Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver

Hirotsune Tagawa, Junichiro Irie, Arata Itoh, Yukie Kusumoto, Mari Kato, Nana Kobayashi, Kumiko Tanaka, Rieko Morinaga, Masataka Fujita, Yuya Nakajima, Kohkichi Morimoto, Taichi Sugizaki, Yoshinaga Kawano, Satoru Yamada, Toshihide Kawai, Mitsuhiro Watanabe, Hiroshi Itoh

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Aims: Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. Methods: Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for ≥6 months. Results: BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. Conclusions: BAR improved hepatic insulin resistance in FLS mice by reducing hepatic cholesterol without affecting hepatic triglyceride levels or body fat distribution. Our study revealed that BAR improves glycaemic control at least in part by downregulating the hepatic cholesterol-LXR-IRS2 pathway.

Original languageEnglish
Pages (from-to)85-94
Number of pages10
JournalDiabetes Research and Clinical Practice
Volume109
Issue number1
DOIs
Publication statusPublished - 2015 Jul 1

Keywords

  • Bile acid binding resin
  • Hepatic insulin resistance
  • Non-alcoholic fatty liver disease

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Fingerprint Dive into the research topics of 'Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver'. Together they form a unique fingerprint.

Cite this