Improved glycemic control with colesevelam treatment in patients with type 2 diabetes is not directly associated with changes in bile acid metabolism

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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Bile acid sequestrants for glycemic control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials

Journal of Diabetes and its Complications ◽

10.1016/j.jdiacomp.2017.01.011 ◽

2017 ◽

Vol 31 (5) ◽

pp. 918-927 ◽

Cited By ~ 36

Author(s):

Morten Hansen ◽

David P. Sonne ◽

Kristian H. Mikkelsen ◽

Lise Lotte Gluud ◽

Tina Vilsbøll ◽

...

Keyword(s):

Systematic Review ◽

Type 2 Diabetes ◽

Bile Acid ◽

Glycemic Control ◽

Randomized Controlled Trials ◽

Meta Analysis ◽

Controlled Trials ◽

Bile Acid Sequestrants ◽

Randomized Controlled

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MECHANISMS IN ENDOCRINOLOGY: Bile acid sequestrants in type 2 diabetes: potential effects on GLP1 secretion

Acta Endocrinologica ◽

10.1530/eje-14-0154 ◽

2014 ◽

Vol 171 (2) ◽

pp. R47-R65 ◽

Cited By ~ 36

Author(s):

David P Sonne ◽

Morten Hansen ◽

Filip K Knop

Keyword(s):

Type 2 Diabetes ◽

Bile Acid ◽

Bile Acids ◽

G Protein ◽

Farnesoid X Receptor ◽

Bile Acid Metabolism ◽

Bile Acid Sequestrants ◽

G Protein Coupled

Bile acid sequestrants have been used for decades for the treatment of hypercholesterolaemia. Sequestering of bile acids in the intestinal lumen interrupts enterohepatic recirculation of bile acids, which initiate feedback mechanisms on the conversion of cholesterol into bile acids in the liver, thereby lowering cholesterol concentrations in the circulation. In the early 1990s, it was observed that bile acid sequestrants improved glycaemic control in patients with type 2 diabetes. Subsequently, several studies confirmed the finding and recently – despite elusive mechanisms of action – bile acid sequestrants have been approved in the USA for the treatment of type 2 diabetes. Nowadays, bile acids are no longer labelled as simple detergents necessary for lipid digestion and absorption, but are increasingly recognised as metabolic regulators. They are potent hormones, work as signalling molecules on nuclear receptors and G protein-coupled receptors and trigger a myriad of signalling pathways in many target organs. The most described and well-known receptors activated by bile acids are the farnesoid X receptor (nuclear receptor) and the G protein-coupled cell membrane receptor TGR5. Besides controlling bile acid metabolism, these receptors are implicated in lipid, glucose and energy metabolism. Interestingly, activation of TGR5 on enteroendocrine L cells has been suggested to affect secretion of incretin hormones, particularly glucagon-like peptide 1 (GLP1 (GCG)). This review discusses the role of bile acid sequestrants in the treatment of type 2 diabetes, the possible mechanism of action and the role of bile acid-induced secretion of GLP1 via activation of TGR5.

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Significance of intestinal microbiota in implementing metabolic effects of bariatric surgery

Russian Open Medical Journal ◽

10.15275/rusomj.2021.0112 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Marina A. Berkovskaya ◽

Yulia P. Sych ◽

Olesya Yu. Gurova ◽

Valentin V. Fadeev

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Bariatric Surgery ◽

Type 2 Diabetes Mellitus ◽

Bile Acid ◽

Intestinal Microbiota ◽

Intestinal Microflora ◽

Metabolic Effects ◽

Bile Acid Metabolism

Bariatric surgery is among successful methods of obesity treatment, with effects going beyond weight reduction alone, but rather involving improved glucose tolerance, along with control or remission of the type 2 diabetes mellitus. The precise mechanisms causing metabolic effects of bariatric surgery are not fully elucidated, even though substantial evidence suggest that they include changes in the gut microbiota, bile acid homeostasis, and the close interactions of these factors. Intestinal microflora is directly involved in the energy metabolism of a host human. Obesity and type 2 diabetes mellitus are associated with certain changes in the species composition and diversity of intestinal microflora, which are considered important factors in the development and progression of these ailments. Bariatric surgery leads to significant and persistent changes in the composition of the intestinal microbiota, often bringing it closer to the characteristics of the microbiota of an average person with a normal weight. An important role in implementing the metabolic effects of bariatric surgery, primarily in the improvement of glucose metabolism, belongs to postoperative changes in homeostasis of bile acids. These changes imply close metabolism. Moreover, changes in the bile acid metabolism after bariatric surgery affect the microbiota of the host. Further study of these relationships would clarify the mechanisms underlying metabolic surgery, make it more predictable, targeted and controlled, as well as open new therapeutic targets in the treatment of obesity and associated conditions.

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