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In Obesity, Glucose Load Loses Its Early Inhibitory, But Maintains Its Late Stimulatory, Effect on Somatotrope Secretion¹

Division of Endocrinology, Department of Internal Medicine, University of Torino, Torino; Second Division of Medicine and Endocrinology, Arcispedale of Santa Maria Nuova (M.Z., R.V.), Reggio Emilia, Italy

Address all correspondence and requests for reprints to: E. Ghigo, M.D., Divisione di Endocrinologia, Ospedale Molinette, C.so A.M. Dogliotti 14, 10126 Torino, Italy.

Glucose load has a biphasic effect on GH secretion. In fact, in normal subjects, glucose load has a prompt inhibitory and a late stimulatory effect on both spontaneous and GHRH-induced GH levels. The mechanism underlying the inhibitory effect is probably mediated by the increase in hypothalamic somatostatin, whereas that underlying the stimulatory effect is unclear. On the other hand, in obesity, a reduced somatotrope responsiveness to all GH secretagogues is well known, whereas recently, we found that glucose load, but not pirenzepine and somatostatin, fails to inhibit the GHRH-induced GH rise. Thus, the inhibitory effect of hyperglycemia on GH secretion is selectively lacking in obesity. The aim of the present study was to verify whether in obesity the late stimulatory effect of glucose on GH secretion is preserved. We studied 15 female obese patients (OB; age, 33.9 ± 2.6 yr; body mass index, 36.4 ± 1.5 kg/m²; waist/hip ratio, 0.9 ± 0.1) and 12 normal female subjects (NS; 26.5 ± 1.0 yr; 21.4 ± 0.3 kg/m²) as controls. Two studies were performed. In study A (six OB and six NS) we evaluated the somatotrope response to GHRH (1 µg/kg, iv, at 0 min) alone or preceded by oral glucose (OGTT; 100 g, orally, at -45 min). In study B (nine OB and six NS) we studied the somatotrope response to OGTT (100 g, orally, at 0 min), saline plus GHRH (1 µg/kg, iv, at 150 min), and OGTT plus GHRH. In study A, the GHRH-induced GH rise in NS was higher (P < 0.01) than that in OB. OGTT blunted the GHRH-induced GH rise in NS (0–90 min area under the curve, 318.9 ± 39.1 vs. 696.3 ± 110.8 µg/min·L; P < 0.05), but failed to modify it in OB (289.1 ± 51.7 vs. 283.9 ± 44.0 µg/min·L). In study B, the GHRH-induced GH rise in NS was higher (P < 0.01) than that in OB. OGTT induced a late GH increase in both NS (150–240 min area under the curve, 249.6 ± 45.2 µg/min·L) and OB (103.2 ± 31.4 µg/min·L). Moreover, OGTT enhanced the GHRH-induced GH rise in NS as well as in OB [1433.0 ± 202.0 vs. 967.9 ± 116.3 µg/min·L (P < 0.03) and 763.8 ± 131.0 vs. 278.1 ± 52.3 µg/min·L (P < 0.01), respectively]. The GH responses to OGTT alone and combined with GHRH in OB were lower (P < 0.03) than those in NS. Our data show that in human obesity, the oral glucose load loses its precocious inhibitory effect on the GHRH-induced GH rise but maintains its late stimulatory effect on somatotrope secretion. These findings suggest that the inhibitory and stimulatory effects of glucose load on GH secretion are unlikely to be due to biphasic modulation of hypothalamic somatostatin release, which seems selectively refractory to stimulation by hyperglycemia in obesity.

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