Molecular mechanisms of regulation of glucose-stimulated insulin secretion by novel small-molecule activators and inhibitors in pancreatic beta-cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06950
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Gunma University
• Principal Investigator: MATSUNAGA Kohichi 群馬大学, 生体調節研究所, 助教 (20570162)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: インスリン分泌 / ケミカルバイオロジー / 化合物ライブラリ

Outline of Final Research Achievements

To identify novel small-molecules of insulin secretion regulator, we examined high-throughput screening analysis to identify chemical compounds that activate (or inhibit) insulin secretion in pancreatic beta-cells and identified several kinds of compounds as activator (or inhibitor) of insulin secretion. Pull-down assay experiment using chemical compound conjugated magnetic beads revealed that one of the activators binds to mitochondrial protein, VDAC. siRNA-mediated depletion of VDAC1 in INS1 832/13 cells reduced increase of insulin secretion by the activator, and in addition, intracellular ATP level is increased by the activator in beta-cells. These results demonstrate that glucose-stimulated insulin secretion is up-regulated by increase of intracellular ATP level through binding of the novel activator to VDAC protein.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

糖尿病は我が国を含め世界中で増加の一途をたどっており、より副作用の少ない、インスリン分泌をコントロールできる新規薬剤の開発は以前重要な課題の一つです。本研究で行われた網羅的な薬剤スクリーニングにより、新規に発見されたインスリン分泌促進・阻害化合物と、それら同定された化合物の詳細な分子メカニズム解析の知見は、新しい糖尿病薬開発を行うための基盤になると考えています。