Inhibition of the zonulin pathway blocks the progression from pre-clinical autoimmunity to Type 1 diabetes in BB/wor rats
AbstractBackground: 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 85.410.4 in the placebo group and 86.010.3 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 (0.870.35) compared to the treated animals with the disease developed (1.870.59; 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.
DescriptionPresented at the 2005 American Gastroenterological Association Digestive Disease Week (DDW)
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/2587
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