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Growth and Insulin-Like Growth Factors (IGFs) in Children with Insulin-Dependent Diabetes Mellitus at the Onset of Disease: Evidence for Normal Growth, Age Dependency of the IGF System Alterations, and Presence of a Small (Approximately 18-Kilodalton) IGF-Binding Protein-3 Fragment in Serum

Department of Pediatrics, Tor Vergata University (S.C., M.L.M.B., D.G., B.B.), 00133 Rome; Department of Pediatrics, Scientific Institute H San Raffaele, Milan University (R.B., G.C.), 20132 Milan; and Division of Nuclear Medicine, S. Eugenio Hospital (S.B.), 00144 Rome, Italy

Address all correspondence and requests for reprints to: Stefano Cianfarani, M.D., Laboratory of Pediatric Endocrinology, Room E-178, Tor Vergata University, via di Tor Vergata 135, 00133 Rome, Italy. E-mail: stefano.cianfarani{at}uniroma2.it

Data on growth of children with insulin-dependent diabetes mellitus (IDDM) before the onset of disease are conflicting, and although the insulin-like growth factor (IGF) system has almost invariably been found altered at diagnosis, most of previous studies are affected by the small number of patients investigated. We studied 60 IDDM children at the onset of disease, comparing their stature with target height, normal growth standards, and height of 102 sex- and age-matched controls. Furthermore, we assessed serum IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) levels and IGFBP-3 circulating forms. IDDM children were subdivided into 2 groups according to an age above (n = 26) or below (n = 34) 6 yr. The values of endocrine variables of diabetics older than 6 yr were compared with those of 34 age-matched controls. Although the height of diabetics was higher than growth reference values (mean height ± SD, 0.64 ± 1.4 z-score) and their target height (mean target height ± SD, 0.1 ± 0.84 z-score; P < 0.005), no significant difference in height was found between IDDM children and controls (mean height ± SD, 0.64 ± 0.95 z-score) even analyzing the 2 age groups separately. Overall, IDDM children showed reduced levels of IGF-I (mean ± SD, -0.65 ± 1.9 z-score) and normal levels of IGF-II (mean ± SD, -0.05 ± 1.2 z-score) and IGFBP-3 (mean ± SD, -0.06 ± 1.2 z-score). However, whereas patients younger than 6 yr showed normal values of IGF-I, IGF-II, and IGFBP-3, these peptides were significantly reduced in older subjects compared with either younger IDDM children or controls (P < 0.01). IGFBP-3 immunoblot analysis revealed the presence of an approximately 18-kDa fragment of IGFBP-3 in addition to the major approximately 29-kDa fragment and the intact form (42–39 kDa) in 46 of 60 IDDM patients, whereas the approximately 18-kDa band was absent in all 34 control sera. No relationship was found between the endocrine variables and stature at diagnosis. In conclusion, our results indicate that IDDM children at the onset of disease are not taller than healthy peers and have increased IGFBP-3 proteolytic activity. Finally, although the IGF system is normal in younger IDDM children, older patients have reduced IGF levels.

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