Diabetes mellitus induced by inhibition of cholesterol synthesis: clarification of the pathogenesis and development of its therapy

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09789
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Jichi Medical University
• Principal Investigator: Ishibashi Shun 自治医科大学, 医学部, 教授 (90212919)
• Research Collaborator: TAKEI shoko ; TAKEI akihito ; NAGASHIMA shuichi
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: コレステロール / 糖尿病 / マウス / 膵β細胞 / インスリン / スタチン / HMG-CoA還元酵素 / グルカゴン

Outline of Final Research Achievements

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), statins, which are used to prevent to cardiovascular diseases, are associated with a modest increase in the risk of new-onset diabetes mellitus. To investigate the role of HMGCR in the development of β cells and glucose homeostasis, we deleted Hmgcr in a β cell-specific manner by using Cre-loxP technique in vivo. Mice lacking Hmgcr in β cells (β-KO) exhibited hypoinsulinemic hyperglycemia due to decreases in both β cell mass and insulin secretion. mRNA expression of Ngn3 was maintained despite the striking reduction of the expression of genes which characterize β cell identity such as insulin, Pdx1 and MafA in the islets from β-KO mice. Numbers of β cells were marketly reduced, some of which were also positive for glucagon. In conclusion, HMGCR plays critical roles not only in insulin secretion but also in the development of β cells in mice.

Free Research Field

代謝

Academic Significance and Societal Importance of the Research Achievements

膵β細胞特異的なHMGCRの欠損は、膵β細胞の減少を来たし、インスリン分泌低下及び高血糖を来たすことが明らかとなっている。マウスの遺伝子改変モデルによっても、膵β細胞の形態維持や分化・増殖能におけるHMGCRの関与が確認された。今後、このモデルを用いて、膵β細胞障害の発症機序の詳細の解明が期待出来る。そこを標的にし、スタチン投与または機能低下型HMGCR変異に起因する２型糖尿病の発症予防や治療法の開発が期待される。該当する患者数は少なくないため、世界的に増加し続ける糖尿病患者数の低減に貢献できる可能性が大きい。