Diabetes surpasses obesity as a risk factor for low serum testosterone level.

BACKGROUND: Male obesity is one of the most associated factors with substandard testosterone levels. However, there is growing evidence linking low testosterone levels to insulin resistance and diabetic complications. We aimed to study the impact of diabetes mellitus on testosterone levels and to assess the correlation of various clinical and biochemical factors with hypogonadism. SUBJECTS AND METHODS: This case-control study was conducted on 160 adult males categorized into four equal groups (40 each); Group A: lean men with T2DM, Group B: obese with T2DM, Group C: lean with normal glycemic profile, Group D: obese with normal glycemic profile. Serum total testosterone (TT), SHBG and HbA1c have been measured. Free testosterone (cFT) and HOMA-IR were calculated. RESULTS: A significant negative correlation of serum TT and cFTwith BMI (r -0.16, p 0.04/ r -0.26, p < 0.001, respectively) and with waist circumference (WC) (r -0.23, p 0.003 and r -0.3, p < 0.001, respectively). A significant decrease in TT and cFT in the diabetes group versus the non-diabetes one (p < 0.001 for both). TT level was significantly lower in the diabetic lean group than in the non-diabetic lean (p < 0.001), and even significantly lower than in the non-diabetic obese (p < 0.001). TT level in the diabetic obese group was lower than in the non-diabetic obese (p < 0.001). The same for cFT level, lower in the diabetic lean group than in non-diabetic lean (p < 0.001) and lower in the diabetic obese than in the non-diabetic obese (p < 0.001). Concomitant significant reduction in SHBG in the diabetes group (p < 0.001). Linear regression analysis revealed that TT significantly correlated with HOMA-IR. HOMA-IR with WC, age and the duration of diabetes correlated significantly with cFT. In our model, HOMA-IR and HbA1c accounted for approximately 51.3% of TT variability (adjusted R-squared 0.513). CONCLUSIONS: The impact of T2DM on serum testosterone levels was more significant than that of obesity. Our study showed a decrease in SHBG together with cFT among the diabetes group. Hypogonadism is significantly correlated to insulin resistance and poor glycemic control, which implies another perspective on the impact of suboptimal glycemic control on the development of hypogonadism.

Glucose ingestion does not lower testosterone concentrations in men on testosterone therapy.

Oral calorie intake causes an acute and transient decline in serum testosterone concentrations. It is not known whether this decline occurs in men on testosterone therapy. In this study, we evaluated the change in testosterone concentrations following oral glucose ingestion in hypogonadal men before and after treatment with testosterone therapy. This is a secondary analysis of samples previously collected from a study of hypogonadal men with type 2 diabetes who received testosterone therapy. Study participants (n = 14) ingested 75 grams of oral glucose, and blood samples were collected over 2 h. The test was repeated after 23 weeks of intramuscular testosterone therapy. The mean age and body mass index of study volunteers were 53 ± 8 years and 38 ± 7 kg/m2, respectively. Following glucose intake, testosterone concentrations fell significantly prior to testosterone therapy (week 0, p = 0.04). The nadir of testosterone concentration was at 1 h, followed by recovery to baseline by 2 h. In contrast, there was no change in testosterone concentrations at week 23. The change in serum testosterone concentrations at 60 min was significantly more at week 0 than week 23 (-11 ± 10% vs 0 ± 16%, p = 0.05). We conclude that oral glucose intake has no impact on testosterone concentrations in men on testosterone therapy. Endocrinology societies should consider clarifying in their recommendations that fasting testosterone concentrations are required for the diagnosis of hypogonadism, but not for monitoring testosterone therapy.

Glucagon-like peptide-1 receptor agonists as a possible intervention to delay the onset of type 1 diabetes: A new horizon.

