[Involvement of Diacylglycerol Kinase on the Regulation of Insulin Secretion in Pancreatic ß-Cells during Type 2 Diabetes].

Depression of lipid metabolism in ß-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 ß-cells. Intracellular DAG accumulation is involved in ß-cell dysfunction in the pathogenesis of type 2 diabetes; thus, the regulation of intracellular DAG levels is likely important for maintaining the ß-cell function. We focused on diacylglycerol kinases (DGKs), which strictly regulate intracellular DAG levels, and analyzed the function of type I DGKs (DGKα, γ), which are activated by intracellular Ca2+ and expressed in the cytoplasm, in ß-cells. The suppression of the DGKα and γ expression decreased the insulin secretory response, and the decreased expression of DGKα and γ was observed in islets of diabetic model mice. In the pancreatic ß-cell line MIN6, 1 µM R59949 (a type I DGK inhibitor) and 10 µM DiC8 (a cell permeable DAG analog) enhanced glucose-induced [Ca2+]i oscillation in a PKC-dependent manner, while 10 µM R59949 and 100 µM DiC8 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 DGKα and γ 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.