Involvement of Diacylglycerol Kinase on the Regulation of Insulin Secretion in Pancreatic β-Cells during Type 2 Diabetes

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  • Kaneko Yukiko K.
    Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka
  • Sawatani Toshiaki
    Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka
  • Ishikawa Tomohisa
    Department of Pharmacology, School of Pharmaceutical Sciences, University of Shizuoka

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Other Title
  • 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
  • スイvサイボウ シシツ タイシャ ブンシ ニ ヨル インスリン ブンピ セイギョ オヨビ 2ガタ トウニョウビョウ ビョウタイ ケイセイ エ ノ カンヨ

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Abstract

<p>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.</p>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 142 (5), 457-463, 2022-05-01

    The Pharmaceutical Society of Japan

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