Growth hormone binding protein levels in children are associated with birth weight, postnatal weight gain, and insulin secretion Ken K. Ong a,b , Martin Elmlinger c , Richard Jones d , Pauline Emmett d , the ALSPAC Study Team d , Jeff Holly e , Michael B. Ranke c , David B. Dunger b, ⁎ a Medical Research Council Epidemiology Unit, Cambridge CB2 0QQ, UK b Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK c University Children's Hospital, 72076 Tuebingen, Germany d Department of Community Based Medicine, University of Bristol, Bristol BS8 1TQ, UK e Department of Clinical Science, University of Bristol, Southmead Hospital, Bristol BS10 5NB, UK Received 18 April 2006; accepted 6 June 2007 Abstract Rapid infancy weight gain is associated with subsequent higher circulating insulin-like growth factor (IGF) I levels in normal children. We hypothesized that circulating levels of growth hormone binding protein (GHBP), a putative marker of GH sensitivity, may also be associated with postnatal weight gain and insulin secretion. In 751 normal children aged 7 to 8 years, we measured insulin, glucose, GHBP, IGF-I, IGF binding protein (IGFBP) 1, and IGFBP-3 levels in a fasting venous blood sample. Insulin secretion was assessed by measuring insulin and glucose levels 30 minutes after an oral glucose load. After adjustment for current weight, birth weight was inversely related to IGF-I and GHBP levels. Children with lower birth weight and rapid weight gain between birth and 3 years had higher IGF-I and GHBP levels and also lower IGFBP-1 levels than other children. Allowing for current body mass index, GHBP levels were positively related to insulin secretion. In conclusion, children who showed rapid early postnatal weight gain after low birth weight have higher levels of GHBP than other children. Increased GH sensitivity in such children could contribute to links between rapid infancy weight gain and subsequent faster rates of childhood growth and maturation. © 2007 Elsevier Inc. All rights reserved. 1. Introduction There seems to be a wide range of growth hormone (GH) sensitivity in normal individuals. In a recent study, the insulin-like growth factor (IGF) I increment to a single injection of GH was 80% higher in obese children and 36% higher in tall children compared with controls; in contrast, short children had a stimulated IGF-I absolute level below that of the controls [1]. We previously observed in normal children that differences in circulating levels of IGF-I were predicted by birth weight and early weight gain between 0 and 2 years [2]. Relatively low birth weights and rapid postnatal weight gain predicted higher IGF-I levels at age 5 years [2]. We hypothesized that variations in early postnatal weight gain may predict further markers of receptor sensitivity and bioactivity of the GH/IGF-I axis at age 8 years. Insulin-like growth factor I generation is dependent on the combination of both GH and insulin [3-5]. Growth hormone binding protein (GHBP) is the cleaved extramembranous portion of the GH receptor (GHR) [6]. In Laron syndrome, genetic defects in the GHR typically lead to absent GHBP, low IGF-I levels, and poor growth despite high GH secretion [7,8]. Hepatic GHR numbers and circulating GHBP levels are regulated by insulin activity [9,10]. Children and adolescents with type 1 diabetes mellitus are relatively GH resistant, reflecting their portal insulin insufficiency [4]. In contrast, increased GH sensitivity in obese children [1] could reflect their hyperinsulinemia, which up-regulates GHBP levels and IGF-I generation and also increases IGF-I bioactivity by lowering levels of IGF binding protein (IGFBP) 1 [11]. Metabolism Clinical and Experimental 56 (2007) 1412 – 1417 www.elsevier.com/locate/metabol ⁎ Corresponding author. Tel.: +44 0 1223 336 886; fax: +44 0 1223 336 996. E-mail address: dbd25@cam.ac.uk (D.B. Dunger). 0026-0495/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.metabol.2007.06.004