Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives

Diabetes. 2006 May;55(5):1443-9. doi: 10.2337/db05-1593.

Abstract

Zonulin, a protein that modulates intestinal permeability, is upregulated in several autoimmune diseases and is involved in the pathogenesis of autoimmune diabetes in the BB/Wor animal model of the disease. To verify the association between serum zonulin levels and in vivo intestinal permeability in patients with type 1 diabetes, both parameters were investigated in different stages of the autoimmune process. Forty-two percent (141 of 339) of the patients had abnormal serum zonulin levels, as compared with age-matched control subjects. The increased zonulin levels correlated with increased intestinal permeability in vivo and changes in claudin-1, claudin-2, and myosin IXB genes expression, while no changes were detected in ZO1 and occludin genes expression. When tested in serum samples collected during the pre-type 1 diabetes phase, elevated serum zonulin was detected in 70% of subjects and preceded by 3.5 +/- 0.9 years the onset of the disease in those patients who went on to develop type 1 diabetes. Combined, these results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of type 1 diabetic patients. Zonulin upregulation seems to precede the onset of the disease, providing a possible link between increased intestinal permeability, environmental exposure to non-self antigens, and the development of autoimmunity in genetically susceptible individuals.

MeSH terms

  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / physiopathology
  • Cholera Toxin / genetics
  • Cholera Toxin / pharmacokinetics*
  • Claudin-1
  • Claudins
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / physiopathology*
  • Family
  • Genetic Predisposition to Disease
  • Humans
  • Intestines / drug effects
  • Intestines / physiopathology*
  • Membrane Proteins / genetics
  • Occludin
  • Permeability / drug effects*

Substances

  • CLDN1 protein, human
  • CLDN2 protein, human
  • Claudin-1
  • Claudins
  • Membrane Proteins
  • OCLN protein, human
  • Occludin
  • zonulin
  • Cholera Toxin