UPR regulation and novel therapeutic strategy by targeting IRE1a in obesity-induced diabetes

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08562
• 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: Wakayama Medical University
• Principal Investigator: Morita Shuhei 和歌山県立医科大学, 医学部, 准教授 (50372868)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 恒常性維持機構

Outline of Final Research Achievements

Unfolded Protein Response (UPR), which could be regulated by IRE1α, was increased just before and after the onset of diabetes in db/db mouse islets, a mouse model of obese diabetes mellitus. We identified factors associated with pancreatic β-cell injury induced by excessive endoplasmic reticulum stress. We confirmed that these candidate factors are expressed in islets of db/db mice at approximately the same time as the expression of UPR markers. We confirmed that KIRA suppressed the deterioration of glucose tolerance in obese diabetic mouse models.

Free Research Field

膵β細胞

Academic Significance and Societal Importance of the Research Achievements

本研究は肥満・糖尿病の病態における生体の恒常性維持機構の一つUnfolded Protein Response (UPR)機構とその主要制御因子IRE1αの役割の一旦を明らかにした。新規開発したIRE1α特異的阻害薬の肥満・糖尿病に対する治療法の開発基盤構築のため、肥満・糖尿病モデルマウスにおいてその耐糖能に対する効果を確認した。肥満糖尿病において、糖尿病初期状態もしくは発症直前の膵β細胞のUPRシグナルへの介入が、新たな治療法の一つとなり得る可能性が示唆された。