Development of therapeutic drugs for insulin-dependent diabetes mellitus with a new mechanism mediated by leptin signaling

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16225
• 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: Nagoya University
• Principal Investigator: Ito Yoshihiro 名古屋大学, 医学系研究科, 特任助教 (80637687)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: レプチン / 1型糖尿病 / PTP1B / IDDM

Outline of Final Research Achievements

We found that (1) while blood glucose levels of IDDM group were higher than those of non-IDDM group, glucose metabolism in IDDM PTP1B deficient (KO) mice was significantly improved compared to IDDM wild-type (WT) mice, (2) peripheral administration of a high dose of leptin significantly improved glucose metabolism in IDDM KO mice compared to IDDM WT, (3) central administration of a low dose of leptin significantly improved glucose metabolism in KO mice compared to WT mice, and (4) peripheral combination therapy of leptin and PTP1B inhibitor in IDDM WT mice improved glucose metabolism to the same levels as control mice. We also found that the phosphorylation of stat3 in the arcuate nucleus of hypothalamus following peripheral leptin administration was enhanced under PTP1B deficiency.In IDDM treatment with leptin, PTP1B deficiency and PTP1B inhibitor enhanced leptin action in the brain to improve glucose metabolism.

Free Research Field

糖尿病

Academic Significance and Societal Importance of the Research Achievements

臨床において、主に1型糖尿病で認められるインスリン依存性糖尿病（IDDM）患者に対する治療の選択肢はインスリンを除けば限られており、ほとんどの経口血糖降下薬に適応や有効性はない。しかしながら、インスリンによる治療を行うも様々な要因により低血糖や高血糖を繰り返し、血糖コントロールに難渋することがある。また、インスリンに対するアレルギー反応や長期使用に伴うインスリン抗体の発生などの問題点があり、臨床において代替の治療法が求められている。私たちの研究が、1型糖尿病患者の治療法において中枢のレプチン受容体シグナルに着目することで将来インスリンに代わる有用な治療法になる可能性がある。