Regulation of glucose and incretin-stimulated insulin secretion by cAMP-EPAC2-TRPM2

• Project/Area Number: 24890219
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Metabolomics
• Research Institution: Jichi Medical University
• Principal Investigator: YOSHIDA Masashi 自治医科大学, 医学部, 助教 (50528411)
• Project Period (FY): 2012-08-31 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 糖尿病 / インスリン分泌 / インクレチンホルモン / GLP-1 / 糖代謝 / GIP / EPAC / Trpm2 / 膵β細胞 / cAMP / exendin-4 / EPAC2

Research Abstract

In pancreatic beta-cells, closure of ATP-sensitive-K+ (K-ATP) channel is an initial process triggering glucose-stimulated insulin secretion. However theoretically, closure of K-ATP channel　alone should be insufficient to shift membrane potential toward threshold level to set on insulin secretion. Opening of background nonselective-cation channels (NSCCs) facilitates excitability of the membrane.　We here show that a class of NSCC is activated by both glucose and incretin hormones, GLP-1 and GIP, via cAMP/EPAC-mediated NSCC (TRPM2 channel) pathway. Our data demonstrate that glucose metabolism leads to opening of TRPM2 channel and closure of K-ATP channel simultaneously. Glucose- and incretin-activated NSCC works in concert to effectively induce membrane depolarization to initiate insulin secretions. The present study reveals a newly confirmed beta-cell mechanism through which glucose and incretin evoke insulin secretion and provides a innovative target to treat type 2 diabetes.

Research Products

• [Journal Article] Involvement of cAMP-EPAC-TRPM2 activation in glucose- and incretin-induced insulin secretion (2014)
  • Author(s): Yoshida M, Dezaki K, Uchida K, Kodera S, Lam NV, Ito K, Rita RS, Yamada H, Shimomura K, Ishikawa SE, Sugawara H, Kawakami M, Tominaga M, Yada T, Kakei M.
  • Journal Title: Diabetes
  • NAID: 40020531124
  • Peer Reviewed
• [Journal Article] Involvement of cAMP-EPAC-TRPM2 activation in glucose- and incretin-induced insulin secretion (2014)
  • Author(s): Yoshida M, Dezaki K, Uchida K, Kodera S, Lam NV, Ito K, Rita RS, Yamada H, Shimomura K, Ishikawa SE, Sugawara H, Kawakami M, Tominaga M, Yada T, Kakei M
  • Journal Title: Diabetes Volume: (Epub ahead of print) Issue: 10 Pages: 3394-3403
  • DOI: 10.2337/db13-1868
  • NAID: 40020531124
  • Peer Reviewed / Open Access
• [Presentation] (2013)
  • Organizer: American Diabetes Association's 73^<rd> Scientific Sessions
• [Presentation] 若手研究奨励賞(YIA)受賞 (2013)
  • Organizer: 第56回日本糖尿病学会年次学術集会
• [Presentation] Activation of Trpm2 Channel by Glucose Metabolism and GLP-1 in Pancreatic Beta - Cell (2013)
  • Author(s): Masashi Yoshida, Shiho Yamato, Katsuya Dezaki Masanori Nakata, Masanobu Kawakami, Toshihiko Yada, Masafumi Kakei
  • Organizer: American Diabetes Association's 73rd Scientific Sessions (ADA)
  • Place of Presentation: 米国 シカゴ
• [Presentation] 膵β細胞における新規GLP-1メカニズムとしてのTrpm2チャネル (2013)
  • Author(s): 吉田昌史、大和志保、出崎克也、中田正範、山田穂高、石川三衛、矢田俊彦、川上正舒、加計正文
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] (2012)
  • Organizer: 48^<th > European Association for the Study of Diabetes Annual Meeting
• [Presentation] (2012)
  • Organizer: 第9回国際糖尿病連合西太平洋地区会議および第4回アジア糖尿病学会
• [Presentation] (2012)
  • Organizer: 第24回分子糖尿病シンポジウム
• [Presentation] Activation of nonselective cation channels via cAMP-EPAC2 pathway is involved in exendin-4 potentiated insulin secretion (2012)
  • Author(s): 吉田昌史
  • Organizer: 48th European Association for the Study of Diabetes Annual Meeting
  • Place of Presentation: ベルリン
• [Presentation] Nonselective cation channel actiivated by GLP-1 in pancreatic beta cells (2012)
  • Author(s): 吉田昌史
  • Organizer: 第9回国際糖尿病連合西太平洋地区会議および第4回アジア糖尿病学会(トラベルサポート）
  • Place of Presentation: 京都
• [Presentation] 膵β細胞新規GLP-1メカニズムとしてのTRPm2チャネル (2012)
  • Author(s): 吉田昌史
  • Organizer: 第24回分子糖尿病学シンポジウム
  • Place of Presentation: 東京
• [Book] ファーマナビゲータインクレチン薬編、Chapter 4、インクレチン薬と糖尿病薬との併用、SU薬(速効型インスリン分泌促進薬を含む) (2012)
  • Author(s): 吉田昌史、加計正文
  • Publisher: メディカルレビュー社
• [Book] 糖尿病レクチャー、新しい経口糖尿病薬療法、Q 11. SU薬とその併用は (2011)
  • Author(s): 吉田昌史、加計正文
  • Publisher: 総合医学社
• [Book] Islet Equality、膵島機能研究のアップデート第2回 (2011)
  • Author(s): 加計正文、吉田昌史、大和志保
  • Publisher: メディカルレビュー社