Molecular mechanisms for pancreatic beta cell failure・a viewpoint from endoplasmic reticulum stress

• Project/Area Number: 17390258
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Tohoku University
• Principal Investigator: OKA Yoshitomo Tohoku University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (70175256)
• Co-Investigator(Kenkyū-buntansha): ISHIHARA Hisamitsu Hospital, Lectured, 病院・講師 (60361086) ; ISHIGAKI Yasushi Hospital, Research Associate, 病院・助手 (50375002) ; TAMURA Akira Hospital, Research Associate, 病院・助手 (00375023)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥15,000,000 (Direct Cost: ¥15,000,000); Fiscal Year 2006: ¥6,700,000 (Direct Cost: ¥6,700,000); Fiscal Year 2005: ¥8,300,000 (Direct Cost: ¥8,300,000)
• Keywords: insulin secretion / pancreatic β cell / endoplasmic reticulum stress / 糖尿病 / WFS1 / 膵ラ島 / 小胞体カルシウム

Research Abstract

Wolfram syndrome, an autosomal recessive disorder associated with diabetes mellitus and optic atrophy is caused by mutations in the WFS1 gene encoding an endoplasmic reticulum (ER) membrane protein. Herein, we report that pancreatic islets of wfs1-deficient mice exhibit increases in PKR-like ER kinase phosphorylation, chaperone gene expressions and active XBP1 protein levels, indicating an enhanced ER stress response. We established wfs1-deficient MIN6 clonal (β-cells by crossing wfs1-deficient mice with mice expressing simian virus 40 large T antigen in β-cells. These cells show essentially the same alterations in ER stress responses as wfs1-deficient islets, which were reversed by re-expression of WFS1 protein or overexpression of GRP78, a master regulator of ER stress. In contrast, these changes are observed neither in heart, skeletal muscle, nor brown adipose tissues with WFS 1-deficiency. The enhanced ER stress results in increased caspase 3 cleavage and reduced BrdU incorporation in the mutant islets, indicating accelerated apoptotic processes and impaired cell cycle progression in the mutant islets. These changes are associated with increased expression of p21^<CIP1> in wfs1-deficient islets and clonal β-cells. Treatment of islets with thapsigargin, an ER stress inducer, caused upregulation of p21^<CIP1>, and forced expression of p21^<CIP1> resulted in reduction in reduced MIN6 β-cell numbers, suggesting that the ER stress-induced increase in p21^<CIP1> expression to be involved in β-cell loss in the mutant islets. These data indicate that WFS1-deficiency activates the ER stress response specifically in β-cells, causing β-cell loss through increased apoptosis and impaired cell cycle progression.

Research Products

• [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・1-2 Pages: 127-136
  • Description: 「研究成果報告書概要(和文)」より
• [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・1-2 Pages: 127-136
• [Journal Article] WFS1-deficiency enhances endoplasmic reticulum stress, triggers apoptotic pathway and impairs cell cycle progression specifically in pancreatic β-cells. (2006)
  • Author(s): Yamada T, Ishihara H, Tamura A, Takahashi R, Yamaguchi S, Takei D, Tokita A, Satake C, Tashiro F, Katagiri H, Aburatani H, Miyazaki J-I, Oka Y
  • Journal Title: Hum Mol Genet 15・10 Pages: 1600-1609
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum. (2006)
  • Author(s): Takei D, Ishihara H, Yamaguchi S, Yamada T, Tamura A, Katagiri H, Maruyama Y, Oka Y
  • Journal Title: FEBS Lett 580・24 Pages: 5635-5640
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] WFS1-deficiency enhances endoplasmic reticulum stress, triggers apoptotic pathway and impairs cell cycle progression specifically in pancreatic 13-cells. (2006)
  • Author(s): Yamada T, Ishihara H, Tamura A, Takahashi R, Yamaguchi S, Takei D, Tokita A, Satake C, Tashiro F, Katagiri H, Aburatani H, Miyazaki J-I, Oka Y.
  • Journal Title: Hum Mol Genet 15・10 Pages: 1600-1609
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum. (2006)
  • Author(s): Takei D, Ishihara H, Yamaguchi S, Yamada T, Tamura A, Katagiri H, Maruyama Y, Oka Y.
  • Journal Title: FEBS Lett 580・24 Pages: 5635-5640
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] WFS1 protein modulates the free Ca2+ concentration in the endoplasmic reticulum. (2006)
  • Author(s): Takei D, Ishihara H, Yamaguchi S, Yamada T, Tamura A, Katagiri H, Maruyama Y, Oka Y
  • Journal Title: FEBS Lett 580.24 Pages: 5635-5640
• [Journal Article] Cell type-specific activation of metabolism reveals that beta-cell secretion suppresses glucagon release from alpha-cells in rat pancreatic islets. (2006)
  • Author(s): Takahashi R, Ishihara H, Tamura A, Yamaguchi S, Yamada T, Takei D, Katagiri H, Endou H, Oka Y.
  • Journal Title: Am J Physiol Endocrinol Metab 290・2
• [Journal Article] Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic β-cells via transcriptional activation. (2005)
  • Author(s): Ueda K, Kawano J, Takeda K, Yujiri T, Tanabe K, Anno T, Akiyama M, Nozaki J, Yoshinaga T, Koizumi A, Shinoda K, Oka Y, Tanizawa Y.
  • Journal Title: Eur J Endocrinol. 153・1 Pages: 167-176
• [Journal Article] Constitutively active PDX1 induced efficient insulin production in adult murine liver. (2005)
  • Author(s): Imai J, Katagiri H, Yamada T, Ishigaki Y, Ogihara T, Uno K, Hasegawa Y, Ishihara H, Sasano H, Mizuguchi H, Asano T, Oka Y.
  • Journal Title: Biochem Biophys Res Commun 326・2 Pages: 402-409
• [Journal Article] Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population. (2005)
  • Author(s): Iwasaki N, Horikawa Y, Tsuchiya T, Kitamura Y, Takahiro Nakamura, Tanizawa Y, Oka Y, et al.
  • Journal Title: J Hum Genet. 50・2 Pages: 92-98
  • NAID: 10014513339
• [Journal Article] Dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated with obesity. (2005)
  • Author(s): Ishigaki Y, Katagiri H, Yamada T, Ogihara T, Imai J, Uno K, Hasegawa Y, Gao Junhong, Ishihara H, Shimosegawa T, Sakoda H, Asano T, Oka Y.
  • Journal Title: Diabetes 54・2 Pages: 322-332