膵β細胞脂質代謝分子によるインスリン分泌制御及び2型糖尿病病態形成への関与

抄録

Depression of lipid metabolism in β-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 β-cells. Intracellular DAG accumulation is involved in β-cell dysfunction in the pathogenesis of type 2 diabetes; thus, the regulation of intracellular DAG levels is likely important for maintaining the β-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 β-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 β-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.