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Cited by 22MicroRNA in disease regulationMetabolism, Diabetes, and CancerCholesterol and Lipid Metabolism

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

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Sedgeman, Leslie R., Beysen, Carine, Allen, Ryan M., Ramirez Solano, Marisol A., Turner, Scott M., Vickers, Kasey C.·2018·American Journal of Physiology-Gastrointestinal and Liver Physiology
DOI 10.1152/ajpgi.00238.2018PMC PMC6415711
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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 db/db mice, and MED1 was experimentally validated to be a direct target of miR-96/182/183 in humans and mice. In summary, these results support that colesevelam likely improves glycemic control through hepatic miR-182–5p, a mechanism that directly links cholesterol and glucose metabolism. NEW & NOTEWORTHY Colesevelam lowers systemic glucose levels in Zucker diabetic fatty rats and db/db mice and increases hepatic levels of the sterol response element binding protein 2-responsive microRNA cluster miR-96/182/183. Inhibition of miR-182 in vivo reverses the glucose-lowering effects of colesevelam in db/db mice. Mediator complex subunit 1 (MED1) is a novel, direct target of the miR-96/182/183 cluster in mice and humans.

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  • Colesevelam improves glycaemic control through hepatic microRNAs 182-5p and increases the level of incretins and glucose-dependent insulin secretion.

    “It improves glycaemic control through hepatic microRNAs (miRNAs) 182–5p. Moreover, it increases the level of incretins and glucose-dependent insulin secretion (93, 94).”

    From A critical review on diabetes mellitus type 1 and type 2 management approaches: from lifestyle modification to current and novel targets and therapeutic agents. (2024) · cites this paper as [94]

    The Introduction and Discussion (page numbers unavailable) support a likely hepatic miR-182-5p contribution to colesevelam’s glucose-lowering effect, rather than establishing it as the sole mechanism. The Results report increased GIP only after a glucose bolus in rats, with no significant GLP-1 increase; treated mice had higher fasting and postglucose insulin, but the paper does not establish increased glucose-dependent insulin secretion. (LLM, conf=0.89)

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Cited by

Sorted by citations

Authors
Sedgeman, L. R., Beysen, C., Allen, R. M., Ramirez Solano, M. A., Turner, S. M., & Vickers, K. C.
Affiliations
  • Vanderbilt University (US)
  • KineMed (United States) (US)
  • Vanderbilt University Medical Center (US)
  • Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
Corresponding author
Vickers, Kasey C.
ORCID
Venue
American Journal of Physiology-Gastrointestinal and Liver Physiology
Publisher
American Physiological Society
Published
2018-11-01
Volume
315
Issue
5
Pages
G810-G823
ISSN
  • 0193-1857 (ISSN-L)
  • 1522-1547
DOI
10.1152/ajpgi.00238.2018
PMC
PMC6415711
OpenAlex
W2889415388
Cited by
22
References
2
Citations by year
2024: 4 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 4 · 2019: 1
FWCI
0.60
Type
journal article
Language
en
Open access
Locations
  • American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association (AHA) (15PRE25090205)
  • HHS | NIH | National Heart, Lung, and Blood Institute (NHBLI) (R01HL128996, T32HL007411)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
colesevelam, bile acid sequestrants, type 2 diabetes, glycemic control, miR-182-5p, MED1, hepatic glycolysis, db/db mice, Zucker diabetic fatty rats
MeSH terms
Colesevelam Hydrochloride, Animals, Anticholesteremic Agents, Bile Acids and Salts, Diabetes Mellitus, Type 2, Glucose, Glycolysis, Humans, Hypoglycemic Agents, Intestinal Mucosa, Liver, Male, Rats, Zucker, MicroRNAs, Rats, Mediator Complex Subunit 1, HEK293 Cells

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