterone concentrations. We evaluated the following: (i) whether bone mineral density (BMD) and bone strength are affected by gonadal status in type 2 diabetes and (ii) the effect of testosterone replacement on markers of osteoblast and osteoclast activity. Design This is a secondary analysis of a previously completed, randomized, placebo-controlled trial. Ninety-four men with type 2 diabetes were recruited; 44 had subnormal free testosterone concentrations. Men with subnormal free testosterone concentrations were randomized to receive intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Dual energy X-ray absorptiometry scans were performed at baseline and at 23 weeks. Results Men with subnormal free testosterone had similar BMD compared with men with normal free testosterone. However, bone strength indices were lower in men with subnormal free testosterone. BMD was related to free estradiol concentrations (r = 0.37, P = 0.004 at hip), whereas bone strength was related to free testosterone concentrations (r = 0.41, P < 0.001). Testosterone replacement increased osteocalcin concentrations [mean change (95% CI), 3.52 (0.45, 6.59), P = 0.008]. C-Terminal telopeptide (CTx) concentrations also increased at 15 weeks but reverted to baseline following that. There were no changes in other bone turnover markers or BMD. Conclusion We conclude that testosterone replacement resulted in an increase in osteocalcin and a transient increase in CTx, indicating an increase in osteoblastic activity and transient increase in bone breakdown. Therefore, a major action of testosterone is to increase bone turnover in men with type 2 diabetes.

CONTEXT: Fibroblast growth factor (FGF)2 is an important stimulatory modulator of satellite cells in skeletal muscle. Satellite cells play a cardinal role in muscle growth and repair. OBJECTIVE: We evaluated whether skeletal muscle expression of FGF2 and muscle growth and differentiation factors are reduced in patients with hypogonadotropic hypogonadism (HH) and whether testosterone replacement therapy results in their restoration. DESIGN: This is a secondary analysis of a previously completed trial of testosterone replacement in men with type 2 diabetes and HH. SETTING: Clinical Research Center at a university. PATIENTS: Twenty-two men with HH and 20 eugonadal men were compared at baseline. INTERVENTIONS: Twelve men with HH were treated with intramuscular injections of 250 mg testosterone every 2 weeks for 22 weeks, and 10 men received placebo injections. Quadriceps muscle biopsies and blood samples were obtained before and after testosterone therapy. OUTCOME MEASURES AND RESULTS: The expression of FGF2 and FGF receptor (FGFR)2 in skeletal muscle of men with HH was significantly lower than that in eugonadal men by 57% and 39%, respectively (P < 0.05). After 22 weeks of testosterone, the expression of FGF2 increased, whereas that of myogenic regulatory factor (MRF)4 and myostatin decreased significantly. There was no change in expression of FGFR2, myogenin, or myogenic differentiation protein in the skeletal muscle. Plasma FGF2 and IGF-1 concentrations increased after testosterone therapy. CONCLUSIONS: These data show that testosterone is a major modulator of FGF2, MRF4, and myostatin expression in skeletal muscle. These effects may contribute to the increase in muscle mass after testosterone therapy.

This cohort study investigates the association of sex hormones with disease severity and inflammatory cytokines in patients with COVID-19., Key Points Question Are circulating sex hormones associated with disease severity in patients with COVID-19? Findings In a cohort study of 152 patients with COVID-19, including 143 patients who were hospitalized, testosterone concentrations at presentation and on day 3 were inversely associated with disease severity and circulating inflammatory cytokine concentrations in men but not in women. Transcriptional profiling of circulating mononuclear cells revealed upregulation of hormone signaling pathways in patients requiring intensive care vs those with milder disease. Meaning These findings suggest that low testosterone concentrations may play a mechanistic role in worse outcomes observed in men with COVID-19, underscoring the need for clinical trials to test this hypothesis., Importance Male sex is a risk factor for developing severe COVID-19 illness. It is not known whether sex hormones contribute to this predisposition. Objective To investigate the association of concentrations of serum testosterone, estradiol, and insulinlike growth factor 1 (IGF-1, concentrations of which are regulated by sex hormone signaling) with COVID-19 severity. Design, Setting, and Participants This prospective cohort study was conducted using serum samples collected from consecutive patients who presented from March through May 2020 to the Barnes Jewish Hospital in St Louis, Missouri, with COVID-19 (diagnosed using nasopharyngeal swabs). Exposures Testosterone, estradiol, and IGF-1 concentrations were measured at the time of presentation (ie, day 0) and at days 3, 7, 14, and 28 after admission (if the patient remained hospitalized). Main Outcomes and Measures Baseline hormone concentrations were compared among patients who had severe COVID-19 vs those with milder COVID-19 illness. RNA sequencing was performed on circulating mononuclear cells to understand the mechanistic association of altered circulating hormone concentrations with cellular signaling pathways. Results Among 152 patients (90 [59.2%] men; 62 [40.8%] women; mean [SD] age, 63 [16] years), 143 patients (94.1%) were hospitalized. Among 66 men with severe COVID-19, median [interquartile range] testosterone concentrations were lower at day 0 (53 [18 to 114] ng/dL vs 151 [95 to 217] ng/dL; P = .01) and day 3 (19 [6 to 68] ng/dL vs 111 [49 to 274] ng/dL; P = .006) compared with 24 men with milder disease. Testosterone concentrations were inversely associated with concentrations of interleukin 6 (β = −0.43; 95% CI, −0.52 to −0.17; P

