Dipeptidyl peptidase-4 inhibitor anagliptin ameliorates diabetes in mice with haploinsufficiency of glucokinase on a high-fat diet

Objective. Type 2 diabetes is a chronic metabolic disorder characterized by hyperglycemia with insulin resistance and impaired insulin secretion. DPP-4 inhibitors have attracted attention as a new class of anti-diabetic agents for the treatment of type 2 diabetes. We investigated the effects of anagliptin, a highly selective DPP-4 inhibitor, on insulin secretion and insulin resistance in high-fat diet-fed mice with haploinsufficiency of glucokinase (GckKO) as animal models of type 2 diabetes. Materials/Methods. Wild-type and GckKO mice were administered two doses of anagliptin by dietary admixture (0.05% and 0.3%) for 10 weeks. Results. Both doses of anagliptin significantly inhibited the plasma DPP-4 activity and increased the plasma active GLP-1 levels in both the wild-type and GckKO mice to a similar degree. After 10 weeks of treatment with 0.3% anagliptin, body weight gain and food intake were significantly suppressed in both wild-type and GckKO mice. In addition, 0.3% anagliptin ameliorated insulin resistance and glucose intolerance in both genotypes of mice. On the other hand, treatment with 0.05% anagliptin was not associated with any significant change of the body weight, food intake or insulin sensitivity in either genotype of mice, but it did improve the glucose tolerance by enhancing insulin secretion and increasing the beta-cell mass in both genotypes of mice. Conclusions. High-dose anagliptin treatment improved glucose tolerance by suppression of body weight gain and amelioration of insulin resistance, whereas low-dose anagliptin treatment improved glucose tolerance by enhancing insulin secretion. (C) 2013 Elsevier Inc. All rights reserved.