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

• 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ブドウ糖毒性 / 膵β細胞 / インスリン転写因子 / 膵β細胞ブドウ糖毒性

Outline of Research at the Start

糖尿病状態において認められる膵β細胞機能障害（ブドウ糖毒性）にはインスリン遺伝子の転写因子（MafA, PDX-1）の発現低下が深く関与する。そうした中で本検討の目的は、種々の小分子化合物ライブラリーを用いて、これらの転写因子の発現を直接的に増加させる薬剤や因子を網羅的に検索して、ブドウ糖毒性の分子機構に基づく新規糖尿病治療薬の検索をすることである。

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.

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。

Research Products

• [Journal Article] Favorable effects of GLP-1 receptor activator against pancreatic beta-cell glucose toxicity and the development of arteriosclerosis: “The earlier, the better” in therapy with incretin-based medicine. (2021)
  • Author(s): Kaneto H, Kimura T, Shimoda M, Obata A, Sanada J, Fushimi Y, Nakanishi S, Mune T, and Kaku K.
  • Journal Title: Int. J. Mol. Sci. Volume: 22 Issue: 15 Pages: 7917-7917
  • DOI: 10.3390/ijms22157917
  • Peer Reviewed / Open Access
• [Journal Article] Unexpected Pleiotropic Effects of SGLT2 Inhibitors: Pearls and Pitfalls of This Novel Antidiabetic Class (2021)
  • Author(s): Kaneto H, Obata A, Kimura T, Shimoda M, Kinoshita T, Matsuoka TA, Kaku K.
  • Journal Title: Int J Mol Sci . Volume: 22 Issue: 6 Pages: 3062-3062
  • DOI: 10.3390/ijms22063062
  • Peer Reviewed / Open Access
• [Journal Article] Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History (2021)
  • Author(s): Kaneto H, Kimura T, Obata A, Shimoda M, Kaku K.
  • Journal Title: Int J Mol Sci . Volume: 22 Issue: 5 Pages: 2596-2596
  • DOI: 10.3390/ijms22052596
  • Peer Reviewed / Open Access
• [Journal Article] Notable underlying mechanism for pancreatic beta-cell dysfunction and atherosclerosis: Pleiotropic role of incretin and insulin signaling in various situation. (2020)
  • Author(s): Kaneto H, Obata A, Kimura T, Shimoda M, Sanada J, Fushimi Y, Katakami N, Matsuoka T, and Kaku K.
  • Journal Title: Int. J. Mol. Sci. Volume: 21 Issue: 24 Pages: 1-13
  • DOI: 10.3390/ijms21249444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vascular endothelial PDK1 plays pivotal roles for maintenance of pancreatic beta-cell mass and function in adult male mice. (2019)
  • Author(s): Obata A, Kimura T, Obata Y, Shimoda M, Kinoshita T, Kohara K, Okauchi S, Hirukawa H, Kamei S, Nakanishi S, Mune T, Kaku K, and Kaneto H.
  • Journal Title: Diabetologia Volume: 62 Issue: 12 Pages: 1225-1236
  • DOI: 10.1007/s00125-019-04982-y
  • Peer Reviewed / Open Access