The role of testosterone in improving sexual symptoms in men with hypogonadism is well known. However, recent studies indicate that testosterone plays an important role in several metabolic functions in males. Multiple PubMed searches were conducted with the use of the terms testosterone, insulin sensitivity, obesity, type 2 diabetes, anaemia, bone density, osteoporosis, fat mass, lean mass and body composition. This narrative review is focused on detailing the mechanisms that underlie the metabolic aspects of testosterone therapy in humans. Testosterone enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids and suppressing inflammation. At a cellular level, testosterone increases the expression of insulin receptor β subunit, insulin receptor substrate-1, protein kinase B and glucose transporter type 4 in adipose tissue and adenosine 5'-monophosphate-activated protein kinase expression and activity in skeletal muscle. Observational studies show that long-term therapy with testosterone prevents progression from prediabetes to diabetes and improves HbA1c. Testosterone increases skeletal muscle satellite cell activator, fibroblast growth factor-2 and decreases expression of the muscle growth suppressors, myostatin and myogenic regulatory factor 4. Testosterone increases haematocrit by suppressing hepcidin and increasing expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations. Testosterone also increases serum osteocalcin concentrations, which may account for its anabolic actions on bone. In conclusion, testosterone exerts a series of potent metabolic effects, which include insulin sensitization, maintenance and growth of the skeletal muscle, suppression of adipose tissue growth and maintenance of erythropoiesis and haematocrit.

Aims To investigate whether testosterone therapy (TTh) in men with hypogonadism and type 2 diabetes mellitus (T2DM) improves glycaemic control and insulin sensitivity, and results in remission of T2DM. Material and Methods A total of 356 men who had total testosterone levels ≤12.1 nmol/L (350 ng/dL) and symptoms of hypogonadism were included in the study and followed up for 11 years. All patients received standard diabetes treatment and 178 patients additionally received parenteral testosterone undecanoate 1000 mg every 12 weeks following an initial 6‐week interval. A control group comprised 178 hypogonadal patients who opted not to receive TTh. Results Patients with hypogonadism and T2DM treated with testosterone had significant progressive and sustained reductions in fasting glucose, glycated haemoglobin (HbA1c) and fasting insulin over the treatment period. In the control group, fasting glucose, HbA1c and fasting insulin increased. Among the patients treated with testosterone 34.3% achieved remission of their diabetes and 46.6% of patients achieved normal glucose regulation. Of the testosterone‐treated group, 83.1% reached the HbA1c target of 47.5 mmol/mol (6.5%) and 90% achieved the HbA1c target of 53.0 mmol/mol (7%). In contrast, no remission of diabetes or reductions in glucose or HbA1c levels were noted in the control group. There were fewer deaths, myocardial infarctions, strokes and diabetic complications in the testosterone‐treated group. Conclusions Long‐term TTh in men with T2DM and hypogonadism improves glycaemic control and insulin resistance. Remission of diabetes occurred in one‐third of the patients. TTh is potentially a novel additional therapy for men with T2DM and hypogonadism.

