Franko, Andras ORCID: 0000-0003-0485-5439, Irmler, Martin, Prehn, Cornelia ORCID: 0000-0002-1274-4715, Heinzmann, Silke S., Schmitt-Kopplin, Philippe ORCID: 0000-0003-0824-2664, Adamski, Jerzy, Beckers, Johannes ORCID: 0000-0001-7874-3822, von Kleist-Retzow, Juergen-Christoph, Wiesner, Rudolf, Haring, Hans-Ulrich, Heni, Martin ORCID: 0000-0002-8462-3832, Birkenfeld, Andreas L. ORCID: 0000-0003-1407-9023 and de Angelis, Martin Hrabe ORCID: 0000-0002-7898-2353 (2022). Bezafibrate Reduces Elevated Hepatic Fumarate in Insulin-Deficient Mice. Biomedicines, 10 (3). BASEL: MDPI. ISSN 2227-9059

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Franko, AndrasUNSPECIFIEDorcid.org/0000-0003-0485-5439UNSPECIFIED
Irmler, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prehn, CorneliaUNSPECIFIEDorcid.org/0000-0002-1274-4715UNSPECIFIED
Heinzmann, Silke S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmitt-Kopplin, PhilippeUNSPECIFIEDorcid.org/0000-0003-0824-2664UNSPECIFIED
Adamski, JerzyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beckers, JohannesUNSPECIFIEDorcid.org/0000-0001-7874-3822UNSPECIFIED
von Kleist-Retzow, Juergen-ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wiesner, RudolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haring, Hans-UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heni, MartinUNSPECIFIEDorcid.org/0000-0002-8462-3832UNSPECIFIED
Birkenfeld, Andreas L.UNSPECIFIEDorcid.org/0000-0003-1407-9023UNSPECIFIED
de Angelis, Martin HrabeUNSPECIFIEDorcid.org/0000-0002-7898-2353UNSPECIFIED
URN: urn:nbn:de:hbz:38-690291
DOI: 10.3390/biomedicines10030616
Journal or Publication Title: Biomedicines
Volume: 10
Number: 3
Date: 2022
Publisher: MDPI
Place of Publication: BASEL
ISSN: 2227-9059
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
ACTIVATED RECEPTOR-ALPHA; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; SECONDARY PREVENTION; GLUCOSE; INACTIVATION; SUCCINATION; SENSITIVITY; BIOMARKER; PROTEINS; DISEASEMultiple languages
Biochemistry & Molecular Biology; Medicine, Research & Experimental; Pharmacology & PharmacyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69029

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