Elevated insulin levels contribute to the reduced growth hormone (GH) response to GH-releasing hormone in obese subjects

We have recently presented experimental evidence indicating that insulin ha s a physiologic inhibitory effect on growth hormone (GH) release in healthy humans. The aim of the present study was to determine whether in obesity, which is characterized by hyperinsulinemia and blunted GH release, insulin contributes to the GH defect. To this aim, we used a simplified experimenta l protocol previously used in healthy humans to isolate the effect of insul in by removing the interference of free fatty acids (FFAs), which are known to block GH release. Six obese subjects (four men a nd two women; age, 30. 8 +/- 5.2 years; body mass index, 36.8 +/- 2.8 kg/m(2) [mean +/- SE]) and s ix normal subjects (four men and two women; age, 25.8 +/- 1.9 years; body m ass index, 22.7 +/- 1.1 kg/m(2)) received intravenous (IV) GH-releasing hor mone (GHRH) 0.6 mu g/kg under three experimental conditions: (1) IV 0.9% Na Cl infusion and oral placebo, (2) IV 0.9% NaCl infusion and oral acipimox, an antilipolytic agent able to reduce FFA levels (250 mg at 6 and 2 hours b efore GHRH), and (3) euglycemic-hyperinsulinemic clamp (insulin infusion ra te, 0.4 mU.kg(-1).min(-1)). As expected, after placebo, the GH response to GHRH was lower for obese subjects versus normals (488 +/- 139 v 1,755 +/- 4 12 mu g/L.120 min, P < .05). Acipimox markedly reduced FFA levels and produ ced a mild reduction of insulin levels; under these conditions, the GH resp onse to GHRH was increased in both groups, remaining lower in obese versus normal subjects (1,842 +/- 360 v 4,871 +/- 1,286 mu g/L.120 min, P < .05). In both groups, insulin infusion yielded insulin levels usually observed un der postprandial conditions and reduced circulating FFA to the levels obser ved after acipimox administration. Again, the GH response to GHRH was lower for obese subjects versus normals (380 +/- 40 v 1,075 +/- 206 mu g/L.120 m in, P < .05), and in both groups, it was significantly lower than the corre sponding response after acipimox. In obese subjects, as previously reported in normals, the GH response to GHRH was inversely correlated with the mean serum insulin (r = -.70, P < .01). In conclusion, our data indicate that i n the obese, as in normal subjects, the GH response to GHRH is a function o f insulin levels. The finding that after both the acipimox treatment and th e insulin clamp the obese still show higher insulin levels and a lower GH r esponse to GHRH than normal subjects suggests that hyperinsulinemia is a ma jor determinant of the reduced GH release associated with obesity. Copyrigh t(C) 1999 by W.B. Saunders Company.