Type 1 diabetes (T1D) is a chronic autoimmune condition that destroys insulin-producing beta cells in the pancreas, leading to insulin deficiency and hyper-glycemia. The management of T1D primarily focuses on exogenous insulin replacement to control blood glucose levels. However, this approach does not address the underlying autoimmune process or prevent the progressive loss of beta cells. Recent research has explored the potential of glucagon-like peptide-1 receptor agonists (GLP-1RAs) as a novel intervention to modify the disease course and delay the onset of T1D. GLP-1RAs are medications initially developed for treating type 2 diabetes. They exert their effects by enhancing glucose-dependent insulin secretion, suppressing glucagon secretion, and slowing gastric emptying. Emerging evidence suggests that GLP-1RAs may also benefit the treatment of newly diagnosed patients with T1D. This article aims to highlight the potential of GLP-1RAs as an intervention to delay the onset of T1D, possibly through their potential immunomodulatory and anti-inflammatory effects and preservation of beta-cells. This article aims to explore the potential of shifting the paradigm of T1D management from reactive insulin replacement to proactive disease modification, which should open new avenues for preventing and treating T1D, improving the quality of life and long-term outcomes for individuals at risk of T1D.

Vasoactive mediators of hypertension in obesity.

Obesity is associated with hypertension. However, the mechanisms involved are not fully understood. Therefore, we investigated the relationship between obesity and vasoactive mediators. In this cross-sectional study, blood pressure (BP) and vasoactive mediators of hypertension are compared among 135 adults in the nonobese, obese, and morbidly obese body mass index (BMI) ranges (BMI ≤27, 30-40, and >40 kg/m2, respectively). Angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1 (ET-1), neprilysin, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cyclic guanosine monophosphate (cGMP), and cyclic adenosine monophosphate (cAMP) levels were measured and their relationship to BP, BMI, race, and gender were investigated. Systolic and diastolic BP (SBP and DSP) were significantly higher in subjects with obesity and morbid obesity compared with nonobese. Angiotensin II, ET-1, and neprilysin were significantly higher in subjects with morbid obesity while BNP was lower. Levels of angiotensinogen, renin, aldosterone, ANP, cGMP, and cAMP did not differ between the groups. BMI was positively related to SBP, DBP, angiotensin II, ET-1, and neprilysin, and inversely related to cGMP and BNP. Age, male gender, and African-American race were associated with higher SBP. SBP was positively related to angiotensin II and ET-1 and inversely related to aldosterone, renin, and cGMP. On multivariate analyses, age, BMI, gender, and race were the main determinants of SBP, and excluding these variables, angiotensin II, aldosterone, renin, and ET-1 accounted for 21.1% ability to predict SBP. Obesity, especially morbid obesity, is associated with higher BP, higher angiotensin II and ET-1 (vasoconstrictors), and lower levels BNP and cGMP (vasodilators). SBP variability can be partly explained by angiotensin II, aldosterone, renin, and ET-1.NEW & NOTEWORTHY Our data show that obesity, especially morbid obesity, is associated with higher blood pressure levels and increases angiotensin II and endotherlin-1 (ET-1) (vasoconstrictors) and lower levels BNP and cGMP (vasodilators) and that systolic blood pressure variability can be partly explained by levels of angiotensin II, aldosterone, renin, and ET-1. The effect of these mediators on blood pressure is in addition to the effects of other known factors related to age, male gender, and AA race.

Omega-3 Fatty Acids in Cardiovascular Disease and Diabetes: a Review of Recent Evidence.