Aims One-third of males with type 2 diabetes (T2DM) have hypogonadism, characterized by low total and free testosterone concentrations. We hypothesized that this condition is associated with a compensatory increase in the expression of androgen receptors (AR) and that testosterone replacement reverses these changes. We also measured estrogen receptor and aromatase expression. Materials and methods This is a randomized double-blind placebo-controlled trial. Thirty-two hypogonadal and 32 eugonadal men with T2DM were recruited. Hypogonadal men were randomized to receive intramuscular testosterone or saline every 2 weeks for 22 weeks. We measured AR, ERα and aromatase expression in peripheral blood mononuclear cells (MNC), adipose tissue and skeletal muscle in hypogonadal and eugonadal males with T2DM at baseline and after 22 weeks of treatment in those with hypogonadism. Results The mRNA expression of AR, ERα (ESR1) and aromatase in adipose tissue from hypogonadal men was significantly lower as compared to eugonadal men, and it increased significantly to levels comparable to those in eugonadal patients with T2DM following testosterone treatment. AR mRNA expression was also significantly lower in MNC from hypogonadal patients compared to eugonadal T2DM patients. Testosterone administration in hypogonadal patients also restored AR mRNA and nuclear extract protein levels from MNC to that in eugonadal patients. In the skeletal muscle, AR mRNA and protein expression are lower in men with hypogonadism. Testosterone treatment restored AR expression levels to that comparable to levels in eugonadal men. Conclusions We conclude that, contrary to our hypothesis, the expression of AR, ERα and aromatase is significantly diminished in hypogonadal men as compared to eugonadal men with type 2 diabetes. Following testosterone replacement, there is a reversal of these deficits.

Background: Male sex is a risk factor for developing severe COVID-19 illness, hospitalization, and mortality. It is possible that the male sex hormone, testosterone, contributes to the morbidity from COVID-19. SARS-CoV2 viruses use cell membrane protein Angiotensin-Converting Enzyme 2 (ACE2) receptor and undergo S protein priming by the Type II Transmembrane Serine Protease (TMPRSS2) to enter the cells. Hence, the expression level of ACE2 and TMPRSS2 may affect disease susceptibility and possible severity. TMPRSS2 is regulated by the androgen receptor. We, therefore, examined if an association exists between serum testosterone concentrations and ACE2 or TMPRSS2 expression level in men. Methods: We analyzed fasting serum samples and peripheral blood mononuclear cells (MNC) from 42 men. Total and free testosterone and estradiol were measured by liquid chromatography/equilibrium dialysis. Sex hormone binding globulin (SHBG) was measured by chemiluminescence. mRNA was prepared from MNC. Quantitative RT-PCR was conducted using commercially available, pre-designed TaqMan primers and probes targeting ACE2. The ACE2 relative level was calculated after normalization to beta Actin and GAPDH, with lowest ACE2 level being set to 1. Results: Subjects’ age ranged from 20 to 65 years. Type 2 diabetes was present in 74% of the men and the mean HbA1 was 7.2±1.6% (mean ± S.D.). Fifteen subjects had subnormal free testosterone (0.30 for all). ACE2 expression was also not related to age (r= -0.15, p=0.34), BMI (r= -0.2, p=0.23) or presence of diabetes. We were not able to detect a significant expression of TMPRSS2 in MNC. Conclusion: Our results do not support a role for testosterone or estradiol as regulators of ACE2 expression in peripheral blood MNC in males.

Context and ObjectiveHypertriglyceridemia is implicated in ~5% of cases of acute pancreatitis. It is assumed that intravenous insulin is effective in lowering triglyceride (TG) concentrations in hypertriglyceridemia-associated acute pancreatitis (HAAP). However, the efficacy of intravenous insulin versus conservative management alone is not known.Design and SettingCharts of 106 patients who were admitted with HAAP and had TG concentrations >1000 mg/dL at admission were reviewed. Patients who received intravenous insulin for at least 8 hours were included in the intravenous insulin group, while the rest were considered to have received conservative management. We compared the change in TG concentrations from baseline in the 2 groups.ResultsFifty-one patients received intravenous insulin while 55 patients were managed conservatively. Baseline TG concentrations were higher in the intravenous insulin group (median [25th, 75th percentile] 3307 [2106, 4425] mg/dL vs 2304 [1416, 2720] mg/dL; P < 0.001). The TG concentrations declined rapidly in both groups, reaching below 1000 mg/dL by day 3 and < 500 mg/dL by day 4. TG concentrations in the intravenous insulin group had decreased by 69% and 85% on days 2 and 4, respectively. The fall in the conservative management group was 63% and 79%, which was not statistically different than the change in the intravenous insulin group.ConclusionOur results show that intravenous insulin did not result in a more rapid fall in TG compared with conservative treatment in patients with HAAP. Fasting and intravenous fluids were effective in lowering TG concentrations rapidly, with no further contribution from insulin.

