Andras Franko, 1,2,3 Peter Huypens, 1,3 Susanne Neschen, 1,3,4 Martin Irmler, 1 Jan Rozman, 1,3,4 Birgit Rathkolb, 1,4,5 Frauke Neff, 1,6 Cornelia Prehn, 7 Guillaume Dubois, 1 Martina Baumann, 1 Rebecca Massinger, 1 Daniel Gradinger, 1,3 Gerhard K.H. Przemeck, 1,3 Birgit Repp, 8 Michaela Aichler, 9 Annette Feuchtinger, 9 Philipp Schommers, 10,11 Oliver Stöhr, 12 Carmen Sanchez-Lasheras, 13 Jerzy Adamski, 3,7,14 Andreas Peter, 2,3,15 Holger Prokisch, 8 Johannes Beckers, 1,3,16 Axel K. Walch, 9 Helmut Fuchs, 1,3,4 Eckhard Wolf, 5 Markus Schubert, 12,17 Rudolf J. Wiesner, 10,18,19 and Martin Hrab e de Angelis 1,3,4,16 Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice Diabetes 2016;65:2540–2552 | DOI: 10.2337/db15-1670 Bezafibrate (BEZ), a pan activator of peroxisome pro- liferator–activated receptors (PPARs), has been gener- ally 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 glu- cose 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 func- tion 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 glu- cose metabolism by augmenting hepatic mitochon- drial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and met- abolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes. 1 Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany 2 Division of Endocrinology, Diabetology, Angiology, Nephrology and Clinical Chem- istry, Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany 3 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany 4 German Mouse Clinic, Helmholtz Zentrum München, Neuherberg, Germany 5 Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians- Universität-München, Munich, Germany 6 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 11 Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany 12 Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, Cologne, Germany 13 Institute of Genetics, University of Köln, Cologne, Germany 14 Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising- Weihenstephan, Germany 15 Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany 16 Center of Life and Food Sciences Weihenstephan, Technische Universität München, Freising, Germany 17 Internal Medicine, SCIVIAS Hospital St. Josef, Rüdesheim am Rhein, Germany 18 Center for Molecular Medicine Cologne (CMMC), University of Köln, Cologne, Germany 19 Cologne Excellence Cluster on Cellular Stress Responses in Ageing-associated Diseases (CECAD), University of Köln, Cologne, Germany Corresponding author: Martin Hrab e de Angelis, hrabe@helmholtz-muenchen.de. Received 11 December 2015 and accepted 25 May 2016. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db15-1670/-/DC1. S.N. is currently affiliated with Sanofi Deutschland GmbH, R&D Diabetes Research and Translational Medicine, Industriepark Hoechst, Frankfurt am Main, Germany. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://diabetesjournals .org/site/license. 2540 Diabetes Volume 65, September 2016 METABOLISM