The combination of colesevelam with sitagliptin enhances glycemic control in diabetic ZDF rat model

Abstract

Bile acid sequestrants have been shown to reduce glucose levels in patients with type 2 diabetes. We previously reported that the bile acid sequestrant colesevelam HCl (Welchol) (COL) induced the release of glucagon-like peptide (GLP)-1 and improved glycemic control in insulin-resistant rats. In the present study, we tested whether adding sitagliptin (Januvia) (SIT), which prolongs bioactive GLP-1 half life, to COL would further enhance glycemic control. Male Zucker diabetic fatty (ZDF) rats were assigned to four groups: diabetic model without treatment (the model), the model treated with 2% COL or 0.4% (120 mg/day) SIT alone, or with the combination (COL+SIT). After 4 wk of treatment, the glucose area under the curve (AUC) was reduced more in the COL+SIT than the COL although both groups showed decreased glucose AUC with increased AUC of bioactive GLP-1 (GLP-1A) compared with the model group. The above changes were not observed after 8 wk. Increasing the SIT dose by 50% (180 mg SIT/day) in the diet reduced the glucose AUC in the COL+SIT group even after 8 wk but still not in the SIT alone group compared with the model. It was noteworthy that, after 8 wk, insulin levels in the SIT group declined to levels similar to the model. Histological examination of the pancreatic β-cell islets showed that islet sizes were larger, proliferation enhanced, and cell apoptosis reduced in the COL+SIT but not the SIT alone group compared with the model. We hypothesize that the combination of COL with SIT extends the half life of COL-induced GLP-1A and benefits preservation of the islets that delay the development of diabetes and improve glycemic control. This study suggests that the combined therapy (COL+SIT) is more effective than either drug alone for reducing glucose levels in diabetes.