Abstract

It is well established that spontaneous and stimulated growth hormone (GH) secretion is diminished in human obesity. In contrast to classic GH deficiency, obesity is not associated with hypopituitary levels of circulating total (extractable) insulin-like growth factor-I (IGF-I) and reduced somatic growth. Thus, the riddle of “normal growth without GH” in obese children and the mechanisms behind the GH suppression have remained unsolved. Insulin reduces hepatic production of IGF-binding protein-1 (IGFBP-1), an in vitro inhibitor of IGF bioactivity, and it has been suggested that the obesity-related hyperinsulinemia may increase free (bioactive) IGF in vivo by reducing the concentration of IGFBP-1. We have recently developed a method that during near in vivo conditions isolates the free, unbound fractions of IGF-1 and IGF-II in human serum. Using this method, we have determined overnight fasting serum levels of free IGFs in obese subjects and compared the results with levels of total (extractable) IGFs, IGFBPs, GH, and insulin. The study included 92 healthy subjects (56 males and 36 females) allocated to three age-matched groups depending on body mass index (BMI): 31 controls (BMI ≤ 25), 33 subjects with moderate obesity (25 < BMI < 30), and 28 subjects with severe obesity (BMI ≥ 30). Fasting serum insulin correlated positively ( r = .61, P < .0001) with BMI and was significantly elevated in moderate and severe obesity ( P < .05). In contrast, levels of serum GH and IGFBP-1 were suppressed in both obese groups ( P < .05), and the latter inversely correlated ( r = - .60, P < .001) with BMI. Serum free IGF-I was 470 ± 50 ng/L (mean ± SEM) in controls, and was elevated in moderate obesity by 47% (690 ± 90 ng/L, P < .05) and in severe obesity by 72% (810 ± 90 ng/L, P < .05), whereas levels of total IGF-I were unaltered. In addition, serum free IGF-I was inversely correlated with IGFBP-1 ( r = - .47, P < .001). Serum IGFBP-3 and total IGF-II were both increased ( P < .05) in obese subjects, whereas serum free IGF-II was unaltered. All phenomena were more pronounced in males than in females. We conclude that in obesity, the concentration of free IGF-I in fasting serum is increased. This is likely a result of decreased circulating IGFBP-1, again caused by hyperinsulinemia. Elevated serum free IGF-I may, by feedback, explain the low levels of GH and may be responsible for the normal growth without GH in obese children. Increased levels of IGFBP-3 and normal levels of serum total IGF-I support the interpretation that obese subjects are hypersensitive to the actions of GH.

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