IGF-I, IGF Binding Protein (IGFBP)-3, Phosphoisoforms of IGFBP-1, and Postnatal Growth in Very Low Birth Weight Infants

Abstract

Impaired postnatal growth in very low birth weight (VLBW, <1500 g) infants is per se a major clinical challenge and may also serve as a model in studying the mechanisms of growth retardation in general. This study was undertaken to characterize the role of IGFs and their binding proteins (IGFBPs), key regulators of fetal and infant growth, during the postnatal period in VLBW infants. Forty-eight VLBW infants (gestational age 27.6 ± 2.2 wk, birth weight 923 ± 257 g) were studied. Blood samples were drawn at 1, 2, 4, and 8 wk of age for measurements of IGF-I, IGFBP-1 (lesser phosphorylated, lpIGFBP-1, and highly phosphorylated, hpIGFBP-1), IGFBP-3, and insulin, simultaneous growth velocities being assessed by a rigorous protocol of repeated, frequent lower leg length and body weight measurements. All regression analyses were adjusted for postnatal age and repeated measurements. Lower leg growth velocity showed a positive correlation with IGF-I (P = 0.01) and IGFBP-3 (P = 0.03), and weight growth velocity with IGFBP-3 (P = 0.057) and with lpIGFBP-1/hpIGFBP-1 ratio (P = 0.01). Moreover, concurrent glucocorticoid dose showed a negative correlation with both IGFBP-1 isoforms, observable, however, only in samples with high (>10 U/liter) insulin (lpIGFBP-1, P = 0.02; hpIGFBP-1, P = 0.007). In backward multiple regression analysis, the factor remaining significantly associated with lower leg growth velocity (R2 = 0.63) was IGF-I, and factors associated with weight growth velocity (R2 = 0.81) were IGFBP-3 and the lpIGFBP-1/hpIGFBP-1 ratio. In conclusion, circulating IGF-I and IGFBP-3, and the lpIGFBP-1/hpIGFBP-1 ratio, reflect short-term growth velocity in VLBW infants. lpIGFBP-1 isoforms, abundant in the circulation of these infants, may thus also have properties that are at least less inhibitory, if not promoting, on the growth-stimulating action of IGF-I. Finally, the regulation of IGFBP-1 by glucocorticoids may be divergent in situations with a high or low insulin concentration.