Molecular mechanisms of pancreaticβ-cell failure and insulin resistance due to impaired ER stress response

• Project/Area Number: 21591147
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Nihon University
• Principal Investigator: ISHIHARA Hisamitsu 日本大学, 医学部, 教授 (60361086)
• Co-Investigator(Kenkyū-buntansha): OKAMOTO Mayumi 日本大学, 医学部, 講師 (80349993)
• Co-Investigator(Renkei-kenkyūsha): YAMAGUCHI Suguru 日本大学, 医学部, 助教 (70451614) ; SAGAWA Chigako 日本大学, 医学部, 助子 (30459896)
• Project Period (FY): 2009 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2011: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2010: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2009: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 糖尿病 / 膵島 / シグナル伝達 / 膵ランゲルハンス島 / インスリン抵抗性

Research Abstract

Dysfunction of endoplasmic reticulum(ER) is suggested to be a cause of a variety of diseases. ATF6α is an important molecule to maintain ER homeostasis. We have analyzed ATF6α-null mice fed with a high fat diet. ER dysfunction has been revealed to be involved in impaired insulin secretion and insulin resistance. Furthermore, we have identified novel genes responsive to ER stress in the pancreatic beta cells.

Research Products

• [Journal Article] Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance (2012)
  • Author(s): M.Usui, S.Yamaguchi, Y.Tanji, R.Tominaga, Y.Ishigaki, M.Fukumoto, H.Katagiri, K.Mori, Y.Oka, H.Ishihara
  • Journal Title: Metabol Volume: (in press) Issue: 8 Pages: 1118-28
  • DOI: 10.1016/j.metabol.2012.01.004
  • Peer Reviewed
• [Journal Article] Hepatic nuclear factor 1alpha(HNF1alpha) dysfunction down-regulates X-box-binding protein 1(XBP1) and sensitizes beta-cells to endoplasmic reticulum stress (2011)
  • Author(s): Kirkpatrick CL, Wiederkehr A, BaquieM, Akhmedov D, Wang H, Gauthier BR, Akerman I, Ishihara H, Ferrer J, Wollheim CB
  • Journal Title: J Biol Chem Volume: 286 Issue: 37 Pages: 323000-32312
  • DOI: 10.1074/jbc.m111.247866
  • Peer Reviewed
• [Journal Article] Involvement of endoplasmic stress protein C/EBP homologous protein in arteriosclerosis acceleration with augmented biological stress responses (2011)
  • Author(s): Gao J, Ishigaki Y, Yamada T, Kondo K, Yamaguchi S, Imai J, Uno K, HasegawaY, Sawada S, Ishihara H, Oyadomari S, Mori M, Oka Y, Katagiri H
  • Journal Title: Circulation Volume: 124 Issue: 7 Pages: 830
  • DOI: 10.1161/circulationaha.110.014050
  • Peer Reviewed
• [Journal Article] Interleukin-6 enhances glucose-stimulated insulin secretion from pancreatic β-cells: Potential involvement of the PLC-IP₃-dependent pathway (2011)
  • Author(s): Suzuki T, Imai J, Yamada T, IshigakiY, Kaneko K, Uno K, Hasegawa Y, Ishihara H, Oka Y, Katagiri H
  • Journal Title: Diabetes Volume: 60 Issue: 2 Pages: 537
  • DOI: 10.2337/db10-0796
  • Peer Reviewed
• [Journal Article] Interleukin-6 enhances glucose stimulated insulin secretion from pancreatic β cells : potential involvement of the PLC-IP3-dependent pathway (2011)
  • Author(s): 鈴木俊伸
  • Journal Title: Diabetes Volume: 60 Pages: 537-547
  • Peer Reviewed
• [Journal Article] The JNK pathway modulates expression and phosphorylation of the translational suppressor 4E-BP1 in MIN6 pancreatic beta-cells under oxidative stress conditions (2010)
  • Author(s): Tominaga R, Yamaguchi S, Satake C, Usui M, Tanji Y, Kondo K, Katagiri H, Oka Y, Ishihara H
  • Journal Title: Cell Biochem Funct Volume: 28 Issue: 5 Pages: 387-393
  • DOI: 10.1002/cbf.1667
  • Peer Reviewed
• [Journal Article] Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells (2010)
  • Author(s): Fonseca SG, Ishigaki S, Oslowski CM, Lu S, Lipson KL, Ghosh R, Hayashi E, Ishihara H, Oka Y, Permutt MA, Urano F
  • Journal Title: J Clin Invest Volume: 120 Issue: 3 Pages: 744-755
  • DOI: 10.1172/jci39678
  • Peer Reviewed
