Involvement of of Diacylglycerol Kinase on the Regulation of Insulin Secretion in Pancreatic β-Cells during Type 2 Diabetes

Depression of lipid metabolism in beta-cells has been indicated to be one of the causes of impaired insulin secretion in type 2 diabetes. Diacylglycerol (DAG) is an important lipid mediator and is known to regulate insulin secretion in pancreatic beta-cells. Intracellular DAG accumulation is involved in beta-cell dysfunction in the pathogenesis of type 2 diabetes; thus, the regulation of intracellular DAG levels is likely important for maintaining the beta-cell function. We focused on diacylglycerol kinases (DGKs) , which strictly regulate intracellular DAG levels, and analyzed the function of type I DGKs (DGK alpha, gamma) , which are activated by intracellular Ca2+ and expressed in the cytoplasm, in beta-cells. The suppression of the DGK alpha and gamma expression decreased the insulin secretory response, and the decreased expression of DGK alpha and gamma was observed in islets of diabetic model mice. In the pancreatic beta-cell line MINE, 1 mu M R59949 (a type I DGK inhibitor) and 10 mu M DiC(8) (a cell permeable DAG analog) enhanced glucose-induced [Ca2+](i) oscillation in a PKC-dependent manner, while 10 mu M R59949 and 100 mu M DiC(8) suppressed [Ca2+](i) oscillation and voltage-dependent Ca2+ channel activity in a PKC-independent manner. These results suggest that the intracellular accumulation of DAG by the loss of the DGK alpha and gamma functions regulates insulin secretion in a dual manner depending on the degree of DAG accumulation. The regulation of the insulin secretory response through DAG metabolism by type I DGKs may change depending on the degree of progression of type 2 diabetes.