Ghrelin Is Not Necessary for Adequate Hormonal Counterregulation of Insulin-Induced Hypoglycemia

Abstract

Ghrelin is a novel enteric hormone that stimulates growth hormone (GH), ACTH, and epinephrine; augments plasma glucose; and increases food intake by inducing the feeling of hunger. These characteristics make ghrelin a potential counterregulatory hormone. At present, it is not known whether ghrelin increases in response to insulin-induced hypoglycemia. To answer this question, we compared plasma ghrelin concentrations after a short-term insulin infusion that was allowed or not (euglycemic clamp) to cause hypoglycemia (2.7 ؎ 0.2 mmol/l at 30 min) in five healthy volunteers. In both studies, plasma ghrelin concentrations decreased (P < 0.01) after insulin infusion (hypoglycemia by 14%, euglycemia by 22%), reached a nadir at 30 min, and returned to baseline at 60 min, without differences between the hypoglycemia and the euglycemia studies. Glucagon, cortisol, and GH increased in response to hypoglycemia despite the decreased ghrelin. There was a strong correlation (R 2 ‫؍‬ 0.91, P < 0.002) between the insulin sensitivity of the subjects and the percentage suppression of ghrelin from baseline. These data demonstrate that ghrelin is not required for the hormonal defenses against insulin-induced hypoglycemia and that insulin can suppress ghrelin levels in healthy humans. These results raise the possibility that postprandial hyperinsulinemia is responsible for the reduction of plasma ghrelin that occurs during meal intake. Diabetes 51:2911-2914, 2002 