PURPOSE OF REVIEW: Omega-3 fatty acids (n-3 FA) lower triglycerides, have anti-inflammatory properties, and improve metabolism. Clinical evidence of cardiovascular benefit with omega-3 fatty acids is mixed. We discuss mechanisms providing biological plausibility of benefit of omega-3 fatty acids in cardiovascular risk reduction and review clinical trials investigating the benefits of prescription omega-3 fatty acids in dyslipidemia, atherosclerotic cardiovascular disease (ASCVD), and diabetes. RECENT FINDINGS: Although early trials showed no benefit of omega-3 fatty acids in ASCVD, the REDUCE-IT trial noted significant risk reduction in ASCVD events with highly purified EPA (icosapent ethyl) use which has changed the landscape for currently available therapeutic options. However, other large trials like STRENGTH and VITAL, which used different formulations of prescription omega-3 fatty acids, did not note significant cardiovascular risk reduction. Thus the effectiveness of omega-3 fatty acids for cardiovascular disease prevention is an ongoing topic of debate. A relative paucity of studies examining benefits for glycemic outcomes in persons with diabetes exists; however, few studies have suggested lack of benefit to date. Significant residual cardiovascular risk exists for individuals with hypertriglyceridemia. Prescription omega-3 fatty acids are more commonly used for CV risk reduction in these patients. Clinical guideline statements now recommend icosapent ethyl use for selected individuals with hypertriglyceridemia to reduce cardiovascular events given recent evidence from the REDUCE-IT trial. Nonetheless, data from other large scale trials has been mixed, and future research is needed to better understand how different preparations of omega-3 may differ in their cardiovascular and metabolic effects, and the mechanisms for their benefit.

Insulin Resistance and Glycated Hemoglobin in Obesity Are Associated With Preference for Sugar-Sweetened Yogurt: A Pilot Study.

OBJECTIVE: Insulin resistance is associated with elevated activation of food reward, which should be associated with an increased reinforcing value of food. Research has also shown that sugar is a macronutrient strongly associated with reward and reinforcing value of food. This research is designed to assess whether insulin resistance is associated with a stronger preference for sugar-sweetened, thus elevating blood glucose responses in obese people with varying degrees of insulin resistance. METHODS: Thirteen people with obesity (body mass index, 39.1 kg/m 2 ; range, 30.0-45.1 kg/m 2 ) with varying degrees of insulin resistance (Homeostatic Model Assessment of Insulin Resistance, 5.2; range, 0.7-11.6) consumed novel flavored-colored yogurts that were sweetened with either sugar or monkfruit daily for 6 days to assess whether when given the choice of sugar-sweetened versus monkfruit-sweetened yogurts to consume, participants preferred sugar-sweetened yogurts. RESULTS: Participants consumed a greater amount ( p = .009) and percentage ( p = .04) of sugar-sweetened yogurt earned than monkfruit-sweetened yogurt. The percent of sugar-sweetened versus monkfruit-sweetened yogurt consumed in relationship to amount earned was related to insulin resistance ( r = 0.64, p = .019), glycated hemoglobin ( r = 0.61, p = .027), insulin ( r = 0.58, p = .007), and glucose ( r = 0.56, p = .048). CONCLUSIONS: Insulin resistance is associated with preference for sugar-sweetened foods in participants with obesity, which may make it hard to make dietary changes. Research is needed to assess whether treatments that improve insulin resistance also change the preference for sugar-sweetened or high-glycemic-index foods.

Efficacy of lower doses of pioglitazone after stroke or transient ischaemic attack in patients with insulin resistance.

AIMS: Pioglitazone is a potent insulin-sensitizing drug with anti-atherosclerotic properties, but adverse effects have limited its use. We assessed the benefits and risks of lower versus higher doses of pioglitazone taken by participants in the Insulin Resistance Intervention in Stroke Trial. MATERIALS AND METHODS: Efficacy [myocardial infarction (MI) or recurrent stroke] new-onset diabetes) and adverse outcomes (oedema, weight gain, heart failure and bone fracture) were examined for subjects assigned to pioglitazone or placebo within strata defined by mode dose of study drug taken (i.e. the dose taken on most days in the study). RESULTS: Among the 1938 patients randomized to pioglitazone, the mode dose was <15 mg/day in 546 participants, 15 mg/day in 128, 30 mg/day in 89, and 45 mg/day in 1175. There was no significant effect on stroke/MI or new-onset diabetes with <15 mg/day. For 15 mg/30 mg/day pooled, the adjusted hazard ratios (95% CI) for stroke/MI were 0.48 (0.30, 0.76; p = .002) and 0.74 (0.69, 0.94) for 45 mg/day. For new-onset diabetes, the adjusted hazard ratios were 0.34 (0.15, 0.81; p = .001) and 0.31 (0.59, 0.94; p = .001) respectively. For oedema, weight gain and heart failure, the risk estimates for pioglitazone were lower for subjects taking <45 mg daily. For fractures, the increased risk with pioglitazone was similar across all dose strata. CONCLUSIONS: Lower doses of pioglitazone appear to confer much of the benefit with less adverse effects than the full dose. Further study is needed to confirm these findings so that clinicians may optimize dosing of this secondary prevention strategy in patients with stroke.

