The mechanism for the maintenance of pancreatic beta cells derived by in vitro differentiation of human pluripotent stem cells

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02861
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: Kume Shoen 東京工業大学, 生命理工学院, 教授 (70347011)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 膵臓β細胞 / ドパミン / VMAT2 / インスリン分泌

Outline of Final Research Achievements

VMAT2 plays a significant negative regulatory role in the transmission of dopamine. βVMAT2KO beta cells (or WT beta-cells treated with VMAT2 inhibitor TBZ) cannot uptake dopamine into vesicles; thus, dopamine is subjected to degradation by MAO, leading to a reduced dopamine content and an increased generation of ROS. The decreased dopamine content leads to a reduction in the dopamine negative feedback loop which, in turn, leads to elevated insulin secretion. Under HFD conditions, where excess nutrient stress exists, insulin secretion occurs frequently, increasing beta-cell exposure to ROS. Long-term exposure to ROS leads to increased vulnerability of βVMAT2KO beta-cells and accelerated beta-cell failure. βVMAT2KO beta-cells show an initial compensation via beta-cell growth and increased beta-cell mass followed by dedifferentiation and beta-cell death, which is a characteristic of the progression of beta-cell failure.

Free Research Field

糖代謝・内分泌

Academic Significance and Societal Importance of the Research Achievements

VMAT2-ドパミンシグナルは膵臓β細胞の分化抑制シグナルとして働くのみならず、β細胞の量を制御するシグナルでもあり、糖応答性インスリン分泌を負に制御するシグナルである。一方、VMAT2-ドパミンシグナルを欠くと、糖応答性インスリン分泌が亢進した。高脂肪食給餌条件下では、β細胞特異的VMAT2遺伝子変異マウスは、対照の野生型よりも早く耐糖能の改悪を示し、β細胞の脱分化、脱落を引き起こした。これらの結果から、膵臓β細胞を正常に維持するためには、負に制御するシグナルが重要な役割を果たすことが示された。膵臓β細胞の恒常性維持のためには、その機能を適宜に制御することが重要であることが示された。