First-phase insulin response in young healthy children at genetic and immunological risk for Type I diabetes

Abstract

Aims/hypothesis. A reduced first-phase insulin response to intravenous glucose is perceived as a sign of far-advanced deterioration of beta-cell function during the development of Type I “insulin-dependent” diabetes mellitus, but data on insulin responses at the onset of diabetes-related autoimmunity are lacking. We studied the first-phase insulin responses of small children soon after observed seroconversion to autoanti-body positivity. Methods. In the Type I Diabetes Prediction and Prevention Study newborn infants are screened for HLA-DQB1-associated genetic risk for Type I diabetes and those with increased risk are followed-up for the emergence of islet-cell antibodies. If antibodies are detected, autoantibodies to three other antigens “insulin, GAD65 and IA-2” are also measured. To measure first-phase insulin responses, intravenous glucose tolerance tests were carried out in 52 “1 to 5-year-old” children who had recently seroconverted to islet-cell antibody positivity. Results. The first-phase insulin response was subnormal “<38 mU/l, the 5th percentile of insulin responses of 20 islet-cell antibody negative healthy children at this age” in 22 of the 52 children “42%”. Stepwise multiregression analysis showed that islet-cell antibody greater than 20 JDFU “p=0.0005”, insulin auto-antibodies “p=0.0009” and an increasing number of positive autoantibodies “p=0.0011” were independent predictors of low first-phase insulin response. Conclusion/interpretation. A decreased first-phase insulin response could be an early phenomenon in the course of prediabetes in young children, implying a rapid autoimmune destruction or loss of function of beta cells as well as possible metabolic compensation mechanisms, since 11 out of the 22 high risk children remain nondiabetic for a considerable period of time despite low insulin responses.