Autoimmunity to islet beta cells is marked by the appearance of islet autoantibodies and occurs prior to diabetes onset. This seroconversion is pronounced at around 1 year of age, is often against insulin, and is associated with >80% risk for the development of diabetes once it spreads to other antigens such as GAD65, IA-2, or ZnT8. Moreover, we show that islet autoantibody seroconversion is synchronous with CD4+ T cell activation. Factors which associate with seroconversion include HLA class II and PTPN22 genotypes, type 1 interferon transcriptome signatures and disrupted microbiome networks, whereas maternal type 1 diabetes is associated with a relative protection of seroconversion. A number of genes including CD25, IL-2, INS, and IFIH1 influence the rate of progression to diabetes after seroconversion. Moreover, we find that an intrinsic phenotype of autoreactive T cell responsiveness to autoantigen in the preseroconversion period associates with the likelihood of disease progression. These findings identify numerous pathways to islet autoimmunity and diabetes and as a consequence open opportunities for intervention.