Mouse vanin-1 is cytoprotective for islet beta cells and regulates the development of type 1 diabetes

Diabetologia. 2008 Jul;51(7):1192-201. doi: 10.1007/s00125-008-1017-9. Epub 2008 May 8.

Abstract

Aims/hypothesis: Islet cell death is a key initiating and perpetuating event in type 1 diabetes and involves both immune-mediated and endogenous mechanisms. The epithelial pantetheinase vanin-1 is proinflammatory and cytoprotective via cysteamine release in some tissues. We investigated the impact of a vanin-1 deficiency on islet death and type 1 diabetes incidence.

Methods: Vanin-1-deficient mice were produced and tested in drug-induced and autoimmune diabetes models. The contribution of vanin-1 to islet survival versus immune responses was evaluated using lymphocyte transfer and islet culture experiments.

Results: The vanin-1/cysteamine pathway contributes to the protection of islet beta cells from streptozotocin-induced death in vitro and in vivo. Furthermore, vanin-1-deficient NOD mice showed a significant aggravation of diabetes, which depended upon loss of vanin-1 expression by host tissues. This increased islet fragility was accompanied by greater CD4+ insulitis without impairment of regulatory cells. Addition of cystamine, the product of pantetheinase activity, protected islets in vitro and compensated for vanin-1 deficiency in vivo.

Conclusions/interpretation: This study unravels a major cytoprotective role of cysteamine for islet cells and suggests that modulation of pantetheinase activity may offer alternative strategies to maintain islet cell homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases
  • Animals
  • Cell Adhesion Molecules / deficiency
  • Cell Adhesion Molecules / genetics*
  • Cell Adhesion Molecules / metabolism*
  • Cell Death / physiology
  • Cells, Cultured
  • Cystamine / pharmacology
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Experimental / prevention & control
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / pathology*
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • GPI-Linked Proteins
  • Homeostasis / physiology
  • Incidence
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology*
  • Kaplan-Meier Estimate
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, Mutant Strains
  • T-Lymphocytes, Regulatory / pathology
  • Th1 Cells / pathology

Substances

  • Cell Adhesion Molecules
  • Enzyme Inhibitors
  • GPI-Linked Proteins
  • Insulin
  • Amidohydrolases
  • pantetheinase
  • Cystamine