• [Journal Article] The JNK pathway modulates expression and phosphorylation of the translational suppressor 4E-BP1 in MIN6 pancreatic β-cells under oxidative stress conditions (2010)
  • Author(s): 富永竜
  • Journal Title: Cell Biochemistry and Function Volume: 28 Pages: 387-393
  • Peer Reviewed
• [Journal Article] Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells (2010)
  • Author(s): Sonya G.Fonseca
  • Journal Title: Journal Clinical Investigations 120 Pages: 744-755
  • Peer Reviewed
• [Journal Article] The JNK pathway modulates expression and phosphorylation of the translational suppressor 4E-BP1 in MIN6 pancreatic β-cells under oxidative stress conditions (2010)
  • Author(s): 富永竜
  • Journal Title: Cell Biochemistry and Function 未定(印刷中)
  • Peer Reviewed
• [Journal Article] Carotid arterial elasticity is a sensitive atherosclerosis value reflecting visceral fat accumulation in obese subjects (2009)
  • Author(s): Tokita A, Ishigaki Y, Okimoto H, Hasegawa H, Koiwa Y, Kato M, Ishihara H, Hinokio Y, Katagiri H, Kanai H, Oka Y
  • Journal Title: Atherosclerosis Volume: 206 Pages: 168-172
  • Peer Reviewed
• [Journal Article] Carotid arterial elasticity is a sensitive atherosclerosis value reflecting visceral fat accumulation in obese subjects (2009)
  • Author(s): 鴇田藍
  • Journal Title: Atherosclerosis 206 Pages: 168-172
  • Peer Reviewed
• [Presentation] Therapeutic strategy fortype 2 diabetes mellitus based on physiology of islet hormone secretion (2011)
  • Author(s): Ishihara H
  • Organizer: The 16^<th> Japan-Korea symposium on diabetes mellitus
  • Place of Presentation: 浦安市
  • Year and Date: 2011-10-21
• [Presentation] Therapeutic strategy for type 2 diabetes mellitus based on physiology of islet hormone secretion (2011)
  • Author(s): 石原寿光
  • Organizer: The 16^<th> Japan-Korea symposium on diabetes mellitus
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2011-10-21
• [Presentation] Zcchc12/Sizn1 is a novel ER stress-responsive gene expressed in the pancreatic beta cell (2011)
  • Author(s): Ishihara H
  • Organizer: The 47^<th> European association for study of diabetes annual meeting
  • Place of Presentation: Lisbon, Spain
  • Year and Date: 2011-09-14
• [Presentation] ATF6α deletion accelerates beta cell loss but improves insulin sensitivity in mice (2011)
  • Author(s): Usui M
  • Organizer: The 71^<st> Scientific sessions of American diabetes association
  • Place of Presentation: SanDiego, U. S. A.
  • Year and Date: 2011-06-25
• [Presentation] Transcriptional and tran slational control in adaptive stress responses in pancreatic beta cells (2011)
  • Author(s): Ishihara H
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2011-05-27
• [Presentation] 糖尿病とがん (2011)
  • Author(s): 石原寿光
  • Organizer: 第50回日本消化器がん検診学会総会
  • Place of Presentation: 東京
  • Year and Date: 2011-05-22
• [Presentation] 糖尿病とがん (2011)
  • Author(s): 石原寿光
  • Organizer: 第50回日本消化器がん検診学会総会
  • Place of Presentation: 東京(招待講演)
  • Year and Date: 2011-05-22
• [Presentation] ATF6α欠損マウスを用いたATF6α欠損が耐糖能に与える影響についての検討 (2011)
  • Author(s): 薄井正寛
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2011-05-21
• [Presentation] WFS1遺伝子欠損マウスにおけるDPP-4阻害薬(vildagliptin)の膵β細胞保護効果の検討 (2011)
  • Author(s): 丹治泰裕
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2011-05-20
• [Presentation] インスリン治療のup to date (2011)
  • Author(s): 石原寿光
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2011-05-20
• [Presentation] インスリン治療のup to date (2011)
  • Author(s): 石原寿光
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市(招待講演)
  • Year and Date: 2011-05-20
• [Presentation] ATF6α欠損マウスを用いた、ATF6α欠損が耐糖能に与える影響についての検討 (2011)
  • Author(s): 薄井正寛
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 札幌市
  • Year and Date: 2011-05-20
• [Presentation] インスリン・グルカゴン分泌機構からみた2型糖尿病治療 (2011)
  • Author(s): 石原寿光
  • Organizer: 第45回糖尿病学の進歩
  • Place of Presentation: 福岡市
  • Year and Date: 2011-02-18
• [Presentation] インスリン・グルカゴン分泌機構からみた2型糖尿病治療 (2011)
