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Endoplasmic Reticulum Stress and the Development of Diabetes

A Review

  1. Heather P. Harding and
  2. David Ron
  1. Skirball Institute, New York University School of Medicine, New York, New York

    Abstract

    The early steps of insulin biosynthesis occur in the endoplasmic reticulum (ER), and the β-cell has a highly developed and active ER. All cells regulate the capacity of their ER to fold and process client proteins and they adapt to an imbalance between client protein load and folding capacity (so-called ER stress). Mutations affecting the ER stress-activated pancreatic ER kinase (PERK) and its downstream effector, the translation initiation complex eukaryotic initiation factor 2 (eIF2), have a profound impact on islet cell development, function, and survival. PERK mutations are associated with the Wolcott-Rallison syndrome of infantile diabetes and mutations that prevent the α-subunit of eIF2 from being phosphorylated by PERK, block β-cell development, and impair gluconeogenesis. We will review this and other rare forms of clinical and experimental diabetes and consider the role of ER stress in the development of more common forms of the disease.

    Footnotes

    • Address correspondence and reprint requests to David Ron, Skirball Institute 3-10, 540 First Ave., New York, NY 10016. E-mail: ron{at}saturn.med.nyu.edu.

      Received for publication 7 March 2002 and accepted in revised form 21 May 2002.

      ATF, activating transcription factor; eIF2, eukaryotic initiation factor 2; ER, endoplasmic reticulum; GCN2, general control non-depressed 2; ISR, integrated stress response; MHC, major histocompatibility complex; PERK, pancreatic ER kinase; SREBP, sterol regulatory element binding protein; TRAF2, tumor necrosis factor receptor-associated factor 2; XBP-1, X-box binding protein 1.

      The symposium and the publication of this article have been made possible by an unrestricted educational grant from Servier, Paris.

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