Growth hormone therapy does not alter the insulin-like growth factor-I/insulin-like growth factor binding protein-3 molar ratio in growth hormone-deficient children

Background: Recent studies have linked raised levels of IGF-I and/or reduced levels of its main binding protein, IGF binding protein (IGFBP)-3, with the risk of developing cancer. A GH dose-dependent increase in IGF-I/IGFBP-3 molar ratio has been reported in subjects treated with GH, raising concern about the long-term safety. Objective: The aim of this study was to evaluate changes in serum IGF-I, IGFBP-3, and IGF-I/IGFBP-3 molar ratio over the first 12 months of replacement GH therapy in GH deficient (GHD) children. Methods: The study included 20 GHD children who had not previously received GH treatment, and 40 untreated non-GHD short children closely matched for age, gender, pubertal stage, and body mass index (BMI), as controls. Serum IGF-I, IGFBP-3 levels were measured before and after 12 months of GH treatment. Based on the molecular weight of IGF-I (7500) and IGFBP- 3 (40,000, mean of glycosylated variants), we calculated the molar ratio of IGF-I/IGFBP-3. Results: IGF-I/IGFBP-3 molar ratio significantly increased during GH therapy (p=0.01). No significant difference in IGF-I/IGFBP-3 ratio was found between GHD children and controls at the different time points. In the multiple regression analysis, BMI (β=0.33) and age (β=0.33) proved to be the major predictors of the IGF-I/IGFBP-3 molar ratio (adjusted r2=0.53, p<0.0001). Conclusions: Our results suggest that at a conventional replacement dose GH does not alter the IGF-I/IGFBP-3 molar ratio. Potential fears related to long-term cancer risk are likely to be greatest in patients exposed to high-dose GH therapy and with genetic predisposition to high IGF-I and/or low IGFBP-3 concentrations

Catch-up growth in body mass index is associated neither with reduced insulin sensitivity nor with altered lipid profile in children born small for gestational age

Objective: Low birth weight is a risk factor for coronary heart disease. Persons who have coronary events as adults tend to have been small at birth and thin at 2 yr of age, after which they tended to increase their body mass index (BMI). Our aim was to determine whether BMI gain is associated to alterations in insulin sensitivity and/or lipid profile in children born small for gestational age (SGA). Design: Retrospective case-control study. Methods: We studied 78 children (mean age 7.8 +/- 2.5 yr): 26 SGA children with catch-up growth in BMI (CGB-SGA) (BMI = 10(th) to 75(th) centile), 26 SGA without catch-up growth (NCGB-SGA) (BMI<10(th) centile), and 26 appropriate for gestational age (AGA) control children (BMI: 10(th) to 75th centile). For each CGB-SGA child, we selected an NCGB-SGA and an AGA child of the same gender, age (within 1 yr), and pubertal status. SGA children were also subdivided into 2 groups according to post-natal catch-up growth in height (CGH). Results: Glucose was significantly lower in NCGB-SGA than AGA group (p=0.02). No significant differences in fasting insulin, fasting glucose/insulin ratio, homeostasis model assessment, quantitative insulin-sensitivity check index, and lipid profile were found among the 3 groups. HDL-cholesterol proved significantly reduced in SGA children with post-natal CGH (p=0.02). Conclusions: Our findings do not support the hypothesis of early alterations in insulin sensitivity and lipid metabolism in CGB-SGA subjects during childhood provided that BMI remains within the normal range. Finally, the finding of reduced HDL-cholesterol levels in CGH-SGA children suggests detrimental metabolic effects of the height gain

EFFECT OF INSULIN ON HYDROGEN-PEROXIDE PRODUCTION BY HUMAN POLYMORPHONUCLEAR LEUKOCYTES - STUDIES WITH MONOCLONAL ANTIINSULIN RECEPTOR ANTIBODIES, AND AN AGONIST AND AN INHIBITOR OF PROTEIN-KINASE-C

This study evaluated the effect of insulin on the respiratory burst of human polymorphonuclear leukocytes (PMNLs) and the signalling pathways involved in this process, especially the involvement of protein kinase C (PKC). Isolated human PMNLs from healthy volunteers were incubated with different concentrations of insulin (10(-10)-10(-7) mol/l) and for different durations of incubation (5-90 min). The intracellular production of hydrogen peroxide (H2O2) was detected employing a previously validated flow cytometric assay using 2',7'-dichlorofluorescein-diacetate (DCFH-DA) as a marker for H2O2 production. Specificity of insulin action was verified using an insulin antagonist (the monoclonal antibody MA-10). To identify the signalling pathway involved, we used: (a) monoclonal antibody MA-5, directed against the alpha-subunit of the insulin receptor, that partially mimics insulin without activating tyrosine kinase; (b) H7, an inhibitor of PKC involved in O-2- production in PMNLs, and (c) phorbol myristate acetate (PMA) that binds and stimulates PKC. Insulin caused a dose- and time-dependent stimulation of H2O2 release by human PMNLs. The effect of insulin was blocked by MA-10. The actions of insulin and PMA on H2O2 release were additive, whereas the actions of MA-5 and PMA were not. H7 partially inhibited the H2O2 production stimulated by insulin and completely inhibited MA-5 action. We conclude that insulin stimulates, in a dose- and time-related manner, the respiratory burst of human PMNLs. PKC activation can only partially account for the intracellular mechanisms involved in this process

Increased chromosome fragility in lymphocytes of short normal children treated with recombinant human growth hormone

A few years ago it was reported that some growth-hormone-deficient children had developed leukemia following therapy with human growth hormone. This raised concern that this therapy may stimulate tumor development. Since it is known that the tendency to develop cancer is closely related to chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy can increase chromosome fragility. Ten short normal children were studied during their first year of treatment. Lymphocytes were collected at 0, 6 and 12 months of rhGH therapy, and we assessed the rate of spontaneous chromosome aberrations, the frequency of sister chromatid exchanges, the proliferative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomycin. At 6 months of therapy, there was a significant increase in bleomycin-induced chromosome aberrations, which remained unchanged after 1 year of treatment. An increase in spontaneous chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are further supported by data obtained from the analysis of 16 short normal children already on rhGH therapy