Bioenergetic cues shift FXR splicing towards FXR alpha 2 to modulate hepatic lipolysis and fatty acid metabolism

Objective: Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known. Methods: We expressed each FXR variant in primary hepatocytes and evaluated global gene expression, lipid profile, and metabolic fluxes. Gene delivery of FXR variants to Fxr(-/-) mouse liver was performed to evaluate their role in vivo. The effects of fasting and physical exercise on hepatic Fxr splicing were determined. Results: We show that FXR splice isoforms regulate largely different gene sets and have specific effects on hepatic metabolism. FXR alpha 2 (but not alpha 1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXR alpha 2 decreases cellular lipid accumulation and improves cellular insulin signaling to AKT. FXR alpha 2 expression in Fxr(-/-) mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRa1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxr alpha 2 expression. Conclusions: Our results show that the main FXR variants in human liver (alpha 1 and alpha 2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic efficacy of FXR agonists. (C) 2015 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).Novo Nordisk Fonden [NNF12OC1016062]; European Research Council [233285]info:eu-repo/semantics/publishedVersio

Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design

Background Heart failure (HF) and diabetes (DM) are a lethal combination. The current armamentarium of anti-diabetic agents has been shown to be less efficacious and sometimes even harmful in diabetic patients with concomitant cardiovascular disease, especially HF. Sodium glucose linked co-transporter type 2 (SGLT2) inhibitors are a new class of anti-diabetic agent that has shown potentially beneficial cardiovascular effects such as pre-load and after load reduction through osmotic diuresis, blood pressure reduction, reduced arterial stiffness and weight loss. This has been supported by the recently published EMPA-REG trial which showed a striking 38 and 35 % reduction in cardiovascular death and HF hospitalisation respectively. Methods The REFORM trial is a novel, phase IV randomised, double blind, placebo controlled clinical trial that has been ongoing since March 2015. It is designed specifically to test the safety and efficacy of the SLGT2 inhibitor, dapagliflozin, on diabetic patients with known HF. We utilise cardiac-MRI, cardio-pulmonary exercise testing, body composition analysis and other tests to quantify the cardiovascular and systemic effects of dapagliflozin 10 mg once daily against standard of care over a 1 year observation period. The primary outcome is to detect the change in left ventricular (LV) end systolic and LV end diastolic volumes. The secondary outcome measures include LV ejection fraction, LV mass index, exercise tolerance, fluid status, quality of life measures and others. Conclusions This trial will be able to determine if SGLT2 inhibitor therapy produces potentially beneficial effects in patients with DM and HF, thereby replacing current medications as the drug of choice when treating patients with both DM and HF

Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapán and Lagunera regions in Mexico

<p>Abstract</p> <p>Background</p> <p>Human exposures to inorganic arsenic (iAs) have been linked to an increased risk of diabetes mellitus. Recent laboratory studies showed that methylated trivalent metabolites of iAs may play key roles in the diabetogenic effects of iAs. Our study examined associations between chronic exposure to iAs in drinking water, metabolism of iAs, and prevalence of diabetes in arsenicosis-endemic areas of Mexico.</p> <p>Methods</p> <p>We used fasting blood glucose (FBG), fasting plasma insulin (FPI), oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR) to characterize diabetic individuals. Arsenic levels in drinking water and urine were determined to estimate exposure to iAs. Urinary concentrations of iAs and its trivalent and pentavalent methylated metabolites were measured to assess iAs metabolism. Associations between diabetes and iAs exposure or urinary metabolites of iAs were estimated by logistic regression with adjustment for age, sex, hypertension and obesity.</p> <p>Results</p> <p>The prevalence of diabetes was positively associated with iAs in drinking water (OR 1.13 per 10 ppb, p < 0.01) and with the concentration of dimethylarsinite (DMAs^III) in urine (OR 1.24 per inter-quartile range, p = 0.05). Notably, FPI and HOMA-IR were negatively associated with iAs exposure (β -2.08 and -1.64, respectively, p < 0.01), suggesting that the mechanisms of iAs-induced diabetes differ from those underlying type-2 diabetes, which is typically characterized by insulin resistance.</p> <p>Conclusions</p> <p>Our study confirms a previously reported, but frequently questioned, association between exposure to iAs and diabetes, and is the first to link the risk of diabetes to the production of one of the most toxic metabolites of iAs, DMAs^III.</p

Actos Now for the prevention of diabetes (ACT NOW) study

Abstract Background Impaired glucose tolerance (IGT) is a prediabetic state. If IGT can be prevented from progressing to overt diabetes, hyperglycemia-related complications can be avoided. The purpose of the present study was to examine whether pioglitazone (ACTOS®) can prevent progression of IGT to type 2 diabetes mellitus (T2DM) in a prospective randomized, double blind, placebo controlled trial. Methods/Design 602 IGT subjects were identified with OGTT (2-hour plasma glucose = 140–199 mg/dl). In addition, IGT subjects were required to have FPG = 95–125 mg/dl and at least one other high risk characteristic. Prior to randomization all subjects had measurement of ankle-arm blood pressure, systolic/diastolic blood pressure, HbA1C, lipid profile and a subset had frequently sampled intravenous glucose tolerance test (FSIVGTT), DEXA, and ultrasound determination of carotid intima-media thickness (IMT). Following this, subjects were randomized to receive pioglitazone (45 mg/day) or placebo, and returned every 2–3 months for FPG determination and annually for OGTT. Repeat carotid IMT measurement was performed at 18 months and study end. Recruitment took place over 24 months, and subjects were followed for an additional 24 months. At study end (48 months) or at time of diagnosis of diabetes the OGTT, FSIVGTT, DEXA, carotid IMT, and all other measurements were repeated. Primary endpoint is conversion of IGT to T2DM based upon FPG ≥ 126 or 2-hour PG ≥ 200 mg/dl. Secondary endpoints include whether pioglitazone can: (i) improve glycemic control (ii) enhance insulin sensitivity, (iii) augment beta cell function, (iv) improve risk factors for cardiovascular disease, (v) cause regression/slow progression of carotid IMT, (vi) revert newly diagnosed diabetes to normal glucose tolerance. Conclusion ACT NOW is designed to determine if pioglitazone can prevent/delay progression to diabetes in high risk IGT subjects, and to define the mechanisms (improved insulin sensitivity and/or enhanced beta cell function) via which pioglitazone exerts its beneficial effect on glucose metabolism to prevent/delay onset of T2DM. Trial Registration clinical trials.gov identifier: NCT0022096