Zonulin Upregulation Is Associated With Increased Gut Permeability in Subjects With Type 1 Diabetes and Their Relatives
Zonulin Upregulation Is Associated With Increased Gut Permeability in Subjects With Type 1 Diabetes and Their Relatives Anna Sapone 1 2 , Laura de Magistris 2 , Michelle Pietzak 3 , Maria G. Clemente 1 , Amit Tripathi 1 , Francesco Cucca 4 , Rosanna Lampis 4 , Deborah Kryszak 1 , Maria Cartenì 2 , M...
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Published in | Diabetes (New York, N.Y.) Vol. 55; no. 5; pp. 1443 - 1449 |
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Main Authors | , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Alexandria, VA
American Diabetes Association
01.05.2006
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Subjects | |
Online Access | Get full text |
ISSN | 0012-1797 1939-327X 1939-327X |
DOI | 10.2337/db05-1593 |
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Summary: | Zonulin Upregulation Is Associated With Increased Gut Permeability in Subjects With Type 1 Diabetes and Their Relatives
Anna Sapone 1 2 ,
Laura de Magistris 2 ,
Michelle Pietzak 3 ,
Maria G. Clemente 1 ,
Amit Tripathi 1 ,
Francesco Cucca 4 ,
Rosanna Lampis 4 ,
Deborah Kryszak 1 ,
Maria Cartenì 2 ,
Maddalena Generoso 2 ,
Dario Iafusco 2 ,
Francesco Prisco 2 ,
Francesca Laghi 2 ,
Gabriele Riegler 2 ,
Romano Carratu 2 ,
Debra Counts 5 and
Alessio Fasano 1
1 Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, Maryland
2 Department Magrassi-Lanzara, Gastroenterology Unit, II University of Naples, Naples, Italy
3 University of Southern California Keck School of Medicine and the Division of Gastroenterology and Nutrition, Children’s Hospital
Los Angeles, Los Angeles, California
4 Department of Biomedical Science and Biotechnology, University of Cagliari, Cagliari, Italy
5 Division of Pediatric Endocrinology, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland
Address correspondence and reprint requests to Alessio Fasano, MD, Mucosal Biology Research Center, University of Maryland
School of Medicine, 20 Penn St., Room 345, Baltimore, MD 21201. E-mail: afasano{at}mbrc.umaryland.edu
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.
ELISA, enzyme-linked immunosorbent assay
GALT, gut-associated lymphoid tissue
ICA, islet cell antibody
IA-2, insulinoma-associated protein 2
LA/MA, lactulose/mannitol
MAdCAM-1, mucosal vascular addressin cell adhesion molecule 1
TBS-T, Tris-buffered saline 0.05% Tween 20
TJ, tight junction
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted February 13, 2006.
Received December 8, 2005.
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 |
ISSN: | 0012-1797 1939-327X 1939-327X |
DOI: | 10.2337/db05-1593 |