ISLET-CELL AUTOIMMUNITY AND PROGRESSION TO INSULIN-DEPENDENT DIABETES-MELLITUS IN GENETICALLY HIGH-RISK AND LOW-RISK SIBLINGS OF DIABETIC CHILDREN

Insulin-dependent diabetes mellitus (IDDM) risk was evaluated in 765 s iblings based on prospective observation of islet cell antibodies (ICA s) and insulin autoantibodies (IAAs) as a function of the degree of HL A identity to the proband and HLA-DR alleles. Twenty-eight (3 . 7%) si blings progressed to IDDM over a median observation period of 5 . 8 ye ars. ICAs had higher sensitivity than IAAs (100% vs. 33%, P<0 . 001), whereas persistent ICA positivity and double ICA/IAA positivity define d the highest actuarial risk (47% and 70%). Diabetes manifested after a mean of 3 . 2 years from the detection of ICAs in those siblings who were initially ICA negative and, importantly, the risk was equal to t hat of the siblings constantly positive from the first sample obtained . Although the combination of HLA identity and ICAs at or above 80 Juv enile Diabetes Foundation units carried the highest positive predictiv e value (77%), the high-risk HLA markers were insufficient to predispo se siblings with low ICA levels to IDDM and low-risk HLA markers did n ot provide complete protection against high ICA levels and from subseq uent IDDM. These results emphasize ICAs as the primary tool for risk e valuation in siblings followed by restricted HLA subtyping to reduce t he population to be subjected to clinical intervention trials.