DISPROPORTIONATELY ELEVATED PROINSULIN LEVELS PRECEDE THE ONSET OF INSULIN-DEPENDENT DIABETES-MELLITUS IN SIBLINGS WITH LOW FIRST-PHASE INSULIN RESPONSES

The objective of this study was to test whether levels of proinsulin i mmunoreactivity (PIM) relative to those of insulin immunoreactivity (I RI) or C-peptide are changed and related to subclinical beta-cell dysf unction in siblings of insulin-dependent diabetes mellitus (IDDM) pati ents. Twenty-three siblings, previously found positive for islet cell antibodies and/or insulin autoantibodies, were divided into 2 groups a ccording to their first phase insulin response (FPIR) to iv glucose to lerance tests (IVGTTs) sequentially performed during an observation pe riod of 2 yr. Eleven siblings had diminished FPIR on at least 1 occasi on (group 1), whereas 12 siblings had a normal FPIR on all occasions s tudied (group 2). Ah underwent a further IVGTT (0.5 g glucose/kg BW), and serum samples were taken at 0, 1, 3, 6, 10, 20, 30, 40, 50, and 60 min. The 2 groups had comparable median age, female/male ratio, weigh t, height, fasting blood glucose, immunoreactive insulin, C-peptide, a nd insulin autoantibodies levels, but group 1 had significantly higher islet cell antibodies levels. Fasting median PIM/IRI and PIM/C-peptid e ratios were 2- to 3-fold higher in group 1 [10.5% (range, 1.8-93.8%) vs. 5.2% (range, 1.9-14.3%) and 3.3% (range, 0.4-23.1%) us. 1.3% (ran ge, 0.7-2.6%; P < 0.05]. Fasting PIM/C-peptide ratios correlated inver sely with FPIRs (r(s) = -0.68; P < 0.01). During glucose stimulation, maximal responses of IRI and C-peptide were 4-fold lower in group 1, a nd the time of maximal responses of IRI and C-peptide occurred later i n group 1 than in group 2. In contrast, no difference in maximal respo nses of PIM was found, but the time of maximal responses of PIM occurr ed later in group 1. Nine of 11 siblings in group 1 presented with IDD M 1-28 months after the test, compared to none in group 2. In group 1 a paradoxical inhibitory response of PIM was observed during the first 6 min of the IVGTT. These data indicate that fasting PIM/IRI and/or P IM/C-peptide ratio reflects subclinical beta-cell dysfunction in predi abetic subjects with evidence of immunological beta-cell assault and s uggests that an elevated ratio may be an additional marker for later d evelopment of IDDM.