Context Adenosine 5’-monophosphate-activated protein kinase-α (AMPKα) is a mediator of exercise-induced glucose uptake in skeletal muscle. Objective We evaluated whether AMPKα expression and phosphorylation are reduced in skeletal muscle and adipose tissue of patients with hypogonadotropic hypogonadism (HH), and whether testosterone replacement therapy results in restoration of the expression and phosphorylation of AMPKα. Design This is a secondary analysis of a previously completed trial that showed an insulin-sensitizing effect of testosterone therapy in men with type 2 diabetes and HH. Setting Clinical research center at university. Patients Thirty-two men with HH and 32 eugonadal men were compared at baseline. Interventions Men with HH were treated with intramuscular injections of testosterone or placebo every 2 weeks for 22 weeks. Quadriceps muscle biopsies and subcutaneous abdominal fat biopsies were obtained before and after 4-hour euglycemic hyperinsulinemic clamp, prior to and after testosterone or placebo therapy. Outcome Measures and Results mRNA expression of AMPKα in hypogonadal men was lower by 37% in adipose tissue and 29% in skeletal muscle, respectively, compared with levels in eugonadal men, while phosphorylated AMPKα was lower by 22% and 28%, respectively. Following testosterone replacement, the expression of AMPKα did not alter in the fasting state but increased markedly by 41% and 46% in adipose tissue and muscle, respectively, after the clamp. In contrast, phosphorylated AMPKα increased by 69% in muscle after testosterone therapy but did not change following the clamp. Conclusions Testosterone modulates the expression of AMPKα and phosphorylated AMPKα. These effects may contribute to the improved insulin sensitivity following testosterone therapy.

With rising prevalence of obesity and diabetes, nonalcoholic fatty liver disease (NAFLD) is now a leading cause of chronic liver disease. One-third of obese or diabetic men have subnormal free and bioavailable testosterone concentrations.1 Several studies have further shown low testosterone to be associated with imaging-confirmed NAFLD in men,2 although it is unknown whether low testosterone confers increased risk of more clinically relevant manifestations of NAFLD, including nonalcoholic steatohepatitis (NASH) and NASH fibrosis. We therefore aimed to evaluate the association of testosterone with histologic features of NAFLD among a representative cohort of men from the multicenter NASH Clinical Research Network (NASH CRN).

OBJECTIVE To investigate whether addition of three different doses of liraglutide to insulin in patients with type 1 diabetes (T1D) results in significant reduction in glycemia, body weight, and insulin dose. RESEARCH DESIGN AND METHODS We randomized 72 patients (placebo = 18, liraglutide = 54) with T1D to receive placebo and 0.6, 1.2, and 1.8 mg liraglutide daily for 12 weeks. RESULTS In the 1.2-mg and 1.8-mg groups, the mean weekly reduction in average blood glucose was −0.55 ± 0.11 mmol/L (10 ± 2 mg/dL) and −0.55 ± 0.05 mmol/L (10 ± 1 mg/dL), respectively (P < 0.0001), while it remained unchanged in the 0.6-mg and placebo groups. In the 1.2-mg group, HbA1c fell significantly (−0.78 ± 15%, −8.5 ± 1.6 mmol/mol, P < 0.01), while it did not in the 1.8-mg group (−0.42 ± 0.15%, −4.6 ± 1.6 mmol/mol, P = 0.39) and 0.6-mg group (−0.26 ± 0.17%, −2.8 ± 1.9 mmol/mol, P = 0.81) vs. the placebo group (−0.3 ± 0.15%, −3.3 ± 1.6 mmol/mol). Glycemic variability was reduced by 5 ± 1% (P < 0.01) in the 1.2-mg group only. Total daily insulin dose fell significantly only in the 1.2-mg and 1.8-mg groups (P < 0.05). There was a 5 ± 1 kg weight loss in the two higher-dose groups (P < 0.05) and by 2.7 ± 0.6 kg (P < 0.01) in the 0.6-mg group vs. none in the placebo group. In the 1.2- and 1.8-mg groups, postprandial plasma glucagon concentration fell by 72 ± 12% and 47 ± 12%, respectively (P < 0.05). Liraglutide led to higher gastrointestinal adverse events (P < 0.05) and ≤1% increases (not significant) in percent time spent in hypoglycemia ( CONCLUSIONS Addition of 1.2 mg and 1.8 mg liraglutide to insulin over a 12-week period in overweight and obese patients with T1D results in modest reductions of weekly mean glucose levels with significant weight loss, small insulin dose reductions, and frequent gastrointestinal side effects. These findings do not justify the use of liraglutide in all patients with T1D.

