Functional analysis of type 2 diabetes susceptibility genes using animal disease models

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K08466
• 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: International University of Health and Welfare (2020); Japan Association for Development of Community Medicine (2018-2019)
• Principal Investigator: TAKAMOTO ISEKI 国際医療福祉大学, 医学部, 准教授 (60431871)
• Co-Investigator(Kenkyū-buntansha): 桜井 賛孝 東京大学, 医学部附属病院, 助教 (70748376)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 2型糖尿病 / 疾患感受性遺伝子 / 疾患モデル動物 / KCNQ1 / UBE2E2

Outline of Final Research Achievements

Common genetic variations of KCNQ1 and UBE2E2 are associated with type 2 diabetes. In this study, we investigated the physiological and pathophysiological roles of KCNQ1 and UBE2E2 in glucose homeostasis with several genetically engineered mice. We have identified novel genetically engineered mice with loss-of-function KCNQ1 caused by a single-nucleotide mutation, which showed no obvious glucose intolerance under a normal chow diet and a high-fat diet. By contrast, postweaning mice with gain-of-function KCNQ1 in the pancreatic beta cells had a characteristic of reduced insulin secretion, leading to impaired glucose tolerance. Moreover, adult mice with over-expression of UBE2E2 in the pancreatic beta cells showed impaired glucose tolerance with reduction of insulin secretion. Thus, our findings suggest that functional up-regulation and/or over-expression of KCNQ1 and UBE2E2 in the pancreatic beta cells play a crucial role in glucose metabolism in vivo.

Free Research Field

糖尿病

Academic Significance and Societal Importance of the Research Achievements

近年,全ゲノム関連解析(GWAS)によって2型糖尿病疾患感受性遺伝子が続々と同定され,その数は100を超えている. ユビキチン結合酵素であるUBE2E2は欧米人では2型糖尿病との相関が認められず,日本人・アジア人に特有の疾患感受性遺伝子であると推察され,そのPopulation Attributable Riskは電位依存性カリウムチャネルKCNQ1と並んで日本人2型糖尿病疾患感受性遺伝子の中でも重要である.本研究ではインスリンを分泌する膵β細胞においてKCNQ1とUBE2E2が担う生理的・病態生理的役割の一端を個体レベルで明らかにすることができた.