Molecular biology of pancreatic islet β cell proliferation and failure

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591051
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: OHSUGI Mitsuru The University of Tokyo, 医学部附属病院, 助教 (00420216)
• Co-Investigator(Renkei-kenkyūsha): KADOWAKI Takashi 東京大学, 医学部附属病院, 教授 (30185889) ; UEKI Kohjiro 東京大学, 医学部附属病院, 准教授 (00396714) ; KUBOTA Naoto 東京大学, 医学部附属病院, 特任 (50396719)
• Project Period (FY): 2008 – 2010
• Keywords: 膵β細胞 / IRS / CREB

Research Abstract

(1) High glucose levels or glucose stimulation predominantly control pancreatic β cell IRS-2 levels. (2) A transcription factor CREB is critical for regulating β cell IRS-2 expression levels. Calmodulin dependent kinase 4 is stimulated by glucose, and the kinase appears to be the key component of complex regulation of CREB activation in pancreatic β cells. (3) In models of pancreatic β cell failure, such as db/db mice, critical molecules of glucose sensing, including glucokinase and glucose transporter 2, are downregulated, thus leading to a net decrease in glucose flux to β cells. With resultant reduction in IRS-2 levels, pancreatic β cell lose a key component of adaptive β cell proliferation and survival.

Research Products

• [Journal Article] Class IA Phosphatidylinositol 3-Kinase in Pancreatic β Cells Controls Insulin Secretion by Multiple Mechanisms. (2010)
  • Author(s): Hashimoto S, Okamoto M, Awazawa M, Okazaki Y, Ohsugi M, Inabe K, Umehara T, Yoshida M, Kakei M, Kitamura T, Luo J, Kulkarni RN, Kahn CR, Kasai H, Cantley LC, Kadowaki T
  • Journal Title: Cell Metab. 12(6) Pages: 619-32
  • Peer Reviewed
• [Journal Article] Y, Ueki K, Kadowaki T (2010)
  • Author(s): Okazaki Y, Eto K, Yamashita T, Okamoto M, Ohsugi M, Noda M, Terauchi
  • Journal Title: Decreased Insulin Secretion and Accumulation of Triglyceride in beta Cells Overexpressing a Dominant-Negative Form of AMP-Activated Protein Kinase Endocr J. 57(2) Pages: 141-52
  • Peer Reviewed
• [Journal Article] CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. (2009)
  • Author(s): Nishimura S, Manabe I, Naga, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R
  • Journal Title: Nat. Med. 15(8) Pages: 914-20
  • Peer Reviewed
• [Journal Article] Reconsideration of Insulin Signals Induced by Improved Laboratory Animal Diets, Japanese and American Diets, in IRS-2 Deficient Mice. (2009)
  • Author(s): Hashimoto H, Arai T, Hikishima K, Ohnishi Y, Eto T, Ito M, Hioki K, Suzuki R, Ohsugi M, Saito M, Ueyama Y, Okano H, Yamauchi T, Kubota N, Ueki K, Tobe K, Tamaoki N, Kadowaki T, Kosaka K
  • Journal Title: Exp Clin Endocrinol Diabetes. 117(10) Pages: 577-86
  • Peer Reviewed
• [Journal Article] Rimonabant ameliorates insulin resistance via both adiponectin-dependent and adiponectin-independent pathways. (2009)
  • Author(s): Watanabe T, Kubota N, Kubota T, Takamoto I, Iwabu M, Awazawa M, Katsuyama H, Hasegawa C, Tokuyama K, Moroi M, Sugi K, Yamauchi T, Noda T, Nagai R, Terauchi Y, Tobe K, Ueki K, Kadowaki T
  • Journal Title: J Biol Chem. 284(3) Pages: 1803-12
  • Peer Reviewed
• [Journal Article] An Efficient Reproductive Method for Irs2(-/-) Mice with C57BL/6JJcl Genetic Background. (2008)
  • Author(s): Hashimoto H, Eto T, Kamisako T, Hoya N, Hatakeyama T, Arai T, Yokosuka M, Ohnishi Y, Ito M, Hioki K, Suzuki R, Ohsugi M, Saito M, Ueyama Y, Yamauchi T, Kubota N, Tobe K, Kadowaki T, Tamaoki N, Nomura T, Kosaka K
