Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

J Clin Invest. 2012 Jan;122(1):132-41. doi: 10.1172/JCI46177. Epub 2011 Dec 19.

Abstract

The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing β cells. Although T cell dependent, the molecular mechanisms triggering β cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for β cell survival. In vitro, β cells rapidly lost their HS and died. β Cell death was prevented by HS replacement, a treatment that also rendered the β cells resistant to damage from ROS. In vivo, autoimmune destruction of islets in NOD mice was associated with production of catalytically active heparanase, an HS-degrading enzyme, by islet-infiltrating MNCs and loss of islet HS. Furthermore, in vivo treatment with the heparanase inhibitor PI-88 preserved intraislet HS and protected NOD mice from T1D. Our results identified HS as a critical molecular requirement for islet β cell survival and HS degradation as a mechanism for β cell destruction. Our findings suggest that preservation of islet HS could be a therapeutic strategy for preventing T1D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / immunology
  • Cell Survival / physiology
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / pathology
  • Female
  • Glucuronidase / antagonists & inhibitors
  • Glucuronidase / metabolism*
  • Heparitin Sulfate / metabolism*
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • Heparitin Sulfate
  • heparanase
  • Glucuronidase