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.

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.

Trial registration: ClinicalTrials.gov NCT00990184.

Figures

Figure 1

Plasma glucose (A) and insulin (B) levels during the FSIGT. ■ and solid line, before treatment with colesevelam (day 14); □ and dashed line, end of treatment with colesevelam (day 70).

Figure 2

Plasma glucose (A), insulin (B), C-peptide (C), and glucagon (D) levels during the MTT. ■ and solid line, before treatment with colesevelam (day 14); □ and dashed line, end of treatment with colesevelam (day 70).

Figure 3

Plasma total GLP-1 (A), total GIP (B), PYY (C), CCK (D), FGF-19 (E), and FGF-21 (F) levels during the MTT. ■ and solid line, before treatment with colesevelam (day 14); □ and dashed line, end of treatment with colesevelam (day 70).