Elsevier

Molecular Metabolism

Volume 6, Issue 3, March 2017, Pages 256-266
Molecular Metabolism

Original Article
Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice

https://doi.org/10.1016/j.molmet.2016.12.007Get rights and content
Under a Creative Commons license
open access

Highlights

  • Bezafibrate treatment reduced steatosis and ameliorated hepatic insulin resistance.

  • Bezafibrate treatment enhanced hepatic mitochondrial mass and metabolic flexibility.

  • Bezafibrate treatment increased beta-cell mass.

  • Bezafibrate treatment protected mice from developing diabetes.

  • Bezafibrate treatment normalized hyperglycemia in the manifest diabetic state.

Abstract

Objective

Recently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice.

Methods

TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined.

Results

Plasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis.

Conclusions

Our data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism.

Keywords

Bezafibrate
Glucose metabolism
Insulin resistance
Lipid metabolism
NAFLD

Abbreviations

BEZ
Bezafibrate
BG
blood glucose
ED
early onset of diabetes
EM
electron microscopy
HOMA-IR
homeostatic model assessment of insulin resistance
FA
fatty acid
LD
late onset of diabetes
NAFLD
non-alcoholic fatty liver disease
NEFA
non-esterified fatty acid
PPAR
peroxisome proliferator-activated receptor
qNMR
quantitative nuclear magnetic resonance
RER
respiratory exchange ratios
SD
standard diet
T2D
type 2 diabetes
TG
triglyceride

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Current address: Sanofi-Aventis Deutschland GmbH, R&D Diabetes Research & Translational Medicine, Industriepark Hoechst, 65926 Frankfurt am Main, Germany.