Pathophysiologically, excessive accumulation of diacylglycerol (DAG), a lipid signal messenger, in pancreatic β-cells has been shown to lead to the insufficiency of insulin secretion. Thus, the regulation of intracellular DAG levels is expected to be an important factor in maintaining β-cell function. The intracellular DAG levels are strictly controlled by DAG kinases (DGKs). We have previously shown that DGKα and γ, type I DGK isoforms, are highly expressed in mouse β-cells, and that DAG accumulation resulting from dysfunction of these DGKs reduces insulin secretion. In the present study, we investigated the effect of type I DGK dysfunction on the regulation of intracellular Ca2+ concentration ([Ca2+]i), which is correlated with insulin secretion, in the β-cell line MIN6B. We also analyzed changes in expression levels of DGKα and γ in β-cells of type 2 diabetes model NSY mice. The amplitude of glucose-induced [Ca2+]i oscillations was increased by 1 μM R59949, a type I DGK inhibitor, and by 10 μM DiC8, a DAG analog. These effects were abolished by Ro31-8220, a protein kinase C (PKC) inhibitor. In contrast, 10 μM R59949 and 100 μM DiC8 suppressed the glucose-induced [Ca2+]i elevation, which was insensitive to Ro31-8220, and furthermore reduced voltage-dependent Ca2+ channel (VDCC) currents, which were measured by patch-clamp recording, implying that DAG accumulation due to type I DGK dysfunction suppresses VDCC, thereby reducing [Ca2+]i in β-cells. Real-time qPCR showed that the expression level of DGKα and γ was lower in islets from NSY mice compared with control mice. Taken together, the results obtained here suggest that DAG accumulation due to type I DGK dysfunction has contradictory dual effect in β-cells depending on the degree of accumulation; mild accumulation PKC-dependently induces a stimulatory effect on insulin secretion, whereas excessive accumulation suppresses it independently of PKC. DGK is likely a key molecule for the progression of type 2 diabetes.


T. Sawatani: None. Y.K. Kaneko: None. T. Ishikawa: None.

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