Pancreatic β cell impairment and adaptation of type 2 diabetes mellitus in overnutrition era

• Project/Area Number: 19209034
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Tohoku University
• Principal Investigator: OKA Yoshitomo Tohoku University, 大学院・医学系研究科, 教授 (70175256)
• Co-Investigator(Kenkyū-buntansha): 石原 寿光 東北大学, 病院, 講師 (60361086) ; 石垣 泰 東北大学, 病院, 助教 (50375002) ; 山田 哲也 東北大学, 病院, 助教 (90400374)
• Co-Investigator(Renkei-kenkyūsha): ISHIHARA Hisamitsu 日本大学, 医学部・内科学系, 教授 (60361086) ; YAMADA Tetsuya 東北大学, 大学院・医学系研究科, 准教授 (90400374) ; ISHIGAKI Yasusi 東方大学, 病院, 講師 (50375002)
• Project Period (FY): 2007 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥49,660,000 (Direct Cost: ¥38,200,000、Indirect Cost: ¥11,460,000); Fiscal Year 2009: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2008: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2007: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
• Keywords: インスリン分泌 / 膵β細胞 / 小胞体ストレス / 再生治療 / 増殖

Research Abstract

Pancreatic β cell mass contributes to the development of diabetes. We show that induction of 4E-BP1 promotes β cell survival under ER stress. The Eif4ebp1 gene encoding 4E-BP1 was revealed to be a direct target of the transcription factor ATF4. We also found that hepatic activation of extracellular regulated kinase signaling induced pancreatic β cell proliferation through a neuronal-mediated relay of metabolic signals. Thus, inter-organ metabolic relay systems may serve as valuable targets in regenerative treatments for diabetes.

Research Products

• [Journal Article] Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice (2009)
  • Author(s): Akiyama M, Hatanaka M, Ohta Y, Ueda K, Yanai A, Uehara Y, Tanabe K, Tsuru M, Miyazaki M, Saeki S, Saito T, Shinoda K, Oka Y, Tanizawa Y.
  • Journal Title: Diabetologia 52(4) Pages: 653-663
  • 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 206 Pages: 168-172
  • Peer Reviewed
• [Journal Article] Circulating oxidized LDL-a biomarker and a pathogenic factor (2009)
  • Author(s): Ishigaki Y, Oka Y, Katagiri H.
  • Journal Title: Current Opinion in Lipidology 20 Pages: 363-369
  • Peer Reviewed
• [Journal Article] Eradication of insulin resistance (2009)
  • Author(s): Imai J, Yamada T, Saito T, Ishigaki Y, Hinokio Y, Kotake H, Oka Y, Katagiri H.
  • Journal Title: Lancet 374 Pages: 264-264
  • Peer Reviewed
• [Journal Article] Identification of a novel mechanism regulating βcell mass : Neuronal relay from the liver to pancreatic βcells (2009)
  • Author(s): Imai J, Oka Y, Katagiri H.
  • Journal Title: Islet 1 Pages: 75-77
  • Peer Reviewed
• [Journal Article] Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice (2009)
  • Author(s): Akiyama M, Hatanaka M, Ohta Y, Ueda K, Yanai A, Uehara Y, Tanabe K, Tsuru M, Miyazaki M, Saeki S, Saito T, Shinoda K, Oka Y, Tanizawa Y.
  • Journal Title: Diabetologia 52 Pages: 653-663
  • Peer Reviewed
• [Journal Article] Obesity Alters Circadian Expressions of Molecular Clock Genes in the Brainstem (2009)
  • Author(s): Kaneko K, Yamada T, Tsukita S, Takahashi K, Ishigaki Y, Oka Y, Katagiri H.
  • Journal Title: Brain Res 1263 Pages: 58-68
  • Peer Reviewed
• [Journal Article] Peginterferon (PEG-IFN) plus ribavirin combination therapy, but neither interferon nor PGE-IFN alone, induced type 1 diabetes in a patient with chronic hepatitis C. (2009)
  • Author(s): Ogihara T, Katagiri H, Yamada T, Kudo H, Imai J, Ishigaki Y, Hinokio Y, Yamagiwa Y, Ueno Y, Shimosegawa T, Oka Y.
