Hyperglucagonaemia and amino acid alterations in individuals with type 2 diabetes and non-alcoholic fatty liver disease.

Aims: Hyperglucagonaemia contributes to the pathophysiology in type 2 diabetes (T2D), but the mechanisms behind the inappropriate glucagon secretion are not fully understood. Glucagon and amino acids are regulated in a feedback loop referred to as the liver-α cell axis. Individuals with non-alcoholic fatty liver disease (NAFLD) appear to be glucagon resistant, disrupting the liver-α cell axis resulting in hyperglucagonaemia and hyperaminoacidaemia. We investigated the associations between circulating glucagon, amino acids, and liver fat content in a cohort of individuals with T2D. Methods: We included 110 individuals with T2D in this cross-sectional study. Liver fat content was quantified using 1H magnetic resonance spectroscopy (MRS). Associations between liver fat content and plasma glucagon and amino acids, respectively, were estimated in multivariate linear regression analyses. Results: Individuals with NAFLD (n = 52) had higher plasma glucagon concentrations than individuals without NAFLD (n = 58). The positive association between plasma glucagon concentrations and liver fat content was confirmed in the multivariable regression analyses. Plasma concentrations of isoleucine and glutamate were increased, and glycine and serine concentrations were decreased in individuals with NAFLD. Concentrations of other amino acids were similar between individuals with and without NAFLD, and no clear association was seen between liver fat content and amino acids in the regression analyses. Conclusion: MRS-diagnosed NAFLD in T2D is associated with hyperglucagonaemia and elevated plasma concentrations of isoleucine and glutamate and low plasma concentrations of glycine and serine. Whether NAFLD and glucagon resistance per se induce these changes remains to be elucidated.

Effect of the mineralocorticoid receptor antagonist eplerenone on liver fat and metabolism in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial (MIRAD trial).

AIM: To investigate whether the mineralocorticoid receptor antagonist eplerenone has beneficial effects on liver fat and metabolism in patients with type 2 diabetes (T2D), the mineralocorticoid receptor antagonist in type 2 diabetes (MIRAD) trial. MATERIAL AND METHODS: In this 26-week, double-blind, randomized, placebo-controlled trial, we enrolled 140 patients with T2D and high risk of cardiovascular disease. Patients were randomized 1:1 to either eplerenone with a target dose of 200 mg/day for patients with estimated glomerular filtration rate (eGFR) of 60 mL/min per 1.73 m2 or more and 100 mg/day for patients with eGFR between 41 and 59 mL/min per 1.73 m2 or placebo. The primary outcome measure was change in liver fat by proton magnetic resonance spectroscopy at week 26 from baseline; secondary outcomes were changes in metabolism, and safety by incident hyperkalaemia. RESULTS: No changes in liver fat in the eplerenone group 0.91% (95% CI -0.57 to 2.39) or the placebo group -1.01% (-2.23 to 0.21) were found. The estimated absolute treatment difference was 1.92% (-3.81 to 0.01; P = 0.049). There was no beneficial impact on supporting secondary outcome variables of metabolism as fat mass distribution, lipid metabolism or insulin resistance. Despite a high dosage of eplerenone 164 versus 175 mg in patients treated with placebo (P = 0.228), the number of patients with incident hyperkalaemia (≥5.5 mmol/L) was low, with six in the eplerenone versus two in the placebo group (P = 0.276). CONCLUSION: The addition of high doses of eplerenone to background antidiabetic and antihypertensive therapy does not show beneficial effects on liver fat and metabolism in patients with T2D.

Cardiac systolic dysfunction in past illicit users of anabolic androgenic steroids.

