Effect of metformin on pancreatic beta cells

• Project/Area Number: 17K16152
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Yokohama City University
• Principal Investigator: TAJIMA Kazuki 横浜市立大学, 医学研究科, 客員研究員 (00725236)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: メトホルミン / 膵β細胞 / 糖尿病

Outline of Final Research Achievements

The effect of metformin on the pancreatic beta cells under hyperglycemic or endoplasmic reticulum stress conditions were analyzed using high-fat fed mice and pancreatic beta cell lines. Metformin suppressed the compensatory beta cell proliferation in short-term high-fat fed mice, which did not exhibit insulin resistance. Metformin repressed the beta cell proliferation induced by high glucose. Metformin induced the phosphorylation of AMPK and reduced the mTOR signal. Metformin suppressed the apoptosis in beta cells induced by tapsigargin and metformin reduced the translation initiation via 4EBP-1. These results suggested that metformin had protective effect on the pancreatic beta cells independent of the improvement of insulin resistance.

Academic Significance and Societal Importance of the Research Achievements

本研究で、メトホルミンによる、インスリン抵抗性とは独立した膵β細胞の保護機構を解明できれば、糖尿病発症前における早期治療の有効性など、糖尿病発症の抑制にもつながる。これは、経済面に多大な影響を及ぼしている糖尿病マネジメントにおいても、社会的な意義があると考えられる。さらには、メトホルミンによる保護機構を明らかにすることで、糖尿病の根本的治療となり得る膵β細胞量の制御機構の解明にも繋がることが期待できる。

Research Products

• [Journal Article] Signaling between pancreatic beta-cells and macrophages via S100 calcium-binding protein A8 exacerbates beta-cell apoptosis and islet inflammation. (2018)
  • Author(s): Inoue H, Shirakawa J, Togashi Y, Tajima K, Okuyama T, Kyohara M, Tanaka Y, Saisho Y, Yamada T, Shibue K, Kulkarni RN, Terauchi Y
  • Journal Title: The Journal of Biological Chemistry Volume: 293 Issue: 16 Pages: 5934-5946
  • DOI: 10.1074/jbc.m117.809228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of metformin on compensatory pancreatic β-cell hyperplasia in mice fed a high-fat diet. (2017)
  • Author(s): Tajima K, Shirakawa J, Okuyama T, Kyohara M, Yamazaki S, Togashi Y, Terauchi Y.
  • Journal Title: Am J Physiol Endocrinol Metab Volume: 313 Issue: 3 Pages: E367-E380
  • DOI: 10.1152/ajpendo.00447.2016
  • Peer Reviewed
• [Journal Article] Metabolic recovery of lipodystrophy, liver steatosis, and pancreatic β cell proliferation after the withdrawal of OSI-906 (2017)
  • Author(s): Tajima K, Shirakawa J, Togashi Y, Yamazaki S, Okuyama T, Kyohara M, Konishi H, Terauchi Y.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 4119-4119
  • DOI: 10.1038/s41598-017-04304-5
  • Peer Reviewed / Open Access
• [Presentation] メトホルミンは、インスリン抵抗性とは独立して、膵β細胞に保護的に作用する (2017)
  • Author(s): 田島一樹, 白川純, 富樫優, 寺内康夫
  • Organizer: 第31回日本糖尿病・肥満動物学会