To date, there is only one primary prevention trial, the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) from Finland (38). The hypothesis of TRIGR is that avoidance of cow's milk protein in the first 6-8 mo of life can prevent subsequent diabetes. The premise was based on early epidemiologic data from Norway and Sweden that reported that the duration of breast-feeding was inversely proportional to the risk of developing diabetes (63). Other Finnish studies of sibling pairs revealed that the siblings with diabetes had higher levels of cow's milk protein antibodies than their age-and HLA-matched sibling pair, and they hypothesized that high levels of IgG antibovine serum albumin (BSA) were an independent risk factor for the development of type 1 diabetes, serving as an environmental trigger (64-66). Diet experiments in the nonobese diabetic (NOD) mouse using a casein hydrolysate formula (which contains no large proteins or BSA) were promising, revealing a marked decreased incidence of autoimmune diabetes in the test diet cohort (67). The hypothesized mechanism is that antibodies to BSA crossreact (via molecular mimicry) with a P-cell membrane protein (p69), which is also induced in islet cells by interferon (IFN)-y. Gut permeability to cow's milk protein early in life could allow for immune sensitization, and a subsequent viral infection producing IFN-y would induce an increase in p69 expression and expose the P-cells to transient immune-mediated destruction (63). The TRIGR study has enrolled infants that have both a first-degree relative with diabetes and a high-risk HLA type to be randomized into either a casein hydrolysate formula or a cow's milk-based formula, with the primary end points being age of diabetes onset and incidence of diabetes by age 10 yr. The results of this trial are still pending.
Some studies, however, have found no association of cow's milk exposure and P-cell autoimmunity, the precursor to clinical type 1 diabetes. The Diabetes Autoimmunity Study in the Young (DAISY) from Denver, Colorado screened 253 children with a first-degree relative with type 1 diabetes for evidence of P-cell autoimmunity, defined as elevated levels of insulin, GAD, or ICA512 (IA-2) autoantibodies. There was no association between the early exposure of cow's milk protein or other dietary protein (cereal, fruit, vegetable, or meat) and the development of P-cell autoimmunity (68). These results were later independently confirmed with the Australian BabyDIAB trial of 317 infants with a first-degree relative with type 1 diabetes and the German BabyDIAB trial. The study prospectively examined infants from birth to 29 mo of age for the effect of both breast-feeding and the introduction of cow's milk protein on the development of P-cell autoimmunity. Analyses were performed on cohorts based on the number of autoantibodies that they developed: none, one transiently detected, one permanently detected, or greater than two autoantibodies detected. There were no significant differences in these cohorts in terms of duration of breast-feeding or introduction of cow's milk protein, thereby leading to the investigators' conclusion that there is no association between cow's milk protein and the development of islet autoimmunity (69).
In addition to early infant diet, other environment risk determinants have been implicated in the potential pathogenesis of type 1 diabetes, including enteroviral infections and vaccine administration. These determinants may serve as immune triggers or disease modulators, but, to date, no large trials are focusing on these agents for primary intervention studies (70-75). At present, only congenital rubella infection is clearly associated with risk for type 1A diabetes (76-78).
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