Long-Term Pancreatic Beta Cell Exposure To High Levels of Glucose but not Palmitate induces DNA Methylation within the Insulin Gene Promoter and represses Transcriptional Activity

• Project/Area Number: 24790920
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Nagoya University
• Principal Investigator: TSUNEKAWA Shin 名古屋大学, 医学部附属病院, 助教 (40612768)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: エピジェネティクス / メチレーション / 糖毒性 / インスリン / 糖尿病

Outline of Final Research Achievements

Genetic and environmental factors influence the development of type 2 diabetes, and especially nutritional condition is a major component of environmental factor. Recently, DNA methylation of Insulin gene promoter has been reported to suppress insulin gene expression and be elevated in the subject with diabetes.
Our study demonstrated that under over-nutritional condition, glucotoxicity, but not lipotoxicity, was essential for DNA methylation of Insulin gene promoter as well as insulin expression in pancreatic beta cell. Glucotoxicity increased the DNA methylation in time- and glucose concentration- dependent manner. Glucotoxicity increased DNA methyltransferase activity and decreased ten-eleven-translocation hydroxylase activity. Ectopic triglyceride accumulation was increased parallel to DNA methylation by glucotoxicity in pancreatic beta cells. This study helps to clarify the effect of an over-nutrition state on DNA methylation of the Ins1 promoter in pancreatic beta cells.

Research Products

• [Journal Article] Long-Term Pancreatic Beta Cell Exposure to High Levels of Glucose but Not Palmitate Induces DNA Methylation within the Insulin Gene Promoter and Represses Transcriptional Activity. (2015)
  • Author(s): Ishikawa K, Tsunekawa S, Ikeniwa M, Izumoto T, Iida A, Ogata H, Uenishi E, Seino Y, Ozaki N, Sugimura Y, Hamada Y, Kuroda A, Shinjo K, Kondo Y, Oiso Y.
  • Journal Title: PLoS One Volume: 10(2) Issue: 2 Pages: e0115350-e0115350
  • DOI: 10.1371/journal.pone.0115350
  • NAID: 120006872353
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 膵β細胞における過剰栄養によるエピゲノム修飾の検討 (2013)
  • Author(s): 石川孝太、恒川新、清野祐介、上西栄太、泉本貴子、飯田淳史、尾方秀忠、藤谷淳、大川哲司、濱田洋司、大磯ユタカ
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本 (熊本市）
• [Presentation] Over-nutrition Increased DNA Methylation of Insulin Gene Promoter in Pancreatic Beta-Cells (2013)
  • Author(s): Kota Ishikawa, Shin Tsunekawa, Takako Izumoto, Atsushi Iida, Hidetada Ogata, Tetsuji Okawa, Atsushi Fujiya, Eita Uenishi, Yusuke Seino, Yoji Hamada, Yutaka Oiso
  • Organizer: America Diabetes Association 73rd Scientific Sessions
  • Place of Presentation: Chicago, USA