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Frankó, A. ; Irmler, M. ; Prehn, C. ; Heinzmann, S.S. ; Schmitt-Kopplin, P. ; Adamski, J. ; Beckers, J. ; von Kleist-Retzow, J.C.* ; Wiesner, R.* ; Häring, H.-U. ; Heni, M. ; Birkenfeld, A.L. ; Hrabě de Angelis, M.

Bezafibrate reduces elevated hepatic fumarate in insulin-deficient mice.

Biomedicines 10:616 (2022)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Glucotoxic metabolites and pathways play a crucial role in diabetic complications, and new treatment options which improve glucotoxicity are highly warranted. In this study, we analyzed bezafibrate (BEZ) treated, streptozotocin (STZ) injected mice, which showed an improved glucose metabolism compared to untreated STZ animals. In order to identify key molecules and pathways which participate in the beneficial effects of BEZ, we studied plasma, skeletal muscle, white adipose tissue (WAT) and liver samples using non-targeted metabolomics (NMR spectroscopy), targeted metabolomics (mass spectrometry), microarrays and mitochondrial enzyme activity measurements, with a particular focus on the liver. The analysis of muscle and WAT demonstrated that STZ treatment elevated inflammatory pathways and reduced insulin signaling and lipid pathways, whereas BEZ decreased inflammatory pathways and increased insulin signaling and lipid pathways, which can partly explain the beneficial effects of BEZ on glucose metabolism. Furthermore, lysophosphatidylcholine levels were lower in the liver and skeletal muscle of STZ mice, which were reverted in BEZ-treated animals. BEZ also improved circulating and hepatic glucose levels as well as lipid profiles. In the liver, BEZ treatment reduced elevated fumarate levels in STZ mice, which was probably due to a decreased expression of urea cycle genes. Since fumarate has been shown to participate in glucotoxic pathways, our data suggests that BEZ treatment attenuates the urea cycle in the liver, decreases fumarate levels and, in turn, ameliorates glucotoxicity and reduces insulin resistance in STZ mice.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Bezafibrate ; Diabetes ; Fumarate ; Insulin Resistance ; Lysophosphatidylcholine
ISSN (print) / ISBN 2227-9059
e-ISSN 2227-9059
Zeitschrift Biomedicines
Quellenangaben Band: 10, Heft: 3, Seiten: , Artikelnummer: 616 Supplement: ,
Verlag MDPI
Verlagsort Basel, Switzerland
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Experimental Genetics (IEG)
Institute of Diabetes Research and Metabolic Diseases (IDM)
CF Metabolomics & Proteomics (CF-MPC)
Research Unit Analytical BioGeoChemistry (BGC)
Förderungen German Center for Diabetes Research