  • Journal Title: Internal Medicine 48 Pages: 1387-1390
  • NAID: 130000122019
  • 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 206 Pages: 168-172
  • Peer Reviewed
• [Journal Article] Circulating oxidized LDL-a biomarker and a pathogenic factor. (2009)
  • Author(s): Ishigaki Y, Oka Y, Katagiri H
  • Journal Title: Current Opinion in Lipidology 20 Pages: 363-369
  • Peer Reviewed
• [Journal Article] Eradication of insulin resistance (2009)
  • Author(s): Imai J, Yamada T, Saito T, Ishigaki Y, Hinokio Y, Kotake H, Oka Y, Katagiri H
  • Journal Title: Lancet 374 Pages: 264-264
  • Peer Reviewed
• [Journal Article] Identification of a novel mechanism regulating sscell mass : Neuronal relay from the liver to pancreatic sscells. (2009)
  • Author(s): Imai J, Oka Y, Katagiri H
  • Journal Title: Islet 1 Pages: 75-77
  • Peer Reviewed
• [Journal Article] Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice. (2009)
  • Author(s): Akiyama M, Hatanaka M, Ohta Y, Ueda K, Yanai A, Uehara Y, Tanabe K, Tsuru M, Miyazaki M, Saeki S, Saito T, Shinoda K, Oka Y, Tanizawa Y
  • Journal Title: Diabetologia 52 Pages: 653-663
  • Peer Reviewed
• [Journal Article] Obesity Alters Circadian Expressions of Molecular Clock Genes in the Brainstem. (2009)
  • Author(s): Kaneko K, Yamada T, Tsukita S, Takahashi K, Ishigaki Y, Oka Y, Katagiri H
  • Journal Title: Brain Res 1263 Pages: 58-68
  • Peer Reviewed
• [Journal Article] Peginterferon(PEG-IFN)plus ribavirin combination therapy, but neither interferon nor PGE-IFN alone, induced type 1 diabetes in a patient with chronic hepatitis C. (2009)
  • Author(s): Ogihara T, Katagiri H, Yamada T, Kudo H, Imai J, Ishigaki Y, Hinokio Y, Yamagiwa Y, Ueno Y, Shimosegawa T, Oka Y.
  • Journal Title: Internal Medicine 48 Pages: 1387-1390
  • NAID: 130000122019
  • Peer Reviewed
• [Journal Article] Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfsl knockout mice (2009)
  • Author(s): Akiyama M, Hatanaka M, Ohta Y, Ueda K, Yanai A, Uehara Y, Tanabe K, Tsuru M, Miyazaki M, Saeki S, Saito T, Shinoda K, Oka Y, Tanizawa Y.
  • Journal Title: Diabetologia (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] ATF4-mediated induction of 4E-BP1 contributes to pancreatic β cell survival under endoplasmic reticulum stress (2008)
  • Author(s): Yamaguchi S, Ishihara H, Yamada T, Tamura A, Usui M, Tominaga R, Munakata Y, Satake C, Katagiri H, Tashiro F, Aburatani H, Tsukiyama-Kohara K, Miyazaki J, Sonenberg N, Oka Y.
  • Journal Title: Cell Metabolism 7 Pages: 269-276
  • Peer Reviewed
• [Journal Article] Behavioral and gene expression analyses of WFS1 knockout mice as apossible animal model of mood disorder (2008)
  • Author(s): Kato T, Ishiwata M, Yamada K, Kasahara T, Kakiuchi C, Iwamoto K, Kawamura K, Ishihara H, Oka Y.
  • Journal Title: Neuroscience Research 61 Pages: 143-158
  • Peer Reviewed
• [Journal Article] Impact of plasma oxidized low-density lipoprotein removal on atherosclerosis (2008)
  • Author(s): Ishigaki Y, Katagiri H, Gao J, Yamada T, Imai J, Uno K, Hasegawa Y, Kaneko K, Ogihara T, Ishihara H, Sato Y, Takikawa K, Nishimichi N, Matsuda H, Sawamura T, Oka Y.
  • Journal Title: Circulation 118 Pages: 75-83
  • Peer Reviewed
• [Journal Article] Regulation of pancreatic β cell mass by neuronal signals from the liver (2008)
  • Author(s): Imai J, Katagiri H, Yamada T, Ishigaki Y, Suzuki T, Kudo H, Uno K, Hasegawa Y, Gao J, Kaneko K, Ishihara H, Niijima A, Nakazato M, Asano T, Minokoshi Y, Oka Y.
