The role of vascular endothelial PDK1 on glucose metabolism and beta-cell function

• Project/Area Number: 19K18016
• 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: Kawasaki Medical School
• Principal Investigator: Obata Atsushi 川崎医科大学, 医学部, 特任研究員 (10771298)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: PDK1 / 膵β細胞 / vascularity / 血流 / 虚血 / 小胞体ストレス / インスリン抵抗性 / 骨格筋 / 血管内皮 / 糖代謝 / β細胞

Outline of Research at the Start

Phosphoinositide-dependent protein kinase 1 (PDK1)は、insulin receptor-PI3 kinaseの下流にあり、血管内皮細胞の増殖や生体での血管拡張作用を調節している。本研究では血管内皮特異的PDK1欠損マウスを用いて、血管内皮PDK1が全身の糖代謝及び膵β細胞へ及ぼす影響を包括的に解析することで血管内皮におけるPDK1の病態生理学的役割の解明を目指す。さらにヒト血管内皮で得られたデータをもとに、血管内皮PDK1の発現制御に迫る。

Outline of Final Research Achievements

It is known that 3-phosphoinositide-dependent protein kinase-1 (PDPK1) plays very important roles in insulin signaling. In this study, we elucidated that vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice via maintaining vascular structure and blood flow in pancreatic beta cell.

Academic Significance and Societal Importance of the Research Achievements

血管内皮におけるインスリンシグナルについては、インスリン受容体は膵β細胞機能、量には関与がないこと、その下流にあるIRS2は生体内においては膵β細胞における血流の維持によりインスリン分泌に重要な役割を果たすが、単離した膵β細胞は機能的に問題がないと報告されている。我々はインスリンシグナルのさらなる下流であるPDK1に着眼し、血管内皮PDK1は膵β細胞の血管構築や血流に非常に大切な役割を果たし、膵β細胞量、機能維持に重要な役割を果たすことを明らかにした。このことで、血管内皮PDK1に着眼した新たな糖尿病治療法開発へのシーズとなる成果となったと考えられる。

Research Products

• [Journal Article] Multifaceted Mechanisms of Action of Metformin Which Have Been Unraveled One after Another in the Long History (2021)
  • Author(s): Kaneto H, Kimura T, Obata A, Shimoda M, Kaku K.
  • Journal Title: Int J Mol Sci . Volume: 22 Issue: 5 Pages: 2596-2596
  • DOI: 10.3390/ijms22052596
  • Peer Reviewed / Open Access
• [Journal Article] Unexpected Pleiotropic Effects of SGLT2 Inhibitors: Pearls and Pitfalls of This Novel Antidiabetic Class (2021)
  • Author(s): Kaneto H, Obata A, Kimura T, Shimoda M, Kinoshita T, Matsuoka TA, Kaku K.
  • Journal Title: Int J Mol Sci . Volume: 22 Issue: 6 Pages: 3062-3062
  • DOI: 10.3390/ijms22063062
  • Peer Reviewed / Open Access
• [Journal Article] Dulaglutide exerts beneficial anti atherosclerotic effects in ApoE knockout mice with diabetes: the earlier, the better (2021)
  • Author(s): Sanada J, Obata A, Obata Y, Fushimi Y, Shimoda M, Kohara K, Nakanishi S, Mune T, Kaku K, Kaneto H.
  • Journal Title: Sci Rep . Volume: 11 Issue: 1 Pages: 1425-1425
  • DOI: 10.1038/s41598-020-80894-x
  • Peer Reviewed / Open Access
• [Journal Article] Notable underlying mechanism for pancreatic beta-cell dysfunction and atherosclerosis: Pleiotropic role of incretin and insulin signaling in various situation. (2020)
  • Author(s): Kaneto H, Obata A, Kimura T, Shimoda M, Sanada J, Fushimi Y, Katakami N, Matsuoka T, and Kaku K.
  • Journal Title: Int. J. Mol. Sci. Volume: 21 Issue: 24 Pages: 1-13
  • DOI: 10.3390/ijms21249444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vascular endothelial PDPK1 plays a pivotal role in the maintenance of pancreatic beta cell mass and function in adult male mice (2019)
  • Author(s): Obata A, Kimura T, Obata Y, Shimoda M, Kinoshita T, Kohara K, Okauchi S, Hirukawa H, Kamei S, Nakanishi S, Mune T, Kaku K, Kaneto H
  • Journal Title: Diabetologia Volume: 62 Issue: 7 Pages: 1225-1236
  • DOI: 10.1007/s00125-019-4878-1
  • Peer Reviewed / Open Access