Glucolipotoxicity impairs proinsulin processing through disturbing V-ATPase function leading to impaired acidification within secretory granules

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K17501
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Juntendo University
• Principal Investigator: Iida Hitoshi 順天堂大学, 医学部, 准教授 (60751146)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: インスリン生合成 / 2型糖尿病 / プロインスリンプロセシング / PC1/3 / V-ATPase

Outline of Final Research Achievements

It has been reported in many clinical studies that serum proinsulin level increases, as glucose tolerance progress, which is considered as an indicator of dysfunction of pancreatic beta cells. In order to elucidate this mechanism, this study focused on the dependence of PC1/3, a major proinsulin processing enzyme, on the acidic environment for its enzymatic function. As a result of suppressing acidification in secretory granules by saturated fatty acids and high-concentration glucose, it was clarified that the enzyme function of PC1/3 was reduced and proinsulin processing was impaired. We found that the function of V-ATPase, which regulates acidification in secretory granules, is inhibited by overnutrition, and clarified a part of the mechanisms of exacerbation of type 2 diabetes.

Free Research Field

膵島生物学

Academic Significance and Societal Importance of the Research Achievements

現状膵β細胞機能を臨床的に評価する方法は乏しく、主にインスリン分泌能を測定するのみである。本研究は膵β細胞に過剰な負荷がかかり、主要な機能の一つであるインスリン生合成が障害されることを、特にインスリン前駆体から正常にプロセシングを受けずプロインスリンとして分泌量が増加するという観点から、分子生物学的に明らかにした。血液中のプロインスリン濃度は測定が可能であり、本研究により早期に膵β細胞が機能不全の状態にあることを検知でき、早期治療介入と膵β細胞機能保持につながる可能性がある。