  • Journal Title: Science 322 Pages: 1250-1254
  • Peer Reviewed
• [Journal Article] ATF4-mediated induction of 4E-BP1 contributes to pancreatic β cell survivalunder endoplasmic reticulum stress (2008)
  • Author(s): Yamaguchi S, Ishihara H, Yamada T, Tamura A, Usui M, Tominaga R, Munakata Y, Satake C, Katagiri H, Tasbiro F, Aburatani H, Tsukiyama-Kohara K, Miyazaki J, Sonenberg N, Oka Y.
  • Journal Title: Cell Metabolism 7 Pages: 269-76
  • Peer Reviewed
• [Journal Article] Inter-organ metabolic communication involved in energy homeostasis : potential therapeutic targets for obesity and metabolic syndrome (2008)
  • Author(s): Yamada T, Oka Y, Katagiri H
  • Journal Title: Pharmacol Ther 117 Pages: 188-98
  • Peer Reviewed
• [Journal Article] Regulation of pancreatic β cell mass by neuronal signals from the liver (2008)
  • Author(s): Imai J, Katagiri H, Yamada T, Ishigaki Y, Suzuki T, Kudo H, Uno K, Hasegawa Y, Gao J, Kaneko K, Ishihara H, Niijima A, Nakazato M, Asano T Minokoshi Y, Oka Y.
  • Journal Title: Science 322 Pages: 1250-1254
  • Peer Reviewed
• [Journal Article] Efficient and controlled gene expression in mouse pancreatic islets by arterial delivery of tetracycline-inducible adenoviral vectors (2007)
  • Author(s): Takahashi R, Ishihara H, Takahashi K, Tamura A, Yamaguchi S, Yamada T, Katagiri H, Oka Y.
  • Journal Title: J Mol Endocrinol 38 Pages: 127-136
  • Peer Reviewed
• [Journal Article] Involvement of apolipoprotein E in excess fat accumulation and insulin resistance (2007)
  • Author(s): Gao J, Katagiri H, Ishigaki Y, Yamada T, Ogihara T, Imai J, Uno K, Hasegawa Y, Kanzaki M, Yamamoto T, Ishibashi S, Oka Y.
  • Journal Title: Diabetes 56 Pages: 24-33
  • NAID: 10027299912
  • Peer Reviewed
• [Journal Article] Bone marrow (BM) transplantation promotes {beta} cell regeneration after acute injury through BM cell mobilization (2007)
  • Author(s): Hasegawa Y, Ogihara T, Yamada T, Ishigaki Y, Imai J, Uno K, Gao J, Kaneko K, Ishihara H, Sasano H, Nakauchi H, Oka Y, Katagiri H.
  • Journal Title: Endocrinology 148 Pages: 2006-2015
  • Peer Reviewed
• [Journal Article] Efficient and controlled gene expression in mouse pancreatic islets by arterial delivery of tetracycline-inducible adenoviral vectors (2007)
  • Author(s): Takahashi R, Ishihara H, Takahashi K, Tamura A, Yamaguchi S. Yamada T, Katagiri H, Oka Y.
