title: Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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: andras.franko@med.uni-tuebingen.de.
authors.forename: Andras
authors.initials: A
authors.lastname: Franko
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Neschen
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.affiliation: 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.
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Aichler
authors.affiliation: Research Unit Analytical Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Feuchtinger
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Brachthäuser
authors.affiliation: Institute of Pathology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Neff
authors.affiliation: Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, University Hospital Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany.
authors.forename: Marketa
authors.initials: M
authors.lastname: Kovarova
authors.affiliation: Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Hackerstr. 27, 85764 Oberschleißheim, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.affiliation: 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.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Häring
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Peter
authors.affiliation: 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: hrabe@helmholtz-muenchen.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Hrabě de Angelis
mesh_terms: D000818:Animals; D001629:Bezafibrate / Q000378:metabolism / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000188:drug therapy*; D005947:Glucose / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy; D009765:Obesity / Q000097:blood; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D000960:Hypolipidemic Agents; D007328:Insulin; D047492:Peroxisome Proliferator-Activated Receptors; D005947:Glucose; D001629:Bezafibrate
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