Dual effect of reduced type I diacylglycerol kinase activity on insulin secretion from MIN6 β-cells

The role of type I diacylglycerol kinases (DGKs) in the regulation of insulin secretion was investigated in MIN6 β-cells. In intracellular Ca²⁺ concentration ([Ca²⁺]_i) measurement experiments, 1 μM R59949, a type I DGK inhibitor, and 10 μM DiC₈, a diacylglycerol (DAG) analog, amplified 22.2 mM glucose-induced [Ca²⁺]_i oscillations in a protein kinase C (PKC)-dependent manner, whereas 10 μM R59949 and 100 μM DiC₈ decreased [Ca²⁺]_i independent of PKC. High concentrations of R59949 and DiC₈ attenuated voltage-dependent Ca²⁺ channel currents. According to these results, 22.2 mM glucose-stimulated insulin secretion (GSIS) was potentiated by 1 μM R59949 but suppressed by 10 μM of the same. The DGKα inhibitor R59022 showed a similar dual effect. Conversely, DiC₈ at 10 and 100 μM potentiated GSIS, although 100 μM DiC₈ decreased [Ca²⁺]_i. These results suggest that DAG accumulated through declined type I DGK activity shows a dual effect on insulin secretion depending on the degree of accumulation; a mild DAG accumulation induces a PKC-dependent stimulatory effect on insulin secretion, whereas an excessive DAG accumulation suppresses it in a PKC-independent manner, possibly via attenuation of VDCC activity.