2. Academic Validation
  3. Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice

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

  • Mol Metab. 2017 Jan 6;6(3):256-266. doi: 10.1016/j.molmet.2016.12.007.
Andras Franko 1,  Susanne Neschen 2,  Jan Rozman 3,  Birgit Rathkolb 4,  Michaela Aichler 5,  Annette Feuchtinger 5,  Laura Brachthäuser 6,  Frauke Neff 6,  Marketa Kovarova 7,  Eckhard Wolf 8,  Helmut Fuchs 2,  Hans-Ulrich Häring 9,  Andreas Peter 9,  Martin Hrabě de Angelis 10
Affiliations

Affiliations

  • 1 Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. Electronic address: [email protected].
  • 2 Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
  • 3 Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
  • 4 Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Hackerstr. 27, 85764 Oberschleißheim, Germany.
  • 5 Research Unit Analytical Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
  • 6 Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
  • 7 Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
  • 8 Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Hackerstr. 27, 85764 Oberschleißheim, Germany.
  • 9 Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Centre Munich at the University of Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
  • 10 Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; German Center for Diabetes Research (DZD e.V.), Ingolstädter Landstraße 1, 85764 Neuherberg, Germany; Center of Life and Food Sciences Weihenstephan, Technische Universität München, Alte Akademie 8, 85354 Freising, Germany. Electronic address: [email protected].
PMID: 28271032 DOI: 10.1016/j.molmet.2016.12.007
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

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

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