Increased IGFBP Proteolysis, IGF-I Bioavailability, and Pappalysin Levels in Children With Prader-Willi Syndrome

Abstract

Context Prader-Willi syndrome (PWS) is associated with impaired growth hormone (GH) secretion and decreased insulin-like growth factor (IGF)-I levels. Pappalysins (PAPP-A, PAPP-A2) and stanniocalcins (STC-1, STC-2) regulate IGF binding-protein (IGFBP) cleavage and IGF bioavailability, but their implication in PWS is unknown. Objective We determined serum levels of PAPP-As and STCs in association with IGF axis components in pre- and pubertal patients with PWS, also analyzing the effect of GH treatment. Methods Forty children and adolescents with PWS and 120 sex- and age-matched controls were included. The effect of GH was evaluated at six months of treatment in 11 children. Results Children with PWS had lower levels of total IGF-I, total and intact IGFBP-3, acid-labile subunit, intact IGFBP-4, and STC-1, and higher concentrations of free IGF-I, IGFBP-5 and PAPP-A. Patients with PWS after pubertal onset had decreased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4 levels, and increased total IGFBP-4, and STCs concentrations. GH treatment increased total IGF-I, total and intact IGFBP-3, and intact IGFBP-4, with no changes in PAPP-As, STCs and free IGF-I levels. Standardized height correlated directly with intact IGFBP-3 and inversely with PAPP-As and the free/total IGF-I ratio. Conclusion The increase in PAPP-A could be involved in increased IGFBP proteolysis, promoting IGF-I bioavailability in children with PWS. Further studies are needed to establish the relationship between growth, GH resistance, and changes in the IGF axis during development and after GH treatment in these patients.

Implication of Pappalysins and Stanniocalcins in the Bioavailability of IGF-I in Children With Type 1 Diabetes Mellitus

“…The main caveat of this study includes only measurement of circulating concentrations, as quantifying the activity of pappalysins and stanniocalcins in serum or at the cellular level [ 40 ] would provide further in-depth understanding of the physiology of the peripheral GH/IGF axis in these patients. However, we have recently published circulating levels of members of this axis in patients with anorexia nervosa and Prader-Willi syndrome [ 48 , 49 ], with these studies indicating that indeed information on circulating levels can provide relevant information. Another limitation of this study is the lack of growth velocity prior to the diagnosis of T1DM and before starting insulin therapy (during a period of insulinopenia), to confirm the clinical implications of the findings in this study.…”