  • Journal Title: J Mol Endocrinol 38 Pages: 127-136
  • Peer Reviewed
• [Presentation] (若手研究奨励賞審査講演) 肝臓におけるERK経路活性化は膵島再生を促進する (2009)
  • Author(s): 今井淳太, 片桐秀樹, 岡芳知
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 前橋
• [Presentation] 肝からの神経を介した, 肥満に伴う高血圧の発症機序 (2009)
  • Author(s): 宇野健司, 片桐秀樹, 山田哲也, 石垣泰, 今井淳太, 長谷川豊, 高俊弘, 金子慶三, 齋藤徳郎, 鈴木俊伸, 荻原健英, 岡芳知
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
• [Presentation] 肥満による延髄孤束核における概日リズムの変調 (2009)
  • Author(s): 金子慶三, 片桐秀樹, 山田哲也, 荻原健英, 石垣泰, 今井淳太, 宇野健司, 長谷川豊, 澤田正二郎, 高俊弘, 鈴木俊伸, 齋藤徳郎, 突田壮平, 高橋圭, 檜尾好徳, 岡芳知
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
• [Presentation] 自律神経を介した肝臓-膵β細胞連関による膵β細胞増殖機構 (2009)
  • Author(s): 今井淳太, 片桐秀樹, 荻原健英, 石垣泰, 山田哲也, 宇野健司, 長谷川豊, 高俊弘, 金子慶三, 鈴木俊伸, 齋藤徳郎, 突田壮平, 高橋圭, 檜尾好徳, 岡芳知
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
• [Presentation] 膵β細胞におけるATF6α欠損マウスを用いた検討 (2009)
  • Author(s): 薄井正寛, 石原寿光, 鈴木千登世, 近藤敬一, 丹治泰裕, 冨永竜, 佐竹千尋, 山口賢, 石垣泰, 檜尾好徳, 片桐秀樹, 森和俊, 岡芳知
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
• [Presentation] Obesity and Insulin Resistance Alter Circadian Expressions of Molecular Clock Genes in the Brainstem (2009)
  • Author(s): Keizo Kaneko, Tetsuya Yamada, Yoshitomo Oka, Hideki Katagiri
  • Organizer: 第69回米国糖尿病学会
  • Place of Presentation: ニューオーリンズ(アメリカ)
• [Presentation] 超音波測定による頸動脈血管弾性は内臓肥満に伴う早期動脈硬化を評価できる (2009)
  • Author(s): 石垣泰, 鴇田藍, 片桐秀樹, 岡芳知
  • Organizer: 第2回日本肥満症治療学会学術集会
  • Place of Presentation: 東京
• [Presentation] (若手研究奨励賞審査講演)肝臓におけるERK経路活性化は膵島再生を促進する (2009)
  • Author(s): 今井淳太, 片桐秀樹, 岡芳知
  • Organizer: 第82回日本内分泌学会学術総会
  • Place of Presentation: 前橋
• [Presentation] 肝からの神経を介した、肥満に伴う高血圧の発症機序 (2009)
  • Author(s): 宇野健司, 片桐秀樹, 山田哲也, 石垣泰, 今井淳太, 長谷川豊, 高俊弘, 金子慶三, 齋藤徳郎, 鈴木俊伸, 荻原健英, 岡芳知
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
• [Presentation] Obesity and Insulin Resistance Alter Circadian Expressions of Molecular Clock Genes in the Brainstem. (2009)
  • Author(s): Keizo Kaneko, Tetsuya Yamada, Yoshitomo Oka, Hideki Katagiri
  • Organizer: 第69回米国糖尿病学会
  • Place of Presentation: ニューオーリンズ(アメリカ)
• [Presentation] Arterial elasticity is a new parameter for evaluating atherosclerosis in subjects with visceral adiposity. (2009)
  • Author(s): Yasushi Ishigaki, Ai Tokita, Hisashi Okimoto, Hideyuki Hasegawa, Makoto Kato, Yoshinori Hinokio, Hideki Katagiri, Hiroshi Kanai, Yoshitomo Oka
  • Organizer: 第41回日本動脈硬化学会総会
  • Place of Presentation: 下関
• [Presentation] Role of CHOP in oxidative stress and vascular inflammation. (2009)
  • Author(s): Junhong Gao, Hideki Katagiri, Yasushi Ishigaki, Tetsuya Yamada, Shojiro Sawada, Hisamitsu Ishihara, Junta Imai, Kenji Uno, Yutaka Hasegawa, Suguru Yamaguchi, Yoshinori Hinokio, Masataka Mori, Yoshitomo Oka
  • Organizer: 第41回日本動脈硬化学会総会
  • Place of Presentation: 下関
• [Presentation] 膵β細胞量の調節におけるmRNA翻訳制御の役割 (2008)
  • Author(s): 石原寿光, 山口賢, 岡芳知
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] 肝からの神経を介した臓器間ネットワークとメタボリックシンドローム (2008)
