PROINSULIN IMMUNOREACTIVITY IN RECENT-ONSET IDDM - THE SIGNIFICANCE OF INSULIN-ANTIBODIES AND INSULIN AUTOANTIBODIES

OBJECTIVE - To study the natural history of fasting proinsulin immunor eactivity (PIM) during the first 30 months of IDDM and its relationshi p to fasting C-peptide and insulin antibodies. RESEARCH DESIGN AND MET HODS - An incidence cohort of 204 consecutive newly diagnosed IDDM pat ients were followed prospectively, having blood drawn for measurements at diagnosis and at 1, 3, 6, 9, 12, 18, 24, and 30 months. A sensitiv e enzyme-linked immunosorbent assay was used for the determination of PIM. RESULTS - All patients had detectable fasting PIM in plasma at di agnosis, with a median value and interquartile range of 3.5 pmol/l (2. 2-6.2). The median PIM level increased during the first months of IDDM to reach a peak at 9-12 months (9.9-10.3 pmol/l). PIM then declined g radually to 5.6 pmol/l (1.9-13.5) at 30 months without reaching baseli ne. PIM at each lime point was widely scattered in a skewed log-normal distribution without signs of bimodality. After the onset of insulin treatment, median insulin antibody level increased and declined in a s imilar pattern. Both PIM and antibody level were significantly higher in children and adolescents compared with adults. However, stepwise mu ltiple regression analysis showed that age was only of minor importanc e for the PIM variation during the study period. Insulin antibody leve l and lasting C-peptide were the major determinants at 3-30 months, ac counting for similar to 40% of the variation (R(2)). Blood glucose was of minor importance, and insulin dose, HbA(1c), and BMI were of no im portance The correlation between lasting PIM and lasting C-peptide imp roved (R(2) doubled) ii the insulin antibody level was accounted for. Further, the slope of the correlation curve between PIM and C-peptide increased threefold when antibody binding was >4%. At diagnosis, insul in autoantibodies could be detected in 19% of the patients. Their pres ence predicted higher proinsulin at 1-3 months, a higher insulin dose the Ist year, and higher levels oi insulin antibodies later in the stu dy. CONCLUSIONS - Circulating insulin antibodies may affect the level of PIM in IDDM, probably by adding a pool of IgG-bound PIM thereby inc reasing half-life and plasma concentration. This may explain why C-pep tide and PIM levels do not change in concert during the Ist years of I DDM. Unlike C-peptide, PIM can not therefore quantitate beta-cell secr etion unless the presence of insulin antibodies is ruled out.