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A wheat gluten (WG) diet promotes the development of type 1 diabetes (TID) in diabetes prone BioBreeding (BBdp) rats. Our aim was to examine whether oral exposure of neonates to WG proteins prior to weaning would modify the disease process and to identify candidate wheat proteins that may be related to development of TID. Feeding diabetes-promoting WG proteins during the first week of life protected a proportion (∼1/2) of animals from developing diabetes as adults. Twenty-four hours after exposure to a cereal-based diet there was a downregulation of the Th1 cytokine gene IFN-gamma in the small intestine. A cross-sectional analysis of 1D-Western blots of WG proteins showed that 70 d BBdp rats have higher IgG reactivity to 33 and 36 kDa WG proteins than diabetes resistant BB rats. Similarly, prospective analysis of pre-diabetic and asymptomatic BBdp rats showed that increased reactivity to 33 and 38 kDa WG proteins was associated with progression to disease. We detected increased IgG reactivity to 33 and 38 kDa WG proteins in Finnish children newly diagnosed with diabetes compared with age, sex and HLA-DQ matched children without diabetes. 2D-Western blots showed that 11 wheat proteins were antigenic in the majority of BBdp rats. These 11 proteins were analysed by mass spectrometry and searches of amino acid sequences in public databases suggested that two candidate wheat proteins were alanine aminotransferase 2 transaminase 2 (GPT-2, TC# 8197) and wheat storage globulin (WSG, Acc.No.AAA3469). GPT-2 and WSG have similar amino acid sequences as human heat shock protein 60 (HSP60), an autoantigen in TID. Moreover, WSG shares sequence homology with the insulin receptor precursor, interleukin-I (IL-1) receptor and IL-1 beta. These structural homologies to diabetes related antigens suggest that wheat proteins may be involved in the autoimmune process that destroys beta-cells. As part of a strategy to develop assays of food protein "diabetogenicity", we showed a major down regulation in protein expression in gut epithelial cells exposed to chymotrypsin digested WG proteins. These studies are the first direct molecular characterisation of diabetes related dietary wheat proteins that may be implicated in the development of T1D.