Metabolic effects of dipeptyl peptidase 4 inhibitor in type 2 diabetes

Abstract

Insulin resistance and abnormal insulin secretion are central to type 2 diabetes. The relationships have been established between lipid accumulation in the liver and muscle and insulin resistance, and that of lipid accumulation in the pancreas and β cell dysfunction. Therefore it is vital to assess the effect of therapies on intra-organ lipid concentration. DPP-4 inhibitor vildagliptin is a new therapeutic agent in type 2 diabetes. Its known primary mechanism of action is to delay GLP-1 and GIP degradation, and enhance their endogenous concentration. GLP-1 and GIP increase the sensitivity of the α- and β-cells to glucose concentration. Although DPP-4 inhibitors have been found to decrease postprandial triglyceride levels and lipolysis, the effect on intra-organ lipid concentration is unknown. Glycogen storage in the liver and muscle in type 2 diabetes is subnormal, nonetheless, the extent of glycogen storage abnormality after a whole day of normal eating has not been previously examined. Although abnormal β cell function has been recognised as a feature of type 2 diabetes, the whole pancreas has not been extensively studied previously. To test the hypothesis that DPP-4 inhibitors modulate intra-organ lipid accumulation, 44 well-controlled type 2 diabetes subjects treated only with metformin were randomised in a double-blinded manner to receive either vildagliptin or placebo for 6 months. In order to assess the extent of change, in intra-organ lipid content, and abnormal glycogen storage, and to provide comparative data for pancreas morphology, 14 normal glucose tolerant subjects matched for weight, BMI, sex and age were studied. A clinically significant decrease in liver triglyceride content after 6 months treatment with vildagliptin was observed. Additionally, the studies demonstrate that the pancreas volume in type 2 diabetes was smaller compared to match controls, and that muscle did not contribute to glycogen storage during normal daily eating in type 2 diabetes.