Intestinal bile acid sequestration improves glucose control by stimulating hepatic miR-182-5p in type 2 diabetes

American Journal of Physiology. Gastrointestinal and Liver Physiology
Leslie R SedgemanKasey C Vickers

Abstract

Colesevelam is a bile acid sequestrant approved to treat both hyperlipidemia and type 2 diabetes, but the mechanism for its glucose-lowering effects is not fully understood. The aim of this study was to investigate the role of hepatic microRNAs (miRNAs) as regulators of metabolic disease and to investigate the link between the cholesterol and glucose-lowering effects of colesevelam. To quantify the impact of colesevelam treatment in rodent models of diabetes, metabolic studies were performed in Zucker diabetic fatty (ZDF) rats and db/db mice. Colesevelam treatments significantly decreased plasma glucose levels and increased glycolysis in the absence of changes to insulin levels in ZDF rats and db/db mice. High-throughput sequencing and real-time PCR were used to quantify hepatic miRNA and mRNA changes, and the cholesterol-sensitive miR-96/182/183 cluster was found to be significantly increased in livers from ZDF rats treated with colesevelam compared with vehicle controls. Inhibition of miR-182 in vivo attenuated colesevelam-mediated improvements to glycemic control in db/db mice. Hepatic expression of mediator complex subunit 1 (MED1), a nuclear receptor coactivator, was significantly decreased with colesevelam treatments in d...Continue Reading

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Citations

Apr 16, 2019·Current Opinion in Lipidology·Leslie R SedgemanKasey C Vickers
Oct 9, 2020·Journal of Cellular and Molecular Medicine·Long ZhaoPenghong Song
Nov 19, 2020·The Journal of Pharmacology and Experimental Therapeutics·Tamara R CastañedaThomas Hübschle
Mar 15, 2021·Placenta·Laura B James-Allan, Sherin U Devaskar

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Datasets Mentioned

BETA
GSE116826

Methods Mentioned

BETA
Transfection
PCR
Assay
sRNA-seq

Software Mentioned

TargetScanSv7
Bowtie1
TIGER
DEseq2
GraphPad Prism

Related Concepts