• Abstract: Celiac Disease in Children With Type I Diabetes in Southern California

      Pietzak, Michelle; Wolfe, Adam; Rongey, Christine; Kaufman, Francine Ratner; Fisher, Lynda; Devoe, Debra; Pisit, Duke; Berti, Irene, M.D.; Gerarduzzi, Tania; Thorpe, Mary; et al. (2002)
    • Expression of Tight Junction Proteins in Diseases With Compromised Intestinal Barrier Function

      Tripathi, Amit; Clemente, Maria Grazia; Sapone, Anna; Musu, Maria Paola; De Virgiliis, Stefano; Fasano, Alessio (2006)
    • Inhibition of the zonulin pathway blocks the progression from pre-clinical autoimmunity to Type 1 diabetes in BB/wor rats

      Fasano, Alessio (2005)
      Background: We have previously studied that zonulin, a protein involved in tight junctions modulation, is up regulated in BB/wor rats and is responsible for the increased intestinal permeability (IP) typical of this animal model of autoimmunity. We have also demonstrated that by blocking the zonulin pathway before the onset of autoimmunity, the incidence of Type 1 Diabetes (T1D) can be prevented in 75% of the animals. Aim : To determine whether the progression of T1D can be blocked, even though the autoimmune process is already established. Methods: 30 BB/ Wor rats were randomized after immune seroconversion (average age 55 days) in a treatment group (N=20) that received autoclaved water supplemented with 3mg /ml of zonulin receptor blocker AT1001 and HCO3- 1.5g/100ml to buffer gastric acidity, and a placebo group (N=10) that received only water with HCO3-. Serum zonulin and autoantibody levels were monitored at the beginning of the study and at its endpoint. Water intake was monitored daily, weight gain and serum glucose levels were checked weekly. Rats with fasting blood glucose  250 mg/dl were considered diabetic and were sacrificed within 24 hours of reaching the diabetic status. Results: Six out of 10 (60%) untreated rats developed T1D, while only 7/20 (35%) of the AT1001-treated animal progressed to T1D. The average age of onset of T1D was 85.410.4 in the placebo group and 86.010.3 in the treated group. AT1001 treatment did not change the serum zonulin levels between beginning (average age 55 days) and the endpoint of the experiment (average age 100 days) of the experiments. Conversely, the anti-glutamic acid decarboxylase (GAD) antibodies were significantly reduced in AT1001-treated rats that did not develop T1D (0.870.35) compared to the treated animals with the disease developed (1.870.59; p<0.05) Conclusions: The blockage of the zonulin pathway in BB/wor rats at their preclinical autoimmune stage significantly reduced the progression to T1D. This decreased incidence of T1D was associated to a significant reduction of the anti-GAD antibodies following AT1001 treatment.
    • Role of Zonulin-Dependent Increased Gut Permeability in the Pathogenesis of Type I Diabetes in Humans

      Sapone, Anna; de Magistris, Laura; Iafusco, Dario; Prisco, Franco; Carratu, Romano; Bizzarri, Barbara; Clemente, Maria Grazia; Musu, Maria Paola; Lampis, Rosanna; Cucca, Francesco; et al. (2003)
    • Serum zonulin and intestinal permeability before and after a gluten-containing meal in both Type 1 diabetes and in their relatives

      Sapone, Anna; Fasano, Alessio (2005)
      Background: The trigger of the autoimmune destruction of pancreatic beta cells in Type 1 diabetes (T1D) is unclear. One theory is that antigens absorbed through the gut may be involved. We have recently described a protein, zonulin, that opens intestinal tight junctions and allows paracellular absorption of macromolecules. We have reported that zonulin is increased in the serum of a subset of patients with T1D and first degree relatives. Aim: The objective of this study was to determine if dysregulation of the zonulin pathway, both at baseline and following a gluten-containing meal, is linked to increased intestinal permeability (IP) and is involved in the pathogenesis of T1D. Methods: After obtaining informed consent, blood was obtained from children with T1D, parents, and siblings. Zonulin was measured in the serum of children with T1D (n=11) and their first degree relatives (n=19), by sandwich ELISA. IP was determined by HPLC measurement of both serum (at baseline and every hour up to 5 hours) and urine (5 hours collection) lactulose (LA) and mannitol (MA) after subjects ingested the sugars test solution. Results were expressed as LA/MA ratio. Results: There was a significant increase in zonulin (53%) and IP (47 %) in subjects compared to the negative cutoff. There was a significant relationship between elevation of zonulin and increased IP (p=0.026) and between LA/MA ratio in post-prandial serum samples and LA/MA ratio in urine (p=0.01). Although there was no change in mean zonulin levels with a meal, all subjects for whom IP data is available had elevation of zonulin at baseline and post-meal, and all had an increase in IP 1-hour post-meal. The 1 h post-prandial IP increase was statistically higher in T1D subjects (5.6 folds) as compared to their relatives (2.7 folds, p<0.01). There was no relationship between serum glucose and zonulin levels. Conclusions: Zonulin is significantly correlated with increased IP in children with T1D and their first degree relatives. These data suggest that increased serum zonulin is indicative of increased gut leakiness in children with T1D. Studies of the temporal relationship of an increase in serum zonulin and the development of diabetes autoantibodies are planned to suggest a causative relationship in a subset of genetically susceptible individuals.