Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.
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.
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.
Andras
0000-0003-0485-5439
A
Franko
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Peter
P
Huypens
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.
Susanne
S
Neschen
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Martin
M
Irmler
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.
Jan
J
Rozman
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.
Birgit
B
Rathkolb
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Institute of Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
Frauke
F
Neff
Genome Analysis Center, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Cornelia
C
Prehn
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Guillaume
G
Dubois
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Martina
M
Baumann
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Rebecca
R
Massinger
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Daniel
D
Gradinger
Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg, Germany German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
Gerhard K H
GK
Przemeck
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Birgit
B
Repp
Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
Michaela
M
Aichler
Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
Annette
A
Feuchtinger
Institute of Vegetative Physiology, University of Köln, Cologne, Germany Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.
Philipp
P
Schommers
Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, Cologne, Germany.
Oliver
O
Stöhr
Institute of Genetics, University of Köln, Cologne, Germany.
Carmen
C
Sanchez-Lasheras
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.
Jerzy
J
Adamski
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.
Andreas
A
Peter
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Holger
H
Prokisch
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.
Johannes
J
Beckers
Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
Axel K
AK
Walch
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.
Helmut
H
Fuchs
Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians-Universität-München, Munich, Germany.
Eckhard
E
Wolf
Center for Endocrinology, Diabetes and Preventive Medicine, University of Köln, Cologne, Germany Internal Medicine, SCIVIAS Hospital St. Josef, Rüdesheim am Rhein, Germany.
Markus
M
Schubert
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.
Rudolf J
RJ
Wiesner
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.
Martin
M
Hrabě de Angelis
D000818:Animals; D001629:Bezafibrate / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000960:Hypolipidemic Agents / Q000627:therapeutic use; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010101:Oxygen Consumption / Q000187:drug effects; D047492:Peroxisome Proliferator-Activated Receptors / Q000037:antagonists & inhibitors
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D000960:Hypolipidemic Agents; D047492:Peroxisome Proliferator-Activated Receptors; D001629:Bezafibrate