FREE INSULIN-LIKE GROWTH-FACTORS IN HUMAN OBESITY

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) a nd reduced somatic growth. Thus, the riddle of ''normal growth without GH'' in obese children and the mechanisms behind the GH suppression h ave remained unsolved. Insulin reduces hepatic production of IGF-bindi ng protein-1 (IGFBP-1), an in vitro inhibitor of IGF bioactivity, and it has been suggested that the obesity-related hyperinsulinemia may in crease free (bioactive) IGF in vivo by reducing the concentration of I GFBP-1. We have recently developed a method that during near in vivo c onditions isolates the free, unbound fractions of IGF-I and IGF-II in human serum. Using this method, we have determined overnight fasting s erum levels of free IGFs in obese subjects and compared the results wi th levels of total (extractable) IGFs, IGFBPs, GH, and insulin. The st udy included 92 healthy subjects (56 males and 36 females) allocated t o three age-matched groups depending on body mass index (BMI): 31 cont rols (BMI less than or equal to 25), 33 subjects with moderate obesity (25 < BMI < 30), and 28 subjects with severe obesity (BMI greater tha n or equal to 30). Fasting serum insulin correlated positively (r = .6 1, 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 inverse ly 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 o besity 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 unalter ed. 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 incre ased (P < .05) in obese subjects, whereas serum free IGF-II was unalte red. All phenomena were more pronounced in males than in females. We c onclude that in obesity, the concentration of free IGF-I in fasting se rum is increased. This is likely a result of decreased circulating IGF BP-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 IG FBP-3 and normal levels of serum total IGF-I support the interpretatio n that obese subjects are hypersensitive to the actions of GH. Copyrig ht (C) 1995 by W.B. Saunders Company.