Investigation of novel diabetic medicine based on glucose toxicity

• Project/Area Number: 16K09770
• 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: Hideaki Kaneto 川崎医科大学, 医学部, 教授 (80448034)
• Co-Investigator(Kenkyū-buntansha): 小畑 淳史 川崎医科大学, 医学部, 助教 (10771298) ; 木村 友彦 川崎医科大学, 医学部, 助教 (50454830) ; 下田 将司 川崎医科大学, 医学部, 講師 (60388957)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膵β細胞 / ブドウ糖毒性 / インスリン遺伝子 / 転写因子 / 膵β細胞糖毒性 / 新規糖尿病治療薬 / インスリン転写因子 / インクレチン受容体 / SGLT2阻害薬 / 糖尿病

Outline of Final Research Achievements

Pancreatic beta-cells secrete insulin when blood glucose levels become high, but when beta-cells are chronically exposed to hyperglycemia, beta-cell function gradually deteriorates which is known as beta-cell glucose toxicity. In the diabetic state, nuclear expression levels of pancreatic transcription factors MafA and PDX-1 are decreased. In addition, it is known that overexpression of such transcription factor expression preserves beta-cell function in diabetic mice. In this study, we searched factors which directly increase MafA and/or PDX-1 expression levels, and found several potential factors inducing such transcription factors. We hope that such findings would lead to the development of new medicine for type 2 diabetes based upon the molecular mechanism for beta-cell glucose toxicity.

Academic Significance and Societal Importance of the Research Achievements

申請者らはインスリンの転写因子MafAやPDX-1の発現が糖尿病状態において低下すること、またそれがブドウ糖毒性と関連することを報告している。しかしながらこれらの転写因子の発現を増加させる因子がまだ報告されていないため、その検索は大変独創的と考えられる。また得られた結果は、膵β細胞機能障害の分子メカニズムをさらに明らかとするとともに、膵β細胞保護効果を有する薬剤の検索にも繋がり、基礎的研究としても、また臨床応用の観点からも極めて重要な検討であると考えられる。

Research Products

• [Journal Article] Vascular endothelial PDK1 plays pivotal roles for maintenance of pancreatic beta-cell mass and function in adult male mice. (2019)
  • Author(s): Obata A, Kimura T, Obata Y, Shimoda M, Kinoshita T, Kohara K, Okauchi S, Hirukawa H, Kamei S, Nakanishi S, Mune T, Kaku K, and Kaneto H.
  • Journal Title: Diabetologia Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic beta-cells in obese diabetic db/db mice: The earlier and longer, the better. (2018)
  • Author(s): Kimura T, Obata A, Shimoda M, Okauchi S, Kanda-Kimura Y, Nogami Y, Hirukawa H, Kohara K, Nakanishi S, Mune T, Kaku K, and Kaneto H.
  • Journal Title: Diabetes Obes. Metab. Volume: 20 Pages: 2442-2457
  • Peer Reviewed
• [Journal Article] Durability of protective effect of dulaglutide on pancreatic beta-cells in diabetic mice: GLP-1 receptor expression is not reduced at all even after long-term exposure to dulaglutide. (2018)
  • Author(s): Kimura T, Obata A, Shimoda M, Hirukawa H, Kanda-Kimura Y, Nogami Y, Kohara K, Nakanishi S, Mune T, Kaku K, and Kaneto H.
  • Journal Title: Diabetes Metab. Volume: 44 Pages: 250-260
  • Peer Reviewed
• [Journal Article] Pancreatic alpha-cells in diabetic rats express active GLP-1 receptor: Evidence for GLP-1 signaling that regulates intra-islet paracrine mechanism. (2018)
  • Author(s): Nakashima K, Kaneto H, Shimoda M, Kimura T, and Kaku K.
  • Journal Title: Scientific Rep. Volume: 1 Issue: 1 Pages: 1-14
  • DOI: 10.1038/s41598-018-21751-w
  • Peer Reviewed / Open Access
• [Journal Article] Increase of cortisol / ACTH ratio after chronic treatment with liraglutide in subjects with type 2 diabetes mellitus. (2017)
  • Author(s): Kamei S, Kaneto H, Tanabe A, Kinoshita T, Obata A, Kimura T, Hirukawa H, Tatsumi F, Shimoda M, Kohara K, Anno T, Nakanishi S, Mune T, and Kaku K.
  • Journal Title: Diabetes Metab Volume: 43 Issue: 4 Pages: 398-399
  • DOI: 10.1016/j.diabet.2017.01.008
  • Peer Reviewed / Open Access
• [Journal Article] Beneficial effects of SGLT2 inhibitors for preservation of pancreatic beta-cell function and reduction of insulin resistance. (2017)
  • Author(s): Kaneto H, Obata A, Kimura T, Shimoda M, Okauchi S, Shimo N, Matsuoka T, and Kaku K.
  • Journal Title: J. Diabetes Volume: 9 Issue: 3 Pages: 219-225
  • DOI: 10.1111/1753-0407.12494
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Promising diabetes therapy based on the molecular mechanism for glucose toxicity: Usefulness of SGLT2 inhibitors as well as incretin-related drugs. (2016)
  • Author(s): Kaneto H, Obata A, Shimoda M, Kimura T, Hirukawa H, Okauchi S, Matsuoka T, and Kaku K.
  • Journal Title: Curr. Med. Chem. Volume: 23 Pages: 3044-3051
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinical effects of liraglutide are possibly influenced by hypertriglyceridemia and remaining pancreatic beta-cell function in subjects with type 2 diabetes mellitus. (2016)
  • Author(s): Tanabe A, Kaneto H, Kamei S, Hirukawa H, Shimoda M, Kimura T, Obata A, Okauchi S, Tatsumi F, Kohara K, Mune T, and Kaku K.
  • Journal Title: J. Diabetes Complications Volume: 30 Pages: 1201-1203
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
• [Presentation] 2型糖尿病の病態および治療に関するトピックス (2018)
  • Author(s): 金藤 秀明
  • Organizer: 日本糖尿病学会中四国地方会第56回総会
• [Presentation] 糖尿病における早期治療の重要性 (2018)
  • Author(s): 金藤 秀明
  • Organizer: 第36回 日本肥満症治療学会学術集会
• [Presentation] Lipotoxicity (2018)
  • Author(s): 金藤 秀明
  • Organizer: 第61回日本糖尿病学会年次学術集会
• [Presentation] ２型糖尿病の病態と治療に関するトピックス (2018)
  • Author(s): 金藤 秀明
  • Organizer: 第21回日本病態栄養学会年次学術集会