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Objective

Type 2 diabetes is characterized by diminished pancreatic β-cell mass and function. Glucagon-like peptide-1 has been reported to increase islet cell proliferation and reduce apoptosis of β-cells in rodents. In this study, we explored the effect of chronic administration of the dipeptidyl peptidase-4 inhibitor vildagliptin on glucose tolerance, β-cell function, and β-cell mass in Irs2-knockout (Irs2(-/-)) mice. Wild-type and Irs2(-/-) mice were fed a high-fat diet for 20 wk, with or without vildagliptin. In both genotypes of mice, vildagliptin significantly decreased the area under the curve (0-120 min) of blood glucose and increased the insulin response to glucose during the oral glucose tolerance test. In the oral glucose tolerance test performed 1 d after discontinuation of vildagliptin administration, the area under the curve (0-120 min) of blood glucose was still significantly decreased and the insulin response to glucose was significantly increased in the Irs2(-/-) mice treated with vildagliptin as compared with the values in the mice not treated with vildagliptin. Histochemical analysis of the pancreatic islets revealed significant increase of the β-cell mass and decrease in the proportion of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive β-cells but no significant increase of the bromodeoxyuridine incorporation in Irs2(-/-) mice treated with vildagliptin. Our results suggest that vildagliptin improved glucose tolerance and increased the β-cell mass by reducing β-cell apoptosis in the Irs2(-/-) mice, and that the reduction of β-cell apoptosis by vildagliptin was independent of the Irs2 expression in the cells.

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The objective of this study was to assess the chronic effects of a bile acid sequestrant, colestimide, on glucose metabolism. After db/db mice were fed a diet containing colestimide or cholic acid (CA) for 12 weeks, we investigated the impact of these agents on glucose and lipid metabolism. Colestimide significantly reduced the elevated fasting blood glucose level (p<0.01), and CA even more markedly reduced fasting blood glucose. The blood glucose level after an oral glucose load was significantly lower in the CA group than in the control group, but the colestimide group showed no significant difference. The insulin response to a glucose load was abolished in the control and colestimide groups. A hyperinsulinemic-euglycemic clamp study revealed that colestimide significantly improved the GIR (p=0.013). Hepatic EGP and Rd were also improved by colestimide, suggesting that it alleviated insulin resistance by suppressing hepatic glucose production and increasing peripheral glucose usage. CA significantly increased both the weight and cholesterol content of the liver, while colestimide reduced these parameters. Colestimide suppressed hepatic gene expression of SHP, but enhanced SREBP2 expression. On the other hand, CA increased the expression of SHP and lipogenic enzymes such as ACC and SCD-1, but had no effect on SREBP2. The present study demonstrated that colestimide improves hyperglycemia and hyperlipidemia, as well as reducing the hepatic lipid content. In contrast, CA exacerbates hyperlipidemia and increases the hepatic lipid content, although it improves glycemic control. Thus, colestimide is a well-balanced drug for the treatment of diabetes mellitus.