  • Author(s): 宇野健司, 山田哲也, 岡芳知, 片桐秀樹
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] 動脈硬化発症・進展における小胞体ストレス応答の役割 (2008)
  • Author(s): 高俊弘, 片桐秀樹, 岡芳知, 他14名
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [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特徴 (2008)
  • Author(s): 冨永竜, 石原寿光, 岡芳知, 他6名
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] 翻訳抑制因子4E-BP1は小胞体ストレス応答転写因子ATF4の直接ターゲットである (2008)
  • Author(s): 佐竹千尋, 石原寿光, 岡芳知, 他6名
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] 翻訳抑制因子4E-BP1は、慢性的な小胞体ストレス下の膵β細胞において、翻訳抑制を介して細胞を保護する (2008)
  • Author(s): 山口賢, 石原寿光, 岡芳知, 他7名
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] インスリン抵抗性におけるCHOPの役割の検討 (2008)
  • Author(s): 石垣泰, 片桐秀樹, 岡芳知, 他14名
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] IL-6の持つ糖反応性インスリン分泌促進作用とそのメカニズムについて (2008)
  • Author(s): 鈴木俊伸, 今井淳太, 片桐秀樹, 荻原健英, 石垣泰, 山田哲也, 宇野健司, 長谷川豊, 澤田正二郎, 高俊弘, 金子慶三, 齋藤徳郎, 突田壮平, 高橋圭, 檜尾好徳, 岡芳知
  • Organizer: 第52回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪
• [Presentation] 肥満による血圧上昇・インスリン抵抗性における血管内皮細胞でのNF-κβシグナルの役割 (2008)
  • Author(s): 長谷川豊、片桐秀樹、岡芳知, 他13名
  • Organizer: 第51回日本糖尿病学会年次学術集会
  • Place of Presentation: 東京
• [Presentation] インスリン需要増大時の膵β細胞小胞体ストレスと細胞死-wfs1欠損マウスをモデルとした検討- (2007)
  • Author(s): 谷澤幸生, 秋山優, 幡中雅行, 植田浩平, 宮崎睦子, 岡芳知
  • Organizer: 第50回日本糖尿病学会年次学術集会
  • Place of Presentation: 仙台
• [Presentation] 翻訳抑制因子4E-BP1の欠損は、小胞体ストレスによる細胞障害を悪化させる (2007)
  • Author(s): 山口賢, 石原寿光, 田村明, 山田高弘, 佐竹千尋, 薄井正寛, 冨永竜, 檜尾好徳, 荻原健英, 鈴木進, 片桐秀樹, 岡芳知
  • Organizer: 第50回日本糖尿病学会年次学術集会
  • Place of Presentation: 仙台
• [Presentation] 膵β細胞における小胞体ストレスによる翻訳抑制因子4E-BP1発現誘導機構 (2007)
  • Author(s): 薄井正寛, 佐竹千尋, 石原寿光, 田村明, 山田高弘, 山口賢, 冨永竜, 宗像佑一郎, 檜尾好徳, 荻原健英, 鈴木進, 片桐秀樹, 岡芳知
  • Organizer: 第50回日本糖尿病学会年次学術集会
  • Place of Presentation: 仙台
• [Presentation] 膵β細胞特異的小胞体ストレス応答の検討 (2007)
  • Author(s): 宗像佑一郎, 石原寿光, 田村明, 山田高弘, 山口賢, 佐竹千尋, 薄井正寛, 冨永竜, 檜尾好徳, 荻原健英, 鈴木進, 片桐秀樹, 岡芳知
  • Organizer: 第50回日本糖尿病学会年次学術集会
  • Place of Presentation: 仙台
• [Presentation] The Translational Suppressor 4E-BP1 is a Critical Component of the ER Stress Response Involved in Component of the ER Stress Response Involved in Pancreatic b Cell Survival (2007)
  • Author(s): Hisamitsu Ishihara, Suguru Yamaguchi, Yoshitomo Oka
  • Organizer: 第50回日本糖尿病学会年次学術集会
  • Place of Presentation: 仙台
• [Patent(Industrial Property Rights)] Methood For Enhancing Pancreatic Beta Cell Proliferation, Increasing Serum Insulin Concentration, Decreasing Blood Glucose Concentration And Treating And/Or Preventing Diabetes (2008)
  • Inventor(s): 片桐秀樹, 岡芳知, 今井淳太
  • Industrial Property Rights Holder: 東北大学
  • Filing Date: 2008-07-01
• [Patent(Industrial Property Rights)] Methood For Enhancing Pancreatic Beta Cell Proliferation, Increasing Serum Insulin Concentration, Decreasing Blood Glucose Concentration And Treating And/Or Preventing Diabetes (2008)
  • Inventor(s): 片桐秀樹、岡芳知、今井淳太
  • Industrial Property Rights Holder: 東北大学
  • Filing Date: 2008-07-01