Low Plasma Ghrelin Level in Gastrectomized Patients Is Accompanied by Enhanced Sensitivity to the Ghrelin-Induced Growth Hormone Release

Abstract

Ghrelin is a brain-gut peptide with potent GH-releasing activities. It has been suggested that the majority of circulating ghrelin originates from the stomach, with a smaller portion from the small intestine. Gastrectomy (GASTRX) significantly reduces circulating ghrelin concentrations. The implication of decreased circulating ghrelin on the somatotropic axis post GASTRX has not been studied. Therefore, we aimed to investigate the somatotropic axis in 10 gastrectomized patients who underwent total GASTRX for various reasons at least 2 yr ago. At baseline circulating total ghrelin, GH, IGF-I, and IGF binding protein (IGFBP)-3 levels were measured. The GH stimulation test consisted of an insulin-induced hypoglycemia, ghrelin in two iv bolus doses (0.1 and 1 microg/kg), and a GHRH test. GH sensitivity was assessed by an IGF-I generation test. All the tests were performed 2 wk apart. At baseline serum ghrelin levels were reduced by 55% in GASTRX patients, compared with the control group (P < 0.05). IGF-I (P < 0.05) and IGFBP-3 (P < 0.01) levels were also significantly lower than in controls. GH response to the insulin-induced hypoglycemia test in both GASTRX and control subjects was of similar magnitude, whereas circulating plasma ghrelin levels in GASTRX patients were not modified during hypoglycemia. Both doses (0.1 and 1.0 microg/kg) of ghrelin stimulated GH release significantly more in GASTRX than control subjects, respectively (peak mean GH +/- se: 18.2 +/- 5.6 vs. 5.4 +/- 1.3 microg/liter, P < 0.03; and 58.7 +/- 7.5 vs. 35.3 +/- 1.9 microg/liter, P < 0.01). There was no difference in GHRH-induced GH response between GASTRX patients and control subjects (P > 0.05). Concomitantly, increased increments in IGF-I and IGFBP-3 to a single bolus of GH were found (P < 0.03). In conclusion, our data suggest that low circulating ghrelin levels, found in GASTRX patients, are accompanied by enhanced ghrelin sensitivity with respect to GH response. This is associated with increased GH responsiveness. GASTRX is a state of acquired chronic hypoghrelinemia that may require replacement with ghrelin, and it is tempting to speculate that this may affect the GH-IGF-IGFBP axis.

The islet ghrelin cell

“…Thus, in rats only 20% of circulating ghrelin remains after fundectomy (Dornonville de la Cour et al 2001). The situation is, however, different in humans where 35-45% remains after total gastrectomy (Ariyasu et al 2001, Popovic et al 2005.…”

“…Hence between three and five million ghrelin cells are present in each adult human pancreas. In humans 35-45% of the circulating ghrelin remains when the stomach, which is regarded as the dominating site of ghrelin production, is surgically removed (Ariyasu et al 2001, Popovic et al 2005. It is highly likely that the islet ghrelin cells together substantially contribute to a substantial part of the remaining circulating ghrelin.…”

Ghrelin restores ‘lean-type’ hunger and energy expenditure profiles in morbidly obese subjects but has no effect on postgastrectomy subjects

“…It is also known that ghrelin has acute effects on glucose disposal and enhances growth hormone release in gastrectomized subjects, suggesting these subjects are sensitive to the acute metabolic effects of ghrelin. 22,23 Subjects who have had a previous total gastrectomy often complain of reduced appetite and have difficulty with weight gain after their operation. 24,25 This may be secondary to low plasma ghrelin levels that follow gastrectomy, and replacement of ghrelin in these patients would seem an attractive therapeutic option.…”

The effect of fundus resection on weight loss and ghrelin levels in rats

“…Moreover, other studies show a signifi cant decrease in ghrelin levels in gastric resections including fundus (12). In patients with total gastrectomy, ghrelin levels found to be 50 % lower than in healthy individuals (13).…”