A quarter of men with obesity or type 2 diabetes have hypogonadotropic hypogonadism. Animal studies and in vitro data have shown that insulin action and insulin responsiveness in the brain are necessary for the maintenance of the functional integrity of the hypothalamo-hypophyseal-gonadal axis. We conducted a randomized, placebo-controlled trial to evaluate the effect of one dose of intranasal insulin (40 IU of regular insulin) or saline on LH concentrations in 14 men (8 with type 2 diabetes and 6 healthy lean men). Insulin or saline was administered intranasally on two different occasions, at least one week apart. Blood samples were collected to measure LH concentrations every 15 minutes for 5 hours. Study drug was administered intranasally after a 2-hour baseline sampling period. Patients remained fasting throughout the procedure. The primary endpoint of the study was to compare the change in LH concentrations after intranasal insulin as compared to placebo (intranasal saline). Change was defined as the difference between baseline LH concentrations (average of the 9 samples collected in two hours prior to drug administration) and average LH concentrations following drug administration (average of the 12 samples collected in 3 hours). There was no change in LH concentrations following insulin administration as compared to placebo in men with diabetes or in lean men. We conclude that one dose of 40 IU of regular insulin administered intranasally does not change LH concentrations acutely in men.

AMP kinase is a key enzyme involved with energy regulation, the intake of macronutrients, the uptake of glucose and fatty acids by cells and the metabolic combustion of fatty acids. We hypothesized that in patients with hypogonadism associated with diabetes, its expression and activity are diminished since there is a quantitative and qualitative loss of skeletal muscle function. Twenty-two men with HH and T2DM were compared with 20 eugonadal men with T2DM at baseline. From the HH patients, 12 were treated with testosterone 200mg every 2 weeks injected intramuscularly for 24 weeks, during which their plasma concentrations were maintained in the physiological range. Hyperinsulinemic, euglycemic clamps (HEC) were carried out prior to and after testosterone replacement and fat (abdomen) and muscle (quadriceps) biopsies were carried out prior to and after HEC procedure on each occasion. In the hypogonadal state, the expression and the activity (measured as phoso-T172-AMPK-α) of AMP kinase-α was significantly lower in HH patients than eugonadal diabetics both in adipose tissue and skeletal muscle by 37% and 29%, respectively, for expression and by 22.1% and 28%, respectively for activity. Following testosterone, there was no change in expression but there was a significant increase in AMP kinase activity by 69±31% (from 14.9±2.8 to 22.8±2.2U/ml, p Disclosure S. Dhindsa: None. H. Ghanim: None. M. Batra: Speaker's Bureau; Self; Eli Lilly and Company. A. Chaudhuri: Speaker's Bureau; Self; AstraZeneca, Eli Lilly and Company, Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc.. S. Abuaysheh: None. P. Dandona: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca.

One-third of men with obesity or type 2 diabetes have subnormal free testosterone concentrations. The lower free testosterone concentrations are observed in obese men at all ages, including adolescents at completion of puberty. The gonadotropin concentrations in these males are inappropriately normal; thus, these patients have hypogonadotropic hypogonadism (HH). The causative mechanism of diabesity-induced HH is yet to be defined but is likely multifactorial. Decreased insulin and leptin signaling in the central nervous system are probably significant contributors. Contrary to popular belief, estrogen concentrations are lower in men with HH. Men with diabesity and HH have more fat mass and are more insulin resistant than eugonadal men. In addition, they have a high prevalence of anemia and higher mortality rates than eugonadal men. Testosterone replacement therapy results in a loss of fat mass, gain in lean mass, and increase in insulin sensitivity in men with diabesity and HH. This is accompanied by an increase in insulin-signaling genes in adipose tissue and a reduction in inflammatory mediators that interfere with insulin signaling. There is also an improvement in sexual symptoms, anemia, LDL cholesterol, and lipoprotein (a). However, testosterone therapy does not consistently affect HbA1c in men with diabetes. The effect of testosterone replacement on cardiovascular events or mortality in men with diabesity is not known and remains to be studied in prospective trials.

