Influence of common polymorphisms in the SLC5A2 gene on metabolic traits in subjects at increased risk of diabetes and on response to empagliflozin treatment in patients with diabetes.

Objective Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes. Patients and methods Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies >= 5%) present in the SLC5A2 gene locus. Results In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA(1c), plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P >= 0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA(1c), fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study. Conclusion Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin

The effect of empagliflozin on muscle sympathetic nerve activity in patients with type 2 Diabetes mellitus

Inhibition of sodium glucose cotransporter 2 with empagliflozin results in caloric loss by increasing urinary glucose excretion and has a mild diuretic effect. Diuretic effects are usually associated with reflex-mediated increases in sympathetic tone, whereas caloric loss is associated with decreased sympathetic tone. In an open-label trial, muscle sympathetic nerve activity (MSNA) (burst frequency, burst incidence, and total MSNA) was assessed using microneurography performed off-treatment and on day 4 of treatment with empagliflozin 25 mg once daily in 22 metformin-treated patients with type II diabetes (mean [range] age 54 [40–65] years). Systolic and diastolic blood pressure (BP), heart rate, urine volume, and body weight were assessed before and on day 4 (BP, heart rate), day 5 (urine volume), or day 6 (body weight) of treatment with empagliflozin. After 4 days of treatment with empagliflozin, no significant changes in MSNA were apparent despite a numerical increase in urine volume, numerical reductions in BP, and significant weight loss. There were no clinically relevant changes in heart rate

Walnut-enriched diet reduces fasting non-HDL-cholesterol and apolipoprotein B in healthy Caucasian subjects: A randomized controlled cross-over clinical trial.

BACKGROUND: Walnut consumption is associated with reduced risk of coronary heart disease (CHD). OBJECTIVE: We assessed the effect of walnuts on lipid and glucose metabolism, adipokines, inflammation and endothelial function in healthy Caucasian men and postmenopausal women ≥50years old. DESIGN: Forty subjects (mean±SEM: age 60±1years, BMI 24.9±0.6kg/m2; 30 females) were included in a controlled, cross-over study and randomized to receive first a walnut-enriched (43g/d) and then a Western-type (control) diet or vice-versa, with each lasting 8weeks and separated by a 2-week wash-out. At the beginning and end of each diet phase, measurements of fasting values, a mixed meal test and an assessment of postprandial endothelial function (determination of microcirculation by peripheral artery tonometry) were conducted. Area under the curve (AUC), incremental AUC (iAUC) and treatment×time interaction (shape of the curve) were evaluated for postprandial triglycerides, VLDL-triglycerides, chylomicron-triglycerides, glucose and insulin. RESULTS: Compared with the control diet, the walnut diet significantly reduced non-HDL-cholesterol (walnut vs. control: -10±3 vs. -3±2mg/dL; p=0.025) and apolipoprotein-B (-5.0±1.3 vs. -0.2±1.1mg/dL; p=0.009) after adjusting for age, gender, BMI and diet sequence. Total cholesterol showed a trend toward reduction (p=0.073). Fasting VLDL-cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and glucose, insulin, HOMA-IR, and HbA1c did not change significantly. Similarly, fasting adipokines, C-reactive protein, biomarkers of endothelial dysfunction, postprandial lipid and glucose metabolism and endothelial function were unaffected. CONCLUSION: Daily consumption of 43g of walnuts for 8weeks significantly reduced non-HDL-cholesterol and apolipoprotein-B, which may explain in part the epidemiological observation that regular walnut consumption decreases CHD risk

Chemerin is associated with markers of inflammation and components of the metabolic syndrome but does not predict coronary atherosclerosis.

Objectives: Chemerin is a recently discovered adipokine that regulates adipocyte differentiation and modulates chemotaxis and activation of dendritic cells and macrophages. Given the convergence of adipocyte and macrophage function, chemerin may provide an interesting link between obesity, inflammation and atherosclerosis in humans. We sought to examine the relationship of 1) chemerin and markers of inflammation, 2) chemerin and components of the metabolic syndrome, and 3) chemerin and coronary atherosclerotic plaque burden and morphology. Design: Serum chemerin levels were determined in 303 patients with stable typical or atypical chest pain who underwent dual-source multi-slice CT-angiography to exclude coronary artery stenosis. Atherosclerotic plaques were classified as calcified, mixed or non-calcified. Results: Chemerin levels were highly correlated with hsCRP (r=0.44, p<0.0001), IL-6 (r=0.18, p=0.002), TNF-{alpha} (r=0.24, p<0.0001), resistin (r=0.28, p<0.0001) and leptin (r=0.36, p<0.0001) concentrations. Furthermore, chemerin was associated with components of the metabolic syndrome including BMI (r=0.23, p=0.0002), triglycerides (r=0.29, p<0.0001), HDL-C (r=-0.18, p=0.003) and hypertension (p<0.0001). In bivariate analysis, chemerin levels weakly correlated with coronary plaque burden (r=0.16, p=0.006) and the number of non-calcified plaques (r=0.14, p=0.02). These associations, however, were lost after adjusting for established cardiovascular risk factors (OR 1.17, 95%CI 0.97 to 1.41, p=0.11 for coronary plaque burden; OR 1.06, 95%CI 0.96 to 1.17, p=0.22 for non-calcified plaques). Conclusions: Chemerin is strongly associated with markers of inflammation and components of the metabolic syndrome. Chemerin, however, does not predict coronary atherosclerosis