B-cell function was tested in siblings of insulin-dependent diabetics (IDD). From previous studies, it is now recognized that the risk of developing IDD is highest in those sharing both haplotypes (S2H) and lowest in those sharing neither haplotype (S0H) with the diabetic. Insulin secretion in response to intravenous arginine and glucose was evaluated in S2H, S0H, and matched controls. Intravenous arginine and glucose elicited an exaggerated acute phase of insulin secretion in S2H compared with controls when analyzed as incremental insulin area 0-10', peak level attained, and mean insulin levels postinjection. Insulin responses to arginine and glucose in S0H and matched controls were identical. We hypothesize that the increased beta-cell activity found in S2H predisposes their beta-cells to damage by environmental factors and may be part of the mechanism conferring the increased risk of IDD in S2H.