Investigation of the mechanism of pancreatic beta-cell death underlying progressive nature of type 2 diabetes mellitus, aiming at the development of treatment strategy for the disease condition.
| Project/Area Number |
20390093
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pathological medical chemistry
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| Research Institution | Yamaguchi University |
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Principal Investigator |
TANIZAWA Yukio Yamaguchi University, 大学院・医学系研究科, 教授 (00217142)
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| Co-Investigator(Kenkyū-buntansha) |
OTA Yasuhru 山口大学, 医学部・附属病院, 講師 (60448280)
EMOTO Masahiro 山口大学, 医学部, 准教授 (50294640)
YUJIRI Toshiharu 山口大学, 大学院・医学系研究科, 准教授 (80346551)
TAKEDA Koumei 山口大学, 医学部・附属病院, 助教 (60467793)
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| Project Period (FY) |
2008 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥19,630,000 (Direct Cost: ¥15,100,000、Indirect Cost: ¥4,530,000)
Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2009: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2008: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
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| Keywords | Wolfram症候群 / 膵β細胞 / インスリン分泌 / 糖尿病 / 視神経萎縮 / 小胞体ストレス / エクソサイトーシス / インスリン / 分泌顆粒 / pioglitazone |
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| Research Abstract |
WFS1 gene, responsible for the Wolfram syndrome, also determines the susceptibility to type 2 diabetes. WFS1 protein localizes to the endoplasmic reticulum. Absence of WFS1 protein induce ER stress in β-cells, and β-cells lacking WFS1 protein is susceptible to the ER stress-induced apoptosis. In Wfs1^<-/-> mice, β-cell apoptosis is accelerated because of increased ER stress. Pioglitazone protects β cell from apoptosis by reducing systemic insulin resistance and ER stress in the β-cells. In addition, pioglitazone directly induced adrenomedullin expression in the β-cells, playing a role in this β-cell protection.
In pancreatic β-cells, WFS1 protein also exists in the insulin secretory granules, and play crucial roles in the maintenance of acidic milieu inside the granules. Intra-granular acidification is reported to be necessary for the "priming" of the granule for the exocytosis. In Wfs1^<-/-> mice, glucose-induced insulin secretion is impaired in the early stage before the β cell number is decreased. Roles of WFS1 protein in the secretory granules need to be further investigated.
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Report
(4 results)
Research Products
(86 results)
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[Journal Article] Glucose and Fatty Acids Synergize to Promote β-Cell Apoptosis through Activation of Glycogen Synthase Kinase 3β Independent of JNK Activation.2011
Author(s)
Tanabe K, Liu Y, Hasan SD, Martinez SC, Cras-Meneur C, Welling CM, Bernal-Mizrachi E, Tanizawa Y, Rhodes CJ, Zmuda E, Hai T, Abumrad NA, Permutt MA.
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Journal Title
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Peer Reviewed
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[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
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Journal Title
Diabetologia. 52
Pages: 653-663
Related Report
Peer Reviewed
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[Journal Article] Identification of Glypican3 as a novel GLUT4-binding protein.2008
Author(s)
Taguchi A, Emoto M, Okuya S, Fukuda N, Nakamori Y, Miyazaki M, Miyamoto S, Tanabe K, Aburatani H, Oka Y, Tanizawa Y
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Journal Title
Biochem Biophys Res Commun. 369
Pages: 1204-1208
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Peer Reviewed
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[Presentation] Wolfram Syndrome 1 Gene (wfs1) Product Localizes to Secretory Granule and Contributes to Maintenance of Granular Acidification in Pancreatic Beta Cells.2010
Author(s)
Hatanaka M., Tanabe K., Ohta Y., Yanai A., Akiyama M., Kondo M., Shinoda K., Oka Y.,Tanizawa Y.
Organizer
70th Annual Meeting and Scientific Sessions of the American Diabetes Association (Abstract A76P)
Place of Presentation
Orange Country Convention Center, Orlando, FL, USA.
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[Presentation] Wolfram Syndrome 1 Gene (wfs1) Product Localizes to Secretory Granule and Determines Acidification of Granule in Pancreatic Beta Cells.2009
Author(s)
Hatanaka M, Tanabe K, Ohta Y, Yanai A, Akiyama M, Kondo M, Shinoda, K Oka Y, Tanizawa Y
Organizer
The 15^h Korea-Japan Symposium onDiabetes Mellitus, (Abstract 167p)
Place of Presentation
International Convention Center Jeju, Jeju, Korea.
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[Presentation] Increased Insulin Demand Causes While Pioglitazone Prevents Pancreatic β-Cell Apoptosis in Wfs1 Knock-out Mice.2008
Author(s)
Akiyama M, Ueda K, Hatanaka M, Uehara Y, Yanai A, Tsuru M, Ohta Y, Miyazaki M, Saeki S, Saito T, Shinoda K, Oka Y, Tanizawa Y
Organizer
Keystone Symposia on Molecular and Cellular Biology, Islet Beta Cell Biology
Place of Presentation
Snowbird Resort, Snowbird, UT, USA
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