Unraveling of the mechanism of the organ-protective effect of GLP-1 and the physiological role of extrapancreatic receptors

• Project/Area Number: 18K16206
• 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: Kyushu University
• Principal Investigator: Inoue Tomoaki 九州大学, 医学研究院, 特任助教 (70815894)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: GLP-1 / 臓器保護 / 膵外受容体

Outline of Final Research Achievements

We succeeded in producing monocyte-specific GLP-1 receptor-deficient mice in this study. No changes in body weight or blood glucose were observed between monocyte-specific GLP-1 receptor-deficient mice and control mice. Echocardiography revealed left ventricular dysfunction at about 18 weeks of age. As one of the mechanisms by which monocyte-specific GLP-1 receptor-deficient mice cause cardiac dysfunction, progression of fibrosis in the myocardium and an increase in myofibroblasts were observed. By the above results, it was suggested that the signal mediated by the monocyte GLP-1 receptor may exert an organ protective effect by suppressing the fibrosis of the heart.

Academic Significance and Societal Importance of the Research Achievements

大規模臨床研究においてGLP-1受容体作動薬が心血管イベントならびに腎イベント抑制作用を有することが示され、大きな注目を集めている。しかしながら、GLP-1受容体の分布と臓器保護効果には解離があり、その臓器保護効果のメカニズムは理解できてない。
本研究において、単球のGLP-1受容体を介したシグナルが臓器保護効果に関与している可能性が示唆された。膵臓以外の組織でのGLP-1シグナルの全貌を明らかになることはGLP-1の生理作用・臓器保護のメカニズムの解明のみならず、糖尿病以外の疾患に対する治療応用という点においても極めて重要な成果である。