Manipulating the type 1 diabetes disease process, man versus mouse.

I n their article in this month's issue of Diabetes Care, Hummell et al. (1) tested the hypothesis that gluten is a driving antigen for type 1 diabetes–associated is-let autoimmunity. They convincingly demonstrated that elimination of dietary gluten for 12 months in humans positive for at least two type 1 diabetes–associated autoantibodies does not consistently alter the titers of these antibodies. The study is well done and carefully analyzed. Their conclusion that gluten does not drive islet autoantibody production in type 1 diabetes , as it does in celiac disease, seems very appropriate. Yet, because the ␤-cell lesion of type 1 diabetes is T-cell and not anti-body mediated, and because antibody and T-cell responses to the same antigen can be markedly different or even reciprocally related, they cannot conclude that the underlying type 1 diabetes disease process in humans is not altered by elimination of dietary gluten for 12 months. Nonetheless, I feel that studies such as this are extremely important because they provide information that allows us to compare specific aspects of the type 1 diabetes disease process in man versus mouse. A tremendous amount has been learned about the molecular and cellular immunogenetic pathophysiology of type 1 diabetes in the NOD mouse, and in this animal model, a large number of manipulations can prevent type 1 diabetes (2), including a gluten-free diet (3). How the findings in the NOD mouse relate to type 1 diabetes in humans is a major question. This is especially important at this time because the diabetes community is eager to test ways to preserve ␤-cell function in recently diagnosed patients with type 1 diabetes and to prevent the development of clinical type 1 diabetes in subjects identified as high risk. To accomplish this goal in the U.S., the National Institutes of Health is funding TrialNet, a consortium of clinical centers, core laboratories, and a coordinating/biostatistical center specifically charged with evaluating ways to alter the type 1 diabetes disease process in humans. The potential relevance of observations in the NOD mouse to the design of such clinical trials in humans is unknown. As mentioned above, a large number of interventions can alter the type 1 diabetes disease process in the NOD mouse (2). Because intervention studies provide much stronger evidence for cause-effect relationships than observational/ association studies, studies in humans using interventions efficacious in the mouse will provide the best data to allow us …