Colesevelam Improves Oral but Not Intravenous Glucose Tolerance by a Mechanism Independent of Insulin Sensitivity and β-Cell Function

OBJECTIVE: To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control. RESEARCH DESIGN AND 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.