OZR Back-up mandate: Biomarkers of impending beta cell loss and dysglycemia in asymptomatic type 1 diabetes

Early diagnosis and prevention trials of type 1 diabetes (T1D) are hampered by lack of knowledge on the evolution of beta cell loss during asymptomatic disease. Making use of the capacity of a nationwide clinical network to identify multiple autoantibody-positive (mAb+) first-degree relatives (FDRs) of T1D patients, we aim to monitor functional beta cell mass and insulin action as assessed by hyperglycemic clamp test (HCT) in pre-T1D in relation to known determinants of disease progression. This knowledge is needed to better understand the variable disease progression in asymptomatic T1D and to derive objective criteria for identifying individuals at high risk of major beta cell loss and clinical onset. The majority of beta cell loss is hypothesized to occur 2-3 years prior to diagnosis. Normo- or dysglycemic mAb+ FDRs (5-39 years) are enrolled and followed biannually by oral glucose tolerance tests, continuous glucose monitoring (CGM) and HCT (only 12-39 years) for at least 2 years or to onset. The efficiency of changes in HCT-derived variables to identify rapid progressors will be tested in prediction models. To translate the acquired knowledge to clinical large scale application, promising minimally invasive alternative techniques (CGM-derived indices of glycemic variability, proinsulin, proinsulin/C-peptide ratio) will be validated against HCT. The results may facilitate early diagnosis, avoidance of ketoacidosis, and development of new prevention trials in pre-T1D.