title: Bile acid binding resin improves hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Hirotsune
authors.initials: H
authors.lastname: Tagawa
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan. Electronic address: j-irie@z8.keio.jp.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Irie
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Itoh
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yukie
authors.initials: Y
authors.lastname: Kusumoto
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Kato
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Nana
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Tanaka
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Morinaga
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Nakajima
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Kohkichi
authors.initials: K
authors.lastname: Morimoto
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Sugizaki
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Kawano
authors.affiliation: Diabetes Center, Kitasato Institute Hospital, Tokyo 108-8642, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Division of Endocrinology, Metabolism and Nephrology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000008:administration & dosage / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism; D005260:Female; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008875:Middle Aged; D057093:Orphan Nuclear Receptors / Q000819:agonists; D012189:Retrospective Studies; D014280:Triglycerides / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D001786:Blood Glucose; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D014280:Triglycerides; D002784:Cholesterol; C106574:cholebine
keywords: Bile acid binding resin; Hepatic insulin resistance; Non-alcoholic fatty liver disease