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Diabetes. 2016 Sep;65(9):2540-52. doi: 10.2337/db15-1670. Epub 2016 Jun 9.

Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.

Author information

1
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
2
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
3
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany.
4
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
5
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Munich, Germany.
6
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
7
Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
8
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
9
Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
10
Institute of Vegetative Physiology, University of Köln, Cologne, Germany Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
11
Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, Cologne, Germany.
12
Institute of Genetics, University of Köln, Cologne, Germany.
13
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany.
14
Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chemistry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany.
15
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany.
16
Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Munich, Germany.
17
Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, Cologne, Germany Internal Medicine, SCIVIAS Hospital St. Josef, Rüdesheim am Rhein, Germany.
18
Institute of Vegetative Physiology, University of Köln, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), University of Köln, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Ageing-associated Diseases (CECAD), University of Köln, Cologne, Germany.
19
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany hrabe@helmholtz-muenchen.de.

Abstract

Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.

PMID:
27284107
DOI:
10.2337/db15-1670
[Indexed for MEDLINE]
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