title: Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study.
abstract: OBJECTIVE
  The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis).
  
  
  METHODS
  Participants with type 2 diabetes (HbA(1c) 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n = 30) or placebo (n = 30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment.
  
  
  RESULTS
  Compared with placebo, colesevelam improved HbA(1c) (mean change from baseline of 0.3 [SD 1.1]% for placebo [n = 28] and -0.3 [1.1]% for colesevelam [n = 26]), glucose concentrations, fasting plasma glucose clearance and glycolytic disposal of oral glucose. Colesevelam did not affect gluconeogenesis or appearance rate (absorption) of oral glucose. Fasting endogenous glucose production and glycogenolysis significantly increased with placebo but were unchanged with colesevelam (treatment effect did not reach statistical significance). Compared with placebo, colesevelam increased total GLP-1 and GIP concentrations and improved HOMA-beta cell function while insulin, glucagon and HOMA-insulin resistance were unchanged. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis.
  
  
  CONCLUSIONS
  Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00596427
  
  
  BACKGROUND
  The study was funded by Daiichi Sankyo.
authors.affiliation: Kinemed, Inc., 5980 Horton Street Suite 470, Emeryville, CA 94608, USA. cbeysen@kinemed.com
authors.forename: C
authors.initials: C
authors.lastname: Beysen
authors.forename: E J
authors.initials: EJ
authors.lastname: Murphy
authors.forename: K
authors.initials: K
authors.lastname: Deines
authors.forename: M
authors.initials: M
authors.lastname: Chan
authors.forename: E
authors.initials: E
authors.lastname: Tsang
authors.forename: A
authors.initials: A
authors.lastname: Glass
authors.forename: S M
authors.initials: SM
authors.lastname: Turner
authors.forename: J
authors.initials: J
authors.lastname: Protasio
authors.forename: T
authors.initials: T
authors.lastname: Riiff
authors.forename: M K
authors.initials: MK
authors.lastname: Hellerstein
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000499:Allylamine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D001647:Bile Acids and Salts / Q000737:chemistry*; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D000069472:Colesevelam Hydrochloride; D003924:Diabetes Mellitus, Type 2 / Q000097:blood*; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood; D005749:Gastric Inhibitory Polypeptide / Q000097:blood; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D019518:Postprandial Period
chemical_list: D000499:Allylamine; D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D001786:Blood Glucose; D002784:Cholesterol; D000069472:Colesevelam Hydrochloride; D005346:Fibroblast Growth Factors; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D010919:Placebos; C117476:FGF19 protein, human; C517652:hemoglobin A1c protein, human