  • Author(s): 石原寿光
  • Organizer: 糖尿病学の進歩
  • Place of Presentation: 福岡市
  • Year and Date: 2011-02-18
• [Presentation] ATF6α deletion accelerates β cell loss but improves insulin sensitivity in mice (2011)
  • Author(s): 薄井正寛
  • Organizer: The 71^<st> Scientific sessions of American diabetes association
  • Place of Presentation: SanDiego
• [Presentation] Zcchc12/Sizn1 is a novel ER stress-responsive gene expressed in the pancreatic beta cell (2011)
  • Author(s): 石原寿光
  • Organizer: The 47^<th> European Association for study of diabetes annual meeting
  • Place of Presentation: Lisbon
• [Presentation] Translational and transcriptional regulation of stress responses in glucose homeostasis (2010)
  • Author(s): Ishihara H
  • Organizer: 第33回日本分子生物学会総会
  • Place of Presentation: 神戸市
  • Year and Date: 2010-12-09
• [Presentation] Translational and Transcriptional Regulation of Stress Responses in Glucose Homeostasis (2010)
  • Author(s): 石原寿光
  • Organizer: 日本分子生物学会総会
  • Place of Presentation: 神戸市
  • Year and Date: 2010-12-09
• [Presentation] Cell type-specific trans criptional regulation of 4E-BP1 under ER stress in MIN6 beta-cells (2010)
  • Author(s): Ishihara H
  • Organizer: The 46^<th> European association for study of diabetes annual meeting
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2010-09-22
• [Presentation] Cell type-specific transcriptional regulation of 4E-BP1 under ER stress in MIN6 beta cells (2010)
  • Author(s): 石原寿光
  • Organizer: European Association for Study of Diabetes
  • Place of Presentation: Stockholm
  • Year and Date: 2010-09-22
• [Presentation] 膵β細胞における小胞体ストレス応答と酸化ストレス応答のクロストーク (2010)
  • Author(s): 富永竜
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-05-28
• [Presentation] 新規小胞体ストレス蛋白CRELD2の蛋白特性についての検討 (2010)
  • Author(s): 山口賢
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-05-28
• [Presentation] Transcriptional and translational control in adaptive stress responses in pancreatic β cells (2010)
  • Author(s): 石原寿光
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-05-28
• [Presentation] 新規小胞体ストレス蛋白・CRELD2の蛋白特性についての検討 (2010)
  • Author(s): 山口賢
  • Organizer: 第53回日本糖尿病学会年次学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2010-05-28
• [Presentation] Transcriptional and tran slational regulation in adaptive res ponses to environmental stress in pancreatic beta cells (2010)
  • Author(s): Ishihara H
  • Organizer: The official satellite symposium of the 14th international congress of endocrinology "New insight into pathogenesis and treatment of diabetes"
  • Place of Presentation: 東京
  • Year and Date: 2010-03-25
• [Presentation] Transcriptional and Translational regulation in Adaptive Responses to Environmental stress in Pancreatic β Cells (2010)
  • Author(s): 石原寿光
  • Organizer: The Official Satellite Symposium of the 14th International Congress of Endocrinology "New Insight into Pathogenesis and Treatment of Diabetes"
  • Place of Presentation: 東京
  • Year and Date: 2010-03-25
• [Presentation] 2型糖尿病の病態形成におけるインスリン分泌機構の障害 (2010)
  • Author(s): 石原寿光
  • Organizer: 第44回糖尿病学の進歩
  • Place of Presentation: 大阪市
  • Year and Date: 2010-03-06
• [Presentation] 膵β細胞におけるATF6αの役割: ATF6α欠損マウスを用いた検討 (2009)
  • Author(s): 薄井正寛
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2009-05-22
• [Presentation] 動脈硬化発症・進展におけるCHOPの役割の検討 (2009)
  • Author(s): 高俊弘
  • Organizer: 第54回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2009-05-22
• [Presentation] 加齢・老化と膵β細胞ストレス応答 (2009)
  • Author(s): 石原寿光
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2009-05-22
• [Presentation] Lilly賞受賞講演: 2型糖尿病発症における膵β細胞障害の分子機構 (2009)
  • Author(s): 石原寿光
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2009-05-22
• [Remarks]
  • URL: http://www.med.nihon-u.ac.jp/department/dmet
• [Remarks]
  • URL: http://www.med.nihon-u.ac.jp/department/dmet/
• [Remarks]
  • URL: http://www.med.nihon-u.ae.jp/department/dmet/