期刊
ENDOCRINOLOGY
卷 154, 期 11, 页码 4089-4098出版社
ENDOCRINE SOC
DOI: 10.1210/en.2013-1356
关键词
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资金
- Japan Society for the Promotion of Science [21790154, 20590085]
- Grants-in-Aid for Scientific Research [25116704, 20590085, 21790154, 23590192] Funding Source: KAKEN
Diacylglycerol kinase (DGK) catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid. This study investigated the expression and function of DGK in pancreatic beta-cells. mRNA expression of type I DGK isoforms (alpha, beta, gamma) was detected in mouse pancreatic islets and the beta-cell line MIN6. Protein expression of DGK alpha and DGK gamma was also detected in mouse beta-cells and MIN6 cells. The type I DGK inhibitor R59949 inhibited high K+- and glucose-induced insulin secretion in MIN6 cells. Moreover, single knockdown of DGK alpha or DGK gamma by small interfering RNA slightly but significantly decreased glucose- and high K+-induced insulin secretions, and the double knockdown further decreased them to the levels comparable with those induced by R59949. R59949 and DiC8, a membrane permeable DAG analog, decreased intracellular Ca2+ concentration elevated by glucose and high K+ in MIN6 cells. Real-time imaging in MIN6 cells expressing green fluorescent protein-tagged DGK alpha or DGK gamma showed that the DGK activator phorbol 12-myristate 13-acetate rapidly induced translocation of DGK gamma to the plasma membrane, whereas high K+ slowly translocated DGK alpha and DGK gamma to the plasma membrane. R59949 increased the DAG content in MIN6 cells when stimulated with high KCl, whereas it did not increase the DAG content but decreased the phosphatidic acid content when stimulated with high glucose. Finally, R59949 was confirmed to inhibit high K+-induced insulin secretion from mouse islets and glucose-induced insulin secretion from rat islets. These results suggest that DGK alpha and DGK gamma are present in beta-cells and that the depression of these DGKs causes a decrease in intracellular Ca2+ concentration, thereby reducing insulin secretion.
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