Background: Illicit use of anabolic androgenic steroids (AAS) is associated with left ventricle (LV) systolic dysfunction and increased LV mass (LVM), but whether these findings persist in former AAS users has yet to be elucidated. The objective was to assess LV systolic function, LVM and myocardial fibrosis in current and former illicit AAS users compared with non-users. Methods: Community-based cross-sectional study among men, aged 18­50 years, involved in recreational resistance training. We included 37 current and 33 former illicit AAS users, geometric mean (95%CI), 30 (21; 44) months since AAS cessation, and 30 non-users as controls. We assessed myocardial function and structure using advanced echocardiography and cardiac MRI with late-gadolinium enhancement. Results: Mean (SE) LV global longitudinal strain (GLS) was impaired in former AAS users compared with non-users, −16.7 (0.5) versus −18.2 (0.4) %, P < .05. Mean (SE) LV ejection fraction (EF) was decreased, 51 (1) versus 58 (1) %, P < .001 and LV GLS impaired, −14.5 (0.4)%, P < .001, in current AAS users compared with non-users. Measures of LVM were increased in current AAS users compared with the other two groups, P < .001. Plasma total testosterone was independently associated with reduced LVEF (P = .049) and increased LVM/body surface area (P = .005) in multivariate linear regressions. Focal myocardial fibrosis was not detected in any participants and diffuse myocardial fibrosis, assessed using post-contrast T1-mapping time, did not differ among the three groups. Conclusions: Past illicit AAS use is associated with impaired LV GLS, suggesting subclinical cardiac systolic dysfunction years after AAS cessation.

Procoagulant State in Current and Former Anabolic Androgenic Steroid Abusers.

BACKGROUND: Anabolic androgenic steroid (AAS) abusers are considered at increased risk of cardiovascular morbidity and mortality. We hypothesized that current and former AAS abuse would induce a procoagulant shift in the haemostatic balance. METHODS: Men 18 to 50 years of age were included as current AAS abusers, former AAS abusers or controls. Morning blood samples were collected after overnight fasting. Thrombin generation (lag time, time to peak, peak height, and endogenous thrombin potential [ETP]) and coagulation factor II (prothrombin), VII and X, antithrombin, protein C, free protein S and tissue factor pathway inhibitor (TFPI) were assessed. Groups were compared by ANOVA or Kruskal-Wallis test and probabilities were corrected for multiple comparisons. Associations were evaluated using linear regression models. RESULTS: ETP was increased around 15% in current (n = 37) and former (n = 33) AAS abusers compared with controls (n = 30; p < 0.001). Prothrombin and factor X were increased ≥10% in AAS abusers and prothrombin was a predictor of ETP (p < 0.0005). Lag time and time to peak were increased 10 to 30% in current AAS abusers (p < 0.001) and associated with higher concentrations of TFPI, antithrombin, protein C and protein S (p < 0.0005; = 0.005). Multivariate linear regression, with all coagulation inhibitors as covariates, identified TFPI to be independently associated with lag time and time to peak (p < 0.0005). CONCLUSION: Thrombin generation is augmented in current and former AAS abusers, reflecting a procoagulant state, with altered concentrations of coagulation proteins. Prospective studies are needed to clarify whether these findings translate into an increased thrombotic risk in AAS abusers potentially even after cessation.

Increased blood pressure and aortic stiffness among abusers of anabolic androgenic steroids: potential effect of suppressed natriuretic peptides in plasma?

BACKGROUND: Abuse of anabolic androgenic steroids (AAS) is prevalent among recreational athletes and adverse effects on blood pressure (BP) and arterial stiffness could be substantial. Testosterone decreases natriuretic peptides which are key components in BP-regulation and may impair BP-homeostasis in AAS abusers. OBJECTIVE: To investigate BP and aortic stiffness in relation to natriuretic peptides among current AAS abusers, former AAS abusers and controls. METHODS: In this cross-sectional study, 37 current AAS abusers, 33 former AAS abusers and 30 controls were included. All participants were men involved in recreational strength training. We used 24-h BP monitoring, assessed proximal aorta distensibility index (ADI) by MRI and obtained overnight fasting blood samples to measure: midregional proatrial natriuretic peptide (MR-proANP), aldosterone, noradrenaline and copeptin. RESULTS: Current AAS abusers exhibited higher mean (95% confidence interval) 24-h systolic BP than controls [132 (129; 135) versus 124 (120; 128) mmHg, P = 0.005] and systolic hypertension was more frequent among current AAS abusers than controls (51 versus 17%, P = 0.009). ADI was lower among both current and former AAS abusers suggesting higher aortic stiffness; %-difference (95% confidence interval) from controls: -21% (-35; -5) and -21% (-36; -4), P < 0.05. Plasma MR-proANP was decreased, whereas aldosterone and noradrenaline were increased among current AAS abusers compared with former AAS abusers and controls. Decreased MR-proANP was independently associated with increased systolic BP and reduced ADI in multivariate linear regressions. CONCLUSION: Current AAS abusers displayed increased 24-h systolic BP and decreased plasma MR-proANP. Both current and former AAS abusers exhibited higher aortic stiffness.