title: Colesevelam improves oral but not intravenous glucose tolerance by a mechanism independent of insulin sensitivity and β-cell function.
abstract: OBJECTIVE
  To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control.
  
  
  METHODS
  We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m(2)) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT.
  
  
  RESULTS
  Fasting plasma glucose and HbA(1c) decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L · min, P < 0.01) and insulin (from 20,130 [13,542-35,292] to 13,086 [9,804-21,138] pmol/L · min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0-130.1] to 127.1 [47.2-295.2] pmol/L · min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346-17,661] to 2,093 [673-6,707] pg/mL · min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change.
  
  
  CONCLUSIONS
  Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.
authors.affiliation: Division of Metabolism, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington, USA.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Marina
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Utzschneider
authors.forename: Lorena A
authors.initials: LA
authors.lastname: Wright
authors.forename: Brenda K
authors.initials: BK
authors.lastname: Montgomery
authors.forename: Santica M
authors.initials: SM
authors.lastname: Marcovina
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kahn
mesh_terms: D000328:Adult; D000368:Aged; D000499:Allylamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D000069472:Colesevelam Hydrochloride; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy*; D005951:Glucose Tolerance Test; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D001786:Blood Glucose; D000499:Allylamine; D000069472:Colesevelam Hydrochloride