INSULIN-TREATMENT NORMALIZES REDUCED FREE INSULIN-LIKE GROWTH-FACTOR-I CONCENTRATIONS IN DIABETIC CHILDREN

OBJECTIVE We have recently demonstrated multiple aberrations in the GH -IGF axis in the sera of children with untreated insulin-dependent dia betes mellitus (IDDM) which were restored after insulin replacement. H owever, the net result of these alterations in the IGF system on the c oncentrations of free/biologically available IGF-I in the serum have n ot been examined directly in diabetic children, In the present study, the effect of diabetes and subsequent insulin replacement on the circu lating free IGF-l concentrations are assessed, DESIGN Fasting venous s erum samples were obtained longitudinally, before and at various times after the initiation of insulin treatment in untreated diabetic subje cts. SUBJECTS Ten prepubertal, aged (mean +/- SEM) 6.3 +/- 1.0 years, and six adolescent, aged 12-24 h, 1 years, subjects with newly diagnos ed and untreated IDDM, and age and pubertal status-matched control chi ldren and adolescents were recruited, METHODS The serum samples were c ollected before initiating insulin treatment and 12-24 h, 1 week, and 1 month thereafter in subjects with IDDM. Insulin doses ranged from 0. 5 to 1.2 U/kg/day. MEASUREMENTS Free IGF-I concentration was assayed b y a recently developed two-site immunoradiometric assay. Total IGF-I w as measured by radioimmunoassay after acid-ethanol extraction of bindi ng proteins, Differences in free and total IGF-I concentrations in IDD M subjects before and during insulin treatment were analysed by repeat ed measures analysis of variance followed by pairwise multiple compari sons test. In seven subjects with IDDM, where serum IGFBP-1 and IGFBP- 3 concentrations, and IGFBP-3 protease activity had also been measured in a previous study, the relationship between these variables and cir culating free IGF-1 concentrations were examined by linear regression analysis, RESULTS Free IGF-I concentrations in prepubertal subjects wi th IDDM were 0.9 +/- 0.2, 1.5 +/- 0.3, 1.6 +/- 0.3 and 2.5 +/- 0.4 mu g/l before, 1 day, 1 week and 7 month after insulin treatment, respect ively, Free IGF-I concentrations of control prepubertal children were 2.6 +/- 0.5 mu g/l. Pubertal subjects had higher free IGF-I concentrat ions than prepubertal subjects but demonstrated a similar type of patt ern; before insulin 2.3 +/- 1.1, 1 day 3.8 +/- 1.3, 1 week 3.7 +/- 0.6 , 1 month 6.5 +/- 1.5 vs pubertal controls 7.7 +/- 2.0 mu g/l. Total I GF-I concentrations were also reduced in untreated diabetic subjects a nd showed a slower pattern of normalization than free IGF-I concentrat ions, Free IGF-I concentrations correlated positively with total IGF-I and negatively with IGFBP-1 concentrations, There was no significant correlation between free IGF-I and either serum IGFBP-3 concentrations or IGFBP-3 protease activity. CONCLUSION Alterations in the IGF syste m during untreated IDDM lead to a reduction in circulating free IGF-I concentrations which is restored progressively during insulin treatmen t, An increase in free IGF-I precedes that of total IGF-I suggesting t hat the former is a more sensitive indicator of the metabolic status, An inverse correlation between free IGF-I and IGFBP-1 supports the hyp othesis that IGFBP-1 plays an important role in the acute modulation o f free IGF-l levels.