Ghrelin Suppresses Glucose-Stimulated Insulin Secretion and Deteriorates Glucose Tolerance in Healthy Humans

OBJECTIVE

The orexigenic gut hormone ghrelin and its receptor are present in pancreatic islets. Although ghrelin reduces insulin secretion in rodents, its effect on insulin secretion in humans has not been established. The goal of this study was to test the hypothesis that circulating ghrelin suppresses glucose-stimulated insulin secretion in healthy subjects.

RESEARCH DESIGN AND METHODS

Ghrelin (0.3, 0.9 and 1.5 nmol/kg/h) or saline was infused for more than 65 min in 12 healthy patients (8 male/4 female) on 4 separate occasions in a counterbalanced fashion. An intravenous glucose tolerance test was performed during steady state plasma ghrelin levels. The acute insulin response to intravenous glucose (AIRg) was calculated from plasma insulin concentrations between 2 and 10 min after the glucose bolus. Intravenous glucose tolerance was measured as the glucose disappearance constant (Kg) from 10 to 30 min.

RESULTS

The three ghrelin infusions raised plasma total ghrelin concentrations to 4-, 15-, and 23-fold above the fasting level, respectively. Ghrelin infusion did not alter fasting plasma insulin or glucose, but compared with saline, the 0.3, 0.9, and 1.5 nmol/kg/h doses decreased AIRg (2,152 ± 448 vs. 1,478 ± 2,889, 1,419 ± 275, and 1,120 ± 174 pmol/l) and Kg (0.3 and 1.5 nmol/kg/h doses only) significantly (P < 0.05 for all). Ghrelin infusion raised plasma growth hormone and serum cortisol concentrations significantly (P < 0.001 for both), but had no effect on glucagon, epinephrine, or norepinephrine levels (P = 0.44, 0.74, and 0.48, respectively).

CONCLUSIONS

This is a robust proof-of-concept study showing that exogenous ghrelin reduces glucose-stimulated insulin secretion and glucose disappearance in healthy humans. Our findings raise the possibility that endogenous ghrelin has a role in physiologic insulin secretion, and that ghrelin antagonists could improve β-cell function.Ghrelin has gained considerable attention over the last decade for its unique role in regulating mealtime hunger and lipid metabolism, as well as short- and long-term energy homeostasis (1–3). It is the only known circulating factor that promotes food intake and increases fat mass. Ghrelin is secreted mainly from the stomach and proximal small bowel, and stimulates growth hormone (GH) secretion (4–6), in addition to its effect on energy balance. In healthy subjects, plasma ghrelin levels rise progressively before meals and fall to a nadir within 1 hour after eating, with changes in plasma levels during meals varying two- to threefold (7–8). Under pathologic conditions associated with severe malnutrition and weight loss, such as anorexia nervosa (9), cancer, or cardiac cachexia (10–11), plasma total ghrelin levels are increased up to threefold compared with healthy individuals. Besides its well known effects on feeding behavior, fat mass, and GH secretion, ghrelin has recently been implicated in the regulation of glucose homeostasis (12–13).The GH secretagogue receptor (GHSR)-1a, also known as the ghrelin receptor, is widely distributed and has been localized to the hypothalamus, pituitary, liver, adipocyte, and pancreas (14–15). Both ghrelin and GHSR are expressed in human and rat pancreatic islets on both α- (16–17) and β-cells (18–19), and ghrelin is produced in a novel endocrine islet cell type that shares lineage with glucagon-secreting cells (20–21). Pancreatic ghrelin cells exist as the predominant cell type in fetal human islets, and expression in the pancreas during development significantly precedes its occurrence in the stomach (20). In animal mutant models, an early block in the differentiation of insulin-producing β cells leads to an enormous increase in ghrelin-producing ε cells, suggesting a developmental link between ghrelin and insulin (22). In vitro, ghrelin inhibits glucose-stimulated insulin secretion in a dose-dependent manner from cultured pancreata (23), isolated pancreatic islets (19,24), and immortalized β-cell lines (19,21), suggesting that it acts directly on β cells to achieve this effect. In experimental animals, both ghrelin released from pancreatic islets and exogenous ghrelin inhibit glucose-stimulated insulin secretion (16,24–26). Targeted gene deletion of ghrelin improves glucose tolerance and augments insulin secretion in ob/ob mice, suggesting a possible physiologic role which could be mediated by effects on islet function (27). Consistent with these findings, ghrelin gene deletion was shown to prevent glucose intolerance induced by a high-fat diet, an environmentally-induced model of hyperglycemia (26). Together, these findings indicate the potential of ghrelin blockade to prevent both genetically (ob gene)- and environmentally (high-fat diet)-induced glucose intolerance.The effect of ghrelin on insulin secretion in humans is controversial. Intravenous injection of ghrelin decreases plasma insulin and increases blood glucose in some studies, suggesting inhibition of insulin secretion (12,28). However, this finding has not been universally observed (29), and it is unclear whether such effects occur at physiologic or only pharmacologic doses of ghrelin. Prior studies performed in humans primarily assessed the impact of ghrelin on β-cell function in the fasting state, and there is little information on the effect of the peptide on stimulated insulin release. Therefore, the role of ghrelin in the regulation of glucose homeostasis in humans remains poorly understood.In this study, we determined the effect of ghrelin on glucose-stimulated insulin secretion and glucose tolerance. We infused acyl-ghrelin, the bioactive endogenous ligand of the GHSR-1a, at variable doses with the aim of raising plasma total ghrelin level to physiologic (less than twofold), supraphysiologic (two- to threefold) and pharmacologic (more than threefold) levels. An intravenous glucose tolerance test (IVGTT) was performed at steady state plasma ghrelin levels to determine the effect on glucose-stimulated insulin secretion and glucose tolerance in healthy, nonobese subjects.