BackgroundThere is a need for increased understanding of the pre-diabetic period in individuals with high risk of type 1 diabetes from the general population. MethodsHigh-risk children (n=21) positive for multiple islet autoantibodies were identified by autoantibody screening within the All Babies in Southeast Sweden study. The children and their parents were enrolled in a 2-year prospective follow-up study aiming to characterize the pre-diabetic period. Blood samples were collected every 6months for measurement of C-peptide, HbA1c, fasting glucose, and autoantibodies. Human leukocyte antigen-genotype was determined, and oral glucose tolerance test was performed every 12months. ResultsDespite positivity for multiple autoantibodies, 9 out of 21 individuals had low-risk human leukocyte antigen-genotypes. Children who progressed to manifest diabetes (progressors, n=12) had higher levels of IA2A and ZnT8A than children who did not (non-progressors, n=9). Impaired glucose tolerance and impaired fasting glucose was observed to the same extent in progressors and non-progressors, but HbA1c increased over time in progressors in spite of increased C-peptide. ConclusionsAutoantibodies to IA2 and ZnT8 may be useful discriminators for disease progression in at-risk children from the general population. Dysglycemia was observed long before diagnosis, and difficulties in maintaining glucose homeostasis despite increased C-peptide indicate that insulin resistance might be an important accelerator of disease in risk individuals.