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Insulin-Like Growth Factor-Binding Protein-1: Serum Levels, Promoter Polymorphism, and Associations with Components of the Metabolic Syndrome in Short Subjects Born Small for Gestational Age

Department of Pediatrics (D.v.d.K., S.d.K., R.W., R.L., W.E., A.H.-K.), Division of Endocrinology, Erasmus Medical Center, 3000 CB Rotterdam, The Netherlands; Dutch Growth Research Foundation (D.v.d.K., A.H.-K.), 3016 AH Rotterdam, The Netherlands; Endocrine Service (D.v.d.K., C.D., J.P.), Centre Hospitalier Universitaire Sainte-Justine Hospital Research Center, University of Montreal, Montreal, Quebec, Canada H3T 1C5; and Metabolic and Endocrine Diseases (J.v.D.), University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Cheri Deal, Ph.D., M.D., Centre Hospitalier Universitaire Ste-Justine Hospital Research Center, 3175 Côte Sainte-Catherine, Montréal, Canada H3T 1C5. E-mail: cheri.l.deal{at}umontreal.ca.

Context: IGF binding protein (IGFBP)-1 is the only acute regulator of IGF-I bioavailability. Its production is suppressed by insulin, and low levels are associated with hyperinsulinemia and cardiovascular disease risk in adults. Data on IGFBP-1 levels in short, small for gestational age (SGA) subjects are scarce, and associations with IGFBP1 promoter single nucleotide polymorphisms have not been established.

Objective: The aim of the study was to determine IGFBP-1 levels in short SGA subjects compared with those in controls, to assess genotype frequency of the –575 G/A single nucleotide polymorphism, and to determine its impact on IGFBP-1 levels.

Subjects: A total of 272 short subjects born SGA and 330 subjects with normal stature (245 children, 85 young adults) participated in the study.

Outcome Measures: We measured fasting levels of IGFBP-1, IGF-I, insulin and lipid parameters, and body composition.

Results: IGFBP-1 SD score (SDS) was comparable to controls in lean, short, SGA children but significantly lower in short SGA adults with normal fat mass (P < 0.001). IGFBP-1 SDS correlated significantly with insulin levels, systolic blood pressure SDS, and various lipid parameters. Baseline IGFBP-1 SDS was lowest in SGA children with –575 GG genotype and significantly higher in SGA children with one or two copies of the A allele. In response to a given insulin level, children with the AA genotype had a significantly higher IGFBP-1 SDS compared to children with the GG genotype.

Conclusion: Normal IGFBP-1 levels in lean, short, SGA children may reflect a normal metabolic state, despite reported hyperinsulinemia. IGFBP-1 is modulated by polymorphic variability and seems to be an additional player in the complex interaction between the IGF-IGFBP axis, glucose homeostasis, and lipid metabolism.