Molecular mechanism for pancreatic beta-cell glucose toxicity

• Project/Area Number: 24591327
• 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 (2013-2014); Osaka University (2012)
• Principal Investigator: HIDEAKI Kaneto 川崎医科大学, 医学部, 教授 (80448034)
• Co-Investigator(Kenkyū-buntansha): MATSUOKA Taka-aki 大阪大学, 医学系研究科, 講師 (10379258) ; MIYATSUKA Takeshi 大阪大学, 医学系研究科, 講師 (60622363)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 膵β細胞機能 / 糖尿病 / 膵β細胞

Outline of Final Research Achievements

It is well known that pancreatic transcription factor PDX-1 plays a crucial role in maintenance of pancreatic beta-cell function but that its expression level is decreased under diabetic conditions. We made beta-cell-specific PDX-1 overexpressing transgenic mice. As the results, such PDX-1 overexpresion ameliorated glycemic control in diabetic Akita mice.
It is also known that incretins (GLP-1 and GIP) play a crucial role in maintenance of beta-cell function but that GLP-1 and GIP receptor levels are decreased. We made beta-cell-specific GLP-1 receptor overexpressing transgenic mice. As the results, such GLP-1 receptor overexpresion augmented exendin-4-mediated insulin secretion in diabetic db/db mice.

Research Products

• [Journal Article] Protective effects of pioglitazone and/or liraglutide on pancreatic beta-cells: 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 M, Kaku K.
  • Journal Title: Mol. Cell. Endocrinol. Volume: 400 Pages: 78-89
  • Peer Reviewed / Open Access
• [Journal Article] Preserving MafA expression in diabetic islet beta-cells improves glycemic control in vivo. (2015)
  • Author(s): Matsuoka T, Kaneto H, Kawashima S, Miyatsuka T, Tochino Y, Yoshikawa A, Imagawa A, Miyazaki J, Gannon M, Stein R, Shimomura I.
  • Journal Title: J. Biol. Chem. Volume: 290 Pages: 7647-7657
  • Peer Reviewed / Open Access
• [Journal Article] Role of pancreatic transcription factors in maintenance of mature beta-cell function. (2015)
  • Author(s): Kaneto H, Matsuoka T
  • Journal Title: Int. J. Mol. Sci Volume: 16 Pages: 6281-6297
  • Peer Reviewed / Open Access
• [Journal Article] Pancreatic beta-cell glucose toxicity in type 2 diabetes mellitus. (2015)
  • Author(s): Kaneto H
  • Journal Title: Curr. Diabetes Rev. Volume: 11 Pages: 2-6
  • Peer Reviewed / Open Access
• [Journal Article] Molecular mechanism for pancreatic beta-cell glucose toxicity: Down-regulation of insulin gene transcription factors and incretin receptors. (2013)
  • Author(s): Kaneto, H. and Matsuoka, T.
  • Journal Title: World J. Diabetes Volume: 15 Pages: 263-269
  • Peer Reviewed
• [Journal Article] A novel function of Onecut 1 as a negative regulator of MafA. (2013)
  • Author(s): Yamamoto, K., Matsuoka, T., Kawashima, S., Takebe, S., Kubo, N., Miyatsuka, T., Kaneto, H., and Shimomura, I.
  • Journal Title: J. Biol. Chem. Volume: 288 Pages: 21648-21658
  • Peer Reviewed
• [Journal Article] Involvement of oxidative stress in suppression of insulin biosynthesis under diabetic conditions. (2012)
  • Author(s): Kaneto, H. and Matsuoka, T.
  • Journal Title: Int. J. Mol. Sci. Volume: 13 Pages: 13680-13690
  • Peer Reviewed