CLINICAL STUDY Serum markers of GH and insulin action in 12-year-old children born small for gestational age Sirpa Tenhola 1 , Pirjo Halonen 2 , Jarmo Ja ¨a ¨skela ¨inen 1 and Raimo Voutilainen 1 1 Department of Pediatrics, Kuopio University and University Hospital, PO Box 1777, FI-70211 Kuopio, Finland and 2 IT Service Center, Kuopio University, PO Box 1627, FI-70211 Kuopio, Finland (Correspondence should be addressed to R Voutilainen; Email: raimo.voutilainen@uku.fi) Abstract Objectives: Our aim was to determine whether markers of growth hormone and insulin action differ between children born small for gestational age (SGA) and those born of an appropriate size for gesta- tional age (AGA). Design: Fifty-five SGA children and their 55 age- and sex-matched AGA control subjects were studied in a case-control setting at 12 years of age. Methods: We examined serum concentrations of insulin-like growth factor (IGF)-I, IGF-II, IGF-binding protein (IGFBP)-1 and IGFBP-3, sex hormone binding globulin (SHBG), leptin, fasting insulin, and blood glucose. Insulin sensitivity was evaluated by the homeostasis model assessment for insulin resistance (HOMA-IR). Results: The body mass index (BMI), sex, and puberty-adjusted mean serum IGF-I concentration was higher in the SGA than in the AGA children (303.4 vs 282.3 mg/l, P ¼ 0.006). The mean serum con- centrations of IGF-II, IGFBP-I, IGFBP-3, SHBG, fasting insulin, blood glucose and HOMA-IR did not differ between the SGA and the AGA group. The BMI, sex, and puberty-adjusted mean serum leptin concentration was lower in the SGA than in the AGA children (7.9 vs 10.1 mg/l, P ¼ 0.037). In multiple logistic regression analysis, high HOMA-IR predicted high serum IGF-I levels in the SGA children (odds ratio 8.3; 95% confidence interval 1.7–41; P ¼ 0.010), whereas in the AGA group HOMA-IR did not associate with the serum IGF-I level. Conclusions: The BMI, sex, and puberty-adjusted mean serum IGF-I concentration was significantly higher and the leptin concentration was lower in the SGA than in the AGA children. No differences were found in the indices of insulin action or sensitivity between the SGA and AGA children at 12 years of age. However, HOMA-IR strongly associated with serum IGF-I levels in the SGA children. European Journal of Endocrinology 152 335–340 Introduction Low birth weight has been associated with type-2 dia- betes, cardiovascular diseases and also with short stature in later life (1–4). Approximately 10% of children born small for gestational age (SGA) are short as adults (adult height ,2 2 S.D. scores) (3, 4). Furthermore, intrauterine growth restriction (IUGR) may influence the growth hormone (GH) secretion profile in prepuber- tal children (5 – 7). The insulin-like growth factors (IGFs) mediate many of the anabolic and mitogenic actions of GH. Serum levels of IGF-I and IGF binding protein (IGFBP)-3 reflect the endogenous GH secretion in healthy children; short children have lower IGF-I and IGFBP-3 levels than taller ones (8). During fetal life serum IGF-I levels are relatively low increasing with gestational age (9). In newborns, serum IGF-I levels correlate with birth weight and length; the IGF-I concentrations are lower in SGA than in appropriate for gestational age (AGA) babies (9, 10). Serum IGF-I and IGFBP-3 concen- trations increase slowly in early childhood with a steep increase during puberty, decreasing thereafter, while serum IGF-II concentrations are constant after the first few weeks of life (11, 12). Low birth weight has been associated with increased circulating concen- trations of IGF-I in childhood (13–16). Cutfield and co- workers have reported that short IUGR born children have higher IGF-I and IGFBP-3 concentrations than their short AGA born control subjects at 7 to 8 years mean age (16). Furthermore, it has been hypothesized that abnormalities in somatotropic actions of GH and IGF-I in short SGA children may contribute directly to reduced insulin sensitivity (7). IGFBP-1 is a specific IGF binding protein acutely modulating IGF bioactivity. Its expression in hepatocytes is downregulated by insu- lin, and serum IGFBP-1 concentration is a sensitive marker of insulin action (17). IGFBP-1 serum levels decline with age in prepubertal children, and the lowest values are found in puberty (12). European Journal of Endocrinology (2005) 152 335–340 ISSN 0804-4643 q 2005 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.01869 Online version via www.eje-online.org