Comprehensive searching for compounds which can directly enhance MafA and/or PDX-1 expression

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08990
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Kaneto Hideaki 川崎医科大学, 医学部, 教授 (80448034)
• Co-Investigator(Kenkyū-buntansha): 小畑 淳史 川崎医科大学, 医学部, 特任研究員 (10771298) ; 下田 将司 川崎医科大学, 医学部, 講師 (60388957)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ブドウ糖毒性

Outline of Final Research Achievements

It has been shown that chronic hyperglycemia gradually decreases insulin biosynthesis and secretion which is accompanied by reduced expression of very important insulin gene transcription factors MafA and PDX-1. The down-regulation of MafA and/or PDX-1 expression considerably explains the molecular mechanism for glucose toxicity. It remained unknown, however, which molecules can directly enhance MafA and/or PDX-1 expression. In this study, we searched for compounds which can directly enhance MafA and/or PDX-1 expression using a small molecule compound library in pancreatic beta-cell line MIN6 cells and islets isolated from non-diabetic C57BL/6 mice and obese type 2 diabetic C57BL/KsJ-db/db mice. As the results, we found that two molecules increased MafA, PDX-1 or insulin expression in MIN6 cells and islets isolated from non-diabetic mice and obese type 2 diabetic db/db mice.

Free Research Field

糖尿病

Academic Significance and Societal Importance of the Research Achievements

今回申請させて頂いた研究においては、各種小分子化合物ライブラリーを用いて、ブドウ糖毒性で低下するMafAやPDX-1の発現を直接増加させる薬剤や因子を網羅的に検索し、膵β細胞機能障害の分子機構に基づいた新規糖尿病治療薬の探索を目的とした。MafA や PDX-1 の発現を直接増加させる因子はまだ世界でも報告がないため、見つかれば世界に先駆けた報告であり、また膵β細胞機能障害の分子メカニズムに基づいた新規糖尿病治療薬の探索にも繋がるため、研究成果の学術的意義や社会的意義は大きい。