BACKGROUND: Serum testosterone levels and insulin sensitivity both decrease with age. Severe testosterone deficiency is associated with the development of insulin resistance. However, the effects of long-term testosterone administration on insulin sensitivity in older men with low or low-normal testosterone levels remain unknown. METHODS: The Testosterone Effects on Atherosclerosis in Aging Men Trial was a placebo-controlled, randomized, double-blind trial. The participants were 308 community-dwelling men, ≥60 years old, with total testosterone 100 to 400 ng/dL or free testosterone

OBJECTIVE One-third of men with type 2 diabetes have hypogonadotropic hypogonadism (HH). We conducted a randomized placebo-controlled trial to evaluate the effect of testosterone replacement on insulin resistance in men with type 2 diabetes and HH. RESEARCH DESIGN AND METHODS A total of 94 men with type 2 diabetes were recruited into the study; 50 men were eugonadal, while 44 men had HH. Insulin sensitivity was calculated from the glucose infusion rate (GIR) during hyperinsulinemic-euglycemic clamp. Lean body mass and fat mass were measured by DEXA and MRI. Subcutaneous fat samples were taken to assess insulin signaling genes. Men with HH were randomized to receive intramuscular testosterone (250 mg) or placebo (1 mL saline) every 2 weeks for 24 weeks. RESULTS Men with HH had higher subcutaneous and visceral fat mass than eugonadal men. GIR was 36% lower in men with HH. GIR increased by 32% after 24 weeks of testosterone therapy but did not change after placebo (P = 0.03 for comparison). There was a decrease in subcutaneous fat mass (−3.3 kg) and increase in lean mass (3.4 kg) after testosterone treatment (P < 0.01) compared with placebo. Visceral and hepatic fat did not change. The expression of insulin signaling genes (IR-β, IRS-1, AKT-2, and GLUT4) in adipose tissue was significantly lower in men with HH and was upregulated after testosterone treatment. Testosterone treatment also caused a significant fall in circulating concentrations of free fatty acids, C-reactive protein, interleukin-1β, tumor necrosis factor-α, and leptin (P < 0.05 for all). CONCLUSIONS Testosterone treatment in men with type 2 diabetes and HH increases insulin sensitivity, increases lean mass, and decreases subcutaneous fat.

BackgroundOne-third of men with type 2 diabetes have subnormal testosterone concentrations along with inappropriately normal LH and FSH concentrations. It is not known if the presence of renal insufficiency affects free testosterone concentrations in men with type 2 diabetes.HypothesisWe hypothesized that type 2 diabetic men with chronic renal disease (CKD; estimated glomerular filtration rate (eGFR) 2) have lower free testosterone concentrations than men with normal renal function (eGFR ≥60 ml/min per 1.73 m2).Study design and settingThis is a retrospective chart review of patients attending diabetes and nephrology clinics. Men with type 2 diabetes who had the following information available were included in the study: testosterone (total and free) done by LC/MS-MS followed by equilibrium dialysis, sex hormone binding globulin, LH, FSH and prolactin concentrations.ParticipantsWe present data on T and gonadotropin concentrations in 111 men with type 2 diabetes and CKD (stages 3–5) and 182 type 2 diabetic men without CKD.ResultsThe prevalence of subnormal free testosterone concentrations was higher in men with type 2 diabetes and CKD as compared to those without CKD (66% vs 37%, PPP=0.22). There was an increase in the prevalence of hypergonadotropic hypogonadism with decreasing eGFR. Fifty-two percent of men with renal failure (CKD stage 5) had hypergonadotropic hypogonadism and 25% had HH. In men with CKD, the hemoglobin concentrations were lower in those with subnormal free T concentrations as compared to men with normal free T concentrations (119±19 vs 128±19 g/l, P=0.04).ConclusionsTwo-thirds of men with type 2 diabetes and CKD have subnormal free T concentrations. The hypogonadism associated with CKD is predominantly hypergonadotropic.

