The effect of antihyperglycemic drugs on prevention of the diabetes via mTORC1 signal

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09803
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Kobe University
• Principal Investigator: Maki Koyanagi-Kimura (小柳真希) 神戸大学, 医学部附属病院, 特定助教 (40623690)
• Research Collaborator: Kannno Ayumi ; Asahara Shun-ichiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: mTORC1活性

Outline of Final Research Achievements

The preservation of pancreatic βcell mass is an essential factior in the onset and development of type 2 diabetes mellitus.In this study, we aimed at indentification of antihyperglycemic drugs on prevention of the diabetes via mTORC1 signal. We administered βTSC2-/-mice to DPP-4 inhibitors, SGLT2 inhibitors to db/db mice. DPP-4 inhibitors prevented decrease in insulin signaling. SGLT2 inhibitors preserved pancreatic beta cell mass more effectively if administartion is earlier.
Maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic beta cell mass. Our data suggest that GCN2 senses amino acid deficiency in beta cells and limits signaling by mechanistic target of rapamycin complex 1 to prevent beta cell failure during the consumption of a high-fat diet. The present results provide an insight into the genetic predisposition to T2DM in non-obese Asian populations, and they may inform a strategy for intervention in those with the risk allele for this SNP.

Free Research Field

糖尿病における膵β細胞量調節機構

Academic Significance and Societal Importance of the Research Achievements

DPP-4阻害薬はインスリンシグナルの減弱化の改善を介して膵β細胞保護に寄与すると考えられた。早期SGLT2投与db/dbマウスではAgr2、Tff2、Gkn3遺伝子発現上昇により膵β細胞量保持のlegacy effectに寄与している可能性が考えられた。また、GCN2は高脂肪食負荷による過栄養の際、プロインスリンmRNAの翻訳が亢進すると活性化され、SESN2の発現低下によるmTORC1活性の亢進を介して膵β細胞量維持が破綻する可能性が示唆された。すなわち本研究は、2 型糖尿病候補遺伝子GCN2のSNPを有する患者が過食による膵β細胞不全を未然に防ぎうる手段を講じることに役立つと考えられた。