Physiological role of pancreatic incretin on the functional regulation of pancreatic islet cells

• Project/Area Number: 26461350
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kawasaki Medical School
• Principal Investigator: Kaku Kohei 川崎医科大学, 医学部, 教授 (10116709)
• Co-Investigator(Kenkyū-buntansha): 下田 将司 川崎医科大学, 医学部, 講師 (60388957)
• Research Collaborator: NAKASHIMA Koji ; KIMURA Tomohiko ; HIRUKAWA Hidenori ; OKAUCHI Seizo ; OBATA Atsushi ; KANETO Hideaki ; SHIGETO Makoto ; Rorsman Patrik
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 糖尿病 / 膵ラ氏島機能 / 膵灌流 / 膵インクレチン / 膵α細胞 / GLP-1 / GLP-1受容体 / autocrine作用 / 膵GLP-1分泌 / 膵GLP-1受容体 / 膵ラ氏島GLP-1のautocrine機構 / 膵ラ氏島GLP-1のparacrine機構 / 糖尿病GKラット / 膵ラ氏島α細胞 / GLP-1産生細胞 / GLP-1R / GKラット / グルカゴン / インスリン / endosome

Outline of Final Research Achievements

To assess a physiological role of pancreatic GLP-1 on the regulation of pancreatic islet cell function, GLP-1 secretion by using pancreas perfusion study and GLP-1 receptors (GLP-1Rs) in islet cells by immunohistochemical analysis were investigated in non-diabetic and diabetic rats.
The perfusion study of diabetic GK rats demonstrated a significant secretion of GLP-1 from the pancreas. GLP-1Rs were observed in α-cells in diabetic GK rats, but not in non-diabetic rats. Exendin-4 stimulated both glucagon and GLP-1 secretions from α-cells and cAMP-dependent insulin secretion from β-cells. In addition, the immunostochemical analysis revealed that GLP-1/GLP-1R complex induced the endosome formation in pancreatic α-cells of diabetic rats.
These results strongly suggested the existence of autocrine mechanism of GLP-1/GLP-1R in pancreatic α-cells of diabetic rats, by which the deranged islet function in diabetic condition might be restored.

Research Products

• [Journal Article] Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic β-cells in obese type 2 diabetic db/db mice. (2016)
  • Author(s): Okauchi S, Shimoda M, Obata A, Kimura T, Hirukawa H, Kohara K, Mune T, Kaku K, Kaneto H
  • Journal Title: Biochem Biophys Res Commun Volume: 470 Issue: 3 Pages: 772-782
  • DOI: 10.1016/j.bbrc.2015.10.109
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Combination of DPP-4 inhibitor and PPARγ agonist exerts protective effects on pancreatic β-cells in diabetic db/db mice through the augmentation of IRS-2 expression. (2015)
  • Author(s): Hirukawa H, Kaneto H, Shimoda M, Kimura T, Okauchi S, Obata A, Kohara K, Hamamoto S, Tawaramoto K, Hashiramoto M, Kaku K
  • Journal Title: Mol Cell Endocrinol Volume: 413 Pages: 49-60
  • DOI: 10.1016/j.mce.2015.06.010
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] GLP-1 stimulates insulin secretion by PKC-dependentTRPM4 and TRPM5 activation. (2015)
  • Author(s): Shigeto M ,Ramracheya R, Tarasov AI, Cha C-Y, Chibalina MV, Hastoy B, Philippaert K, Reinbothe T, Rorsman N, Salehi A, Sones WR, Vergari E, Weston C, Gorelik J, Katsura M, Nikolaev VO, Vennekens R, Zaccolo M, Galione A, Johnson PVR, Kaku K, Ladds G, and Rorsman P
  • Journal Title: J Clin Invest Volume: 125 Issue: 12 Pages: 1-15
  • DOI: 10.1172/jci81975
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Protective effects of pioglitazone and/or liraglutide on pancreatic β-cells in db/db mice: Comparison of their effects between in an early and advanced stage of diabetes. (2015)
  • Author(s): Kimura T, Kaneto H, Shimoda M, Hirukawa H, Okauchi S, Kohara K, Hamamoto S, Tawaramoto K, Hashiramoto S, Kaku K
  • Journal Title: Mol Cell Endocrinol Volume: 400 Pages: 78-89
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Dietary restriction preserves the mass and function of pancreatic β cells via cell kinetic regulation and suppression of oxidative/ER stress in diabetic mice. (2015)
  • Author(s): Kanda Y, Hashiramoto M, Shimoda M, Hamamoto S, Tawaramoto K, Kimura T, Hirukawa H, Nakajima K, Kaku K
  • Journal Title: J Nutr Biochem Volume: 26 Pages: 219-226
  • Peer Reviewed / Open Access
• [Presentation] 糖尿病モデルラットのα細胞におけるGIP/GIP受容体の発現とGLP-1/GLP-1受容体との相違性 (2016)
  • Author(s): 中島弘二、金藤秀明、木村友彦、下田将司、加来浩平
  • Organizer: 第59回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2016-05-19
• [Presentation] 糖尿病モデルラットのα細胞におけるGIP/GIP受容体の発現とGLP-1/GLP-1受容体との相違性 (2016)
  • Author(s): 中島弘二、金藤秀明、木村友彦、下田将司、加来浩平
  • Organizer: 第５９回日本糖尿病学会年次学術集会
  • Place of Presentation: 国立京都国際会館（京都府・京都市）
  • Year and Date: 2016-05-19
• [Presentation] 糖尿病モデルラット膵α細胞にはGLP-1受容体が発現しGLP-1のautocrine機構が存在する (2015)
  • Author(s): 中島弘二、木村友彦、岡内省三、下田将司、金藤秀明、加来浩平
  • Organizer: 第５８回日本糖尿病学会年次学術集会
  • Place of Presentation: 海峡メッセ下関（山口県下関市）
  • Year and Date: 2015-05-21 – 2015-05-23
• [Presentation] 膵α細胞および消化管由来のGLP-1とGIPの分泌機構の相違性 (2014)
  • Author(s): 中島弘二、下田将司、木村友彦、蛭川英典、岡内省三、加来浩平
  • Organizer: 第５７回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市）
  • Year and Date: 2014-05-22 – 2014-05-24