This study was conducted to investigate whether a high-fat/high-carbohydrate (HFHC) meal induces an increase in plasma concentrations of glucagon, dipeptidyl peptidase-IV (DPP-IV), and CD26 expression in mononuclear cells (MNC) while reducing insulin, C-peptide, proinsulin, GIP, and GLP-1 concentrations. Ten healthy normal subjects were given either a 910-calorie HFHC meal or an American Heart Association (AHA) meal rich in fruit and fiber during the first visit and the other meal during the second visit in crossover design. Blood samples were collected at baseline and at 15, 30, 45, 60, 75, 90, 120, 180, and 300 min following the meal. There was a significantly greater increase in glucose concentrations and lower increase in postprandial insulin, C-peptide, and proinsulin concentrations and lower insulin/glucose ratios following the HFHC meal. HFHC meal intake induced marked increases in plasma glucagon and DPP-IV concentrations and an increase in CD26 mRNA expression in MNC compared with the AHA meal. In addition, the HFHC meal induced a reduction in GIP and peak GLP-1 secretion compared with the AHA meal. This was associated with a significantly greater increase in oxidative stress and proinflammatory mediators including, ROS generation, TNFα, and IL-1β mRNA expression and plasma concentrations of TBARS, FFA, and LPS. We conclude that the proinflammatory HFHC meals result in lower insulin, C-peptide, proinsulin, and GIP secretion in association with higher plasma glucagon and DPP-IV concentrations and CD26 expression in MNC compared with the AHA meal.

Background and Hypothesis. Following our recent demonstration that the chronic inflammatory and insulin resistant state of obesity is associated with an increase in the expression of mediators known to contribute to the pathogenesis of asthma and that weight loss after gastric bypass surgery results in the reduction of these genes, we have now hypothesized that insulin suppresses the cellular expression and plasma concentrations of these mediators.Methods. The expression of IL-4, LIGHT, LTBR, ADAM-33, and TSLP in MNC and plasma concentrations of LIGHT, TGF-β1, MMP-9, MCP-1, TSLP, and NOM in obese patients with T2DM were measured before, during, and after the infusion of a low dose (2 U/h) infusion of insulin for 4 hours. The patients were also infused with dextrose or saline for 4 hours on two separate visits and served as controls.Results. Following insulin infusion, the mRNA expression of IL-4, ADAM-33, LIGHT, and LTBR mRNA expression fell significantly (P<0.05for all). There was also a concomitant reduction in plasma NOM, LIGHT, TGF-β1, MCP-1, and MMP-9 concentrations.Conclusions. Insulin suppresses the expression of these genes and mediators related to asthma and may, therefore, have a potential role in the treatment of asthma.

Objective: Hydrocortisone, at a low dose (100 mg), induces an anti-inflammatory response including inducing IkBα and suppressing intranuclear NFκB and AP-1 binding and the expression of pro-inflammatory mediators like MMPs. We have now investigated the effect of a high dose of hydrocortisone (300mg=60 mg prednisolone) on NFκB binding and the expression of TLRs, the mediators of TLR signal transduction, MyD88 and TRIF and HMG-B1. Design and Subjects: A 300mg of hydrocortisone or saline was injected intravenously in ten normal subjects during 2 separate visits, in a randomized crossover study. Blood samples were obtained at 0, 1, 4, 6 and 24h after the injection and mononuclear cells (MNC) were prepared. Results: There was a significant increase in glucose (from 92±4 to 116±6 mg/dl), insulin (from 4.5±0.7 to 5.3±0.8 mU/ml) and FFA concentrations (from 0.38±0.1 to 0.80±0.15mM) following the administration of hydrocortisone compared to placebo treatment. While NFκB binding and the mRNA expression of MyD88, TRIF, chemokines and chemokine receptors were suppressed significantly in MNC, there was a paradoxical increase in the mRNA expression of TLR 2, 5 and 9 and HMG-B1 was increased by 103±24%, 107±19%, 56±13% and 58±12% above the baseline, respectively in the MNC. Plasma concentrations of HMG-B1 and MMP-9 increased by 37±12% and 125±22%, respectively, while TNF-α concentrations fell by 27±9%. Conclusion: While this high dose of hydrocortisone exerts a powerful anti-inflammatory effect, it also exerts certain proinflammatory effects mainly on TLRs expression. The known pro-inflammatory effects of glucose and FFAs may have contributed to these effects. These paradoxical pro-inflammatory effects may account for the inability of these drugs to show benefit in clinical trials of septicemia and other severe pro-inflammatory states and might contribute to some of the side effects of corticosteroids use.