High prevalence of subnormal testosterone in obese adolescent males: reversal with bariatric surgery.

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 (<0.23 nmol/L). After 2 and 5 years, only 20 and 33%, respectively, had subnormal free testosterone concentrations. Weight regain was related to a fall in free testosterone concentrations. 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.

Recognizing the True Value of Testosterone Therapy in Health Care.

There has been little recognition within the medical community of the health impact of testosterone (T) deficiency (TD), also known as hypogonadism, and the substantial benefits of testosterone therapy (TTh) on health and quality of life despite high-level clinical evidence. In a roundtable symposium, investigators summarized the contemporary evidence in several key clinical areas. TD negatively impacts human health and quality of life and is associated with increased mortality. Several studies have demonstrated that TTh in men with TD reduced all-cause and cardiovascular mortality. The longstanding belief that TTh is associated with increased prostate cancer (PCa) risk is contradicted by recent evidence, including multiple studies showing that TTh is associated with reduced PCa risk. Similarly, the weight of current evidence indicates the purported concern that TTh is associated with increased cardiovascular risk is incorrect. Normalization of physiological T reduces myocardial infarction, stroke, and deaths compared with men whose testosterone levels failed to normalize. In diabetic men TTh improves insulin resistance, and a large 2-year controlled study in men with abnormal glucose tolerance showed a substantially reduced rate of diabetes among men treated with TTh compared with untreated controls. Long-term TTh in diabetic men resulted in progressive improvements in obesity and insulin requirements, including a substantial number who experienced complete remission of diabetes. Finally, TTh has been shown to reduce severe outcomes with Covid-19 infection. These lines of evidence argue strongly for the need for greater awareness in the medical community of the impact of TD on health, and of the health benefits of TTh.

4-Phenylbutyric acid improves free fatty acid-induced hepatic insulin resistance in vivo.

Plasma free fatty acids (FFAs) are elevated in obesity and can induce insulin resistance via endoplasmic reticulum (ER) stress. However, it is unknown whether hepatic insulin resistance caused by the elevation of plasma FFAs is alleviated by chemical chaperones. Rats received one of the following i.v. treatments for 48 h: saline, intralipid plus heparin (IH), IH plus the chemical chaperone 4-phenylbutyric acid (PBA), or PBA alone and a hyperinsulinemic-euglycemic clamp was performed during the last 2 h. PBA co-infusion normalized IH-induced peripheral insulin resistance, similar to our previous findings with an antioxidant and an IκBα kinase ß (IKKß) inhibitor. Different from our previous results with the antioxidant and IKKß inhibitor, PBA also improved IH-induced hepatic insulin resistance in parallel with activation of Akt. Unexpectedly, IH did not induce markers of ER stress in the liver, but PBA prevented IH-induced elevation of phosphorylated eukaryotic initiation factor-2α protein in adipose tissue. PBA tended to decrease circulating fetuin-A and significantly increased circulating fibroblast growth factor 21 (FGF21) without affecting markers of activation of hepatic protein kinase C-δ or p38 mitogen-activated protein kinase that we have previously involved in hepatic insulin resistance in this model. In conclusion: (i) PBA prevented hepatic insulin resistance caused by prolonged plasma FFA elevation without affecting hepatic ER stress markers; (ii) the PBA effect is likely due to increased FGF21 and/or decreased fetuin-A, which directly signal to upregulate Akt activation.

Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors.

AIM: To investigate the mechanisms underlying improvements in blood pressure (BP) and congestive heart failure outcomes following treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor. RESEARCH DESIGN AND METHODS: A total of 52 patients with type 2 diabetes (T2D) with an HbA1c of less than 8% participated in this prospective, double-blind and placebo-controlled study. Patients were randomized (1:1) to either dapagliflozin 10 mg daily or placebo for 12 weeks. Half the patients were also monitored for 6 h following their first dose for acute effects on BP. Blood and urine samples were collected and levels of angiotensinogen, angiotensin II, renin, aldosterone, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide, cyclic adenosine monophosphate, cyclic guanosine monophosphate (cGMP) and neprilysin were measured. The expression of angiotensin-converting enzyme, guanylate cyclase and phosphodiesterase 5 (PDE5) was measured in circulating mononuclear cells (MNC). RESULTS: A total of 24 and 23 patients receiving dapagliflozin and placebo, respectively, completed the 12-week study. Systolic BP decreased significantly, compared with placebo, both after single-dose (by 7 ± 3 mmHg) and 12-week (by 7 ± 2 mmHg) treatment with dapagliflozin. Dapagliflozin suppressed angiotensin II and angiotensinogen (by 10.5 ± 2.1 and 1.45 ± 0.42 µg/mL, respectively) and increased ANP and cGMP (by 34 ± 11 and 29 ± 11 pmol/mL, respectively) compared with the placebo group. cGMP levels also increased acutely following a single dose of dapagliflozin. Dapagliflozin also suppressed PDE5 expression by 26% ± 11% in MNC. There were no changes observed in the other vasoactive mediators investigated. CONCLUSIONS: Dapagliflozin administration in T2D resulted in both acute and chronic reduction in systolic BP, a reduction in vasoconstrictors and an increase in vasodilators. These changes may potentially contribute to its antihypertensive effects and its benefits in congestive cardiac failure.

Mechanisms underlying the metabolic actions of testosterone in humans: A narrative review.

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 ß 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.

The side effects of immune checkpoint inhibitor therapy on the endocrine system.

Immune checkpoint inhibitors (ICIs) are a relatively newer class of drugs approved for the treatment of malignancies such as melanoma, renal, bladder and lung cancer. Immune-related adverse events (IrAEs) involving the endocrine system are a common side effect of these drugs. The spectrum of endocrine adverse events varies by the drug class. Cytotoxic T-lymphocyte-associated antigen-4 inhibitors commonly cause hypophysitis/hypopituitarism, whereas the incidence of thyroid disease is higher with programmed cell death (PD)-1/ ligand (PD-L) protein 1 inhibitors. The focus of this review is to describe the individual endocrinopathies with their possible mechanisms, signs and symptoms, clinical assessment and disease management. Multiple mechanisms of IrAEs have been described in literature including type II/IV hypersensitivity reactions and development of autoantibodies. Patients with pre-existing autoimmune endocrine diseases can have disease exacerbation following ICI therapy rather than de novo IrAEs. Most of the endocrinopathies are relatively mild, and timely hormone replacement therapy allows continuation of ICIs. However, involvement of the pituitary-adrenal axis could be life-threatening if not recognized. Corticosteroids are helpful when the pituitary-adrenal axis is involved. In cases of severe endocrine toxicity (grade 3/4), ICIs should be temporarily discontinued and can be restarted after adequate hormonal therapy. Endocrinologists and general internists need to be vigilant and maintain a high degree of awareness for these adverse events.

Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and -2 studies.

AIM: To evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5%-10.5% were randomized (1:1:1) to receive dapagliflozin 5 mg, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies. RESULTS: Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs. 0.00%) and body weight (-2.45, -2.91 vs. 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment. CONCLUSIONS: Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk-mitigation strategies.

Narcolepsy, depression, and severe flushing in an obese man.

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.