Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing the release of GLP-1.
American journal of physiology. Gastrointestinal and liver physiology 2009 Dec 31; In press
Shang Q, Saumoy M, Holst J JJ, Salen G GE, Xu G
1UMD-New Jersey Medical School.
Bile acid sequestrants have been shown to lower glucose levels in patients with type 2 diabetes. To investigate how Colesevelam HCl improves hyperglycemia, studies were conducted in F-DIO rats which develop insulin-resistance when fed a high-energy (high fat/high sucrose) diet (HE). The rats were fed HE (HE); HE+2% colesevelam (CL); HE+0.02% SC-435, an ASBT inhibitor (SC); and regular chow (controls). After 4 weeks of treatment, both in HE and SC+HE groups, plasma glucose and insulin levels remained elevated compared to baseline values throughout an oral glucose tolerance test (OGTT). In contrast, in the CL+HE group, plasma glucose levels returned to baseline by the end of the test and insulin peaked in 15-30 min then returned to baseline. Colesevelam induced release of GLP-1 as the area under the curve (AUC) of plasma total GLP-1in the CL+HE group was significantly greater than the HE during the OGTT. Bile acid concentrations in the portal blood did not decrease in the HE group but declined significantly both in CL+HE and SC+HE groups with reduced FXR activation as compared to controls. Conclusion: Colesevelam reduces plasma glucose levels by improving insulin-resistance in this rat model. It is unlikely that the improvement is due to decreased bile acid flux to the liver but is likely secondary to induced GLP-1 secretion which improves insulin release.
Keywords: obesity Colesevelam insulin resistance GLP-1