Objective To determine whether the expression of key asthma related genes, IL-4, LIGHT, LTBR, MMP-9, CCR-2, and ADAM-33 in mononuclear cells and the plasma concentration of nitric oxide metabolites (NOM) and MMP-9 are increased in the obese, obese type 2 diabetics (T2DM) and in morbidly obese patients prior to and after gastric bypass surgery (RYGB). Design and Methods The expression of these genes in MNC and plasma concentrations of these indices was measured in healthy lean and in obese with and without T2DM and following RYGB in obese T2DM. Results The expression of IL-4, MMP-9, LIGHT and CCR-2 and plasma NOM concentrations was significantly higher in the obese subjects and in obese T2DM patients than in normal subjects. The expression of IL-4, LIGHT, MMP-9, and CCR-2 expression was related to BMI and HOMA-IR. The expression of IL-4, LIGHT, LTBR, ADAM-33, MMP-9, and CCR-2 fell after RYGB surgery as did plasma concentrations of MMP-9 and NOM. Conclusions Obesity with and without T2DM is associated with an increase in the expression of IL-4, LIGHT, MMP-9 and CCR-2; plasma NOM and MMP-9 concentrations are also increased. Following RYGB surgery and weight loss, the expression of these factors in MNC and plasma concentrations falls significantly.

SummaryContext As the syndrome of hypogonadotropic hypogonadism (HH) is associated with anaemia and the administration of testosterone restores haematocrit to normal, we investigated the potential underlying mechanisms. Design Randomized, double-blind, placebo-controlled trial. Methods We measured basal serum concentrations of erythropoietin, iron, iron binding capacity, transferrin (saturated and unsaturated), ferritin and hepcidin and the expression of ferroportin and transferrin receptor (TR) in peripheral blood mononuclear cells (MNC) of 94 men with type 2 diabetes. Forty-four men had HH (defined as subnormal free testosterone along with low or normal LH concentrations) while 50 were eugonadal. Men with HH were randomized to testosterone or placebo treatment every 2 weeks for 15 weeks. Blood samples were collected at baseline, 3 and 15 weeks after starting treatment. Twenty men in testosterone group and 14 men in placebo group completed the study. Results Haematocrit levels were lower in men with HH (41·1 ± 3·9% vs 43·8 ± 3·4%, P = 0·001). There were no differences in plasma concentrations of hepcidin, ferritin, erythropoietin, transferrin or iron, or in the expression of ferroportin or TR in MNC among HH and eugonadal men. Haematocrit increased to 45·3 ± 4·5%, hepcidin decreased by 28 ± 7% and erythropoietin increased by 21 ± 7% after testosterone therapy (P < 0·05). There was no significant change in ferritin concentrations, but transferrin concentration increased while transferrin saturation and iron concentrations decreased (P < 0·05). Ferroportin and TR mRNA expression in MNC increased by 70 ± 13% and 43 ± 10%, respectively (P < 0·01), after testosterone therapy. Conclusions The increase in haematocrit following testosterone therapy is associated with an increase in erythropoietin, the suppression of hepcidin, and an increase in the expression of ferroportin and TR.

To assess whether liraglutide, a glucagon-like peptide-1 receptor agonist, has cardioprotective properties in addition to its glycemic effects.We performed a retrospective analysis of medical records of 110 obese patients with type 2 diabetes mellitus treated with liraglutide for at least 6 months between March 2010 and April 2011 at our tertiary care referral center. The variables analyzed were body mass index, hemoglobin A(1c) (A1C), systolic blood pressure (SBP), plasma C-reactive protein (CRP) concentrations, and serum lipids.In our overall study cohort, we noted a reduction in mean weight from 120 ± 5 kg to 115 ± 3 kg and a decrease in mean A1C from 7.8% ± 0.6% to 7.2% ± 0.2%. The mean triglyceride concentration decreased from 173 ± 19 mg/dL to 151 ± 15 mg/dL, the mean SBP was reduced from 132 ± 6 mm Hg to 125 ± 4 mm Hg, and the mean CRP concentration declined from 4.7 ± 0.8 mg/L to 3.2 ± 0.4 mg/L after treatment with liraglutide for a minimal duration of 6 months and a mean duration of 7.5 months (for all the foregoing changes, P.05). These variables decreased whether these patients were previously treated with orally administered hypoglycemic agents alone or in combination with insulin or exenatide.Our findings in a clinical practice show that liraglutide is a potent antidiabetes drug, whether given in combination with orally administered agents or insulin or as a substitution for exenatide. It lowers body weight, A1C levels, SBP, and CRP and triglyceride concentrations.