Abstract The incidence of childhood type 1 diabetes (T1D) continues to increase; however, the specific cause remains elusive. Our preliminary results indicate that the incidence of islet autoimmunity (IA) doubled in Colorado children born in 2004-2010, compared to those born in 1993-1998. Our overarching goal is to identify environmental triggers and/or protective factors responsible for the increased risk. Specifically, we will evaluate whether increasing early childhood overweight, decreased exposure to environmental tobacco smoke, delayed introduction of gluten in the infant diet or decreased number of polio vaccine doses in the initial 6 months of life could play a role. We will collaborate with outstanding virology laboratories to further elucidate the role of enteroviral infections in triggering IA. In a nested case-control study we will test serum samples collected at 9, 15, 24 months of life, and annually thereafter, using the VirScan assay, which detects antibodies to thousands of epitopes of human viruses and will test white blood cells from the same subjects and time-points for the presence of enteroviruses. We will test the hypotheses that enteroviral infections with higher viral antibody response breadths and persistent presence of enterovirus in white blood cells are associated with IA and T1D. Finally, we will ascertain the incidence of IA in genetically at-risk youth until age 20 y as well as explore the evolution of dysglycemia and the rate of progression to T1D in youth persistently positive for islet autoantibodies, up to 30 y of age. In the latter, we will monitor the evolution of dysglycemia and progression to T1D using continuous glucose monitoring. The proposed studies will help to find the environmental causes of T1D as well as inform screening for pre-symptomatic T1D and prevention trials in children and adolescents.