Increased Gut Permeability Precedes Type 1 Diabetes

Individuals with type 1 diabetes and their first-degree relatives have higher-than-normal serum levels of zonulin, a protein that helps regulate intestinal permeability by disassembling tight junctions, a new study shows. High zonulin levels correspond with increased intestinal permeability, Dr. Alessio Fasano of the University of Maryland School of Medicine in Baltimore and colleagues report, and are seen in at-risk patients before they develop type 1 diabetes.

The findings suggest, that zonulin-dependent loss of intestinal barrier function may be a key step in the development of autoimmunity leading to type 1 diabetes.

Dr. Fasano and his team previously showed that, in diabetes-prone rats, zonulin upregulation and a resulting increase in intestinal permeability occurred two to three weeks before type 1 diabetes onset, and that blocking zonulin prevented diabetes development.

To investigate whether the protein might be involved in human type 1 diabetes, the researchers tested zonulin levels in 339 type 1 diabetes patients, 89 of their first-degree relatives, and 97 age- and sex-matched controls. The researchers also tested intestinal permeability in a random subgroup of study participants.

Forty-two percent of the diabetic individuals and 29% of their relatives had zonulin levels two standard deviations above the average for the healthy controls, compared to just 4% of the controls. Diabetics and their relatives also showed greater intestinal permeability, and intestinal permeability was directly correlated with zonulin levels.

The researchers also tested serum samples from 10 people at risk for type 1 diabetes before disease onset. Seven of them had elevated zonulin levels, the researchers found, and three of these went on to develop diabetes — as did one subject without abnormally high zonulin — an average of 3.5 years later.

"These results suggest that zonulin upregulation is associated with increased intestinal permeability in a subgroup of diabetic patients," Dr. Fasano and his team conclude. "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."

Diabetes May 2006;55:1443-1449.

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