  • Journal Title: Exp Anim. 57 Pages: 407-11
  • Peer Reviewed
• [Journal Article] Crucial role of insulin receptor substrate-2 in compensatory beta-cell hyperplasia in response to high fat diet-induced insulin resistance. (2008)
  • Author(s): Takamoto I, Terauchi Y, Kubota N, Ohsugi M, Ueki K, Kadowaki T
  • Journal Title: Diabetes Obes Metab. 10(Suppl 4) Pages: 147-56
  • Peer Reviewed
• [Journal Article] Fulminant type 1 diabetes mellitus observed in insulin receptor substrate 2 deficient mice. (2008)
  • Author(s): Arai T, Hashimoto H, Kawai K, Mori A, Ohnishi Y, Hioki K, Ito M, Saito M, Ueyama Y, Ohsugi M, Suzuki R, Kubota N, Yamauchi T, Tobe K, Kadowaki T, Kosaka K
  • Journal Title: Clin Exp Med. 8 Pages: 93-9
  • Peer Reviewed
• [Journal Article] Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. (2008)
  • Author(s): Kubota N, Kubota T, Itoh S, Kumagai H, Kozono H, Takamoto I, Mineyama T, Ogata H, Tokuyama K, Ohsugi M, Sasako T, Moroi M, Sugi K, Kakuta S, Iwakura Y, Noda T, Ohnishi S, Nagai R, Tobe K, Terauchi Y, Ueki K, Kadowaki T
  • Journal Title: Cell Metab. 8(1) Pages: 49-64
  • Peer Reviewed
• [Journal Article] SUMOylation of Kruppel-like transcription factor 5 acts as a molecular switch in transcriptional programs of lipid metabolism involving PPAR-delta. (2008)
  • Author(s): Oishi Y, Manabe I, Tobe K, Ohsugi M, Kubota T, Fujiu K, Maemura K, Kubota N, Kadowaki T, Nagai R
  • Journal Title: Nat Med. 14(6) Pages: 656-66
  • Peer Reviewed
• [Presentation] 膵島IRS-2量調節の分子機構:肥満・糖尿病モデルにおけるIRS-2量 (2010)
  • Author(s): 勝山修行、大杉満、窪田直人、植木浩二郎、門脇孝
  • Organizer: 第3回日本肥満症治療学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2010-09-11
• [Presentation] 膵島IRS-2量調節の分子機構:分子メカニズム (2010)
  • Author(s): 大杉満、勝山修行、窪田直人、植木浩二郎、門脇孝
  • Organizer: 第3回日本肥満症治療学会学術集会
  • Place of Presentation: 東京(口頭発表)
  • Year and Date: 2010-09-11
• [Presentation] 膵島IRS-2量調節の分子機構1:肥満・糖尿病モデルにおけるIRS-2量 (2010)
  • Author(s): 勝山修行、大杉満、窪田直人、植木浩二郎、門脇孝
  • Organizer: 第53回日本糖尿病学会学術総会
  • Place of Presentation: 岡山(口頭発表)
  • Year and Date: 2010-05-27
• [Presentation] 膵島IRS-2量調節の分子機構2:分子メカニズム (2010)
  • Author(s): 大杉満、勝山修行、窪田直人、植木浩二郎、門脇孝
  • Organizer: 第53回日本糖尿病学会学術総会
  • Place of Presentation: 岡山(口頭発表)
  • Year and Date: 2010-05-27
• [Presentation] 膵島代償性増殖とその破綻における膵島IRS-2量調節の分子機構 (2009)
  • Author(s): 大杉満、窪田直人、小林正稔、笹子敬洋、金子和真、勝山修行、植木浩二郎、門脇孝
  • Organizer: 第59回日本体質医学会総会
  • Place of Presentation: 東京(口頭発表)
  • Year and Date: 2009-07-26
• [Presentation] 膵島代償性増殖とその破綻における膵島IRS-2量調節の分子機構:CaMキナーゼ4転写因子CREBの役割 (2009)
  • Author(s): 大杉満、窪田直人、戸邉一之、小林正稔、笹子敬洋、金子和真、勝山修行、植木浩二郎、門脇孝
  • Organizer: 第52回日本糖尿病学会学術総会
  • Place of Presentation: 大阪(口頭発表)
  • Year and Date: 2009-05-22
• [Presentation] 膵島代償性増殖とその破綻における膵島IRS-2量調節の分子機構:糖代謝の重要性 (2009)
  • Author(s): 勝山修行、大杉満、窪田直人、戸邉一之、小林正稔、笹子敬洋、金子和真、植木浩二郎、門脇孝
  • Organizer: 第52回日本糖尿病学会学術総会
  • Place of Presentation: 大阪(口頭発表)
  • Year and Date: 2009-05-22
• [Presentation] GlucoseEB-IR Pathway isponsible for the Failure of Compensatory β Hyperplasia in the Pogression to Diabetes. (2008)
  • Author(s): Mitsuru Ohsugi, Naoto Kubota, Kohjiro Ueki, Takashi Kadowaki
  • Organizer: American Diabetes Association Annual Scientific Sessions
  • Place of Presentation: San Francisco, CA, USA(Oral Presentation)
  • Year and Date: 2008-06-06
• [Presentation] 膵β細胞の代償性増殖とその破綻におけるIRS-2の役割 (2008)
  • Author(s): 大杉満
  • Organizer: 第51回日本糖尿病学会学術総会
  • Place of Presentation: 東京(シンポジスト)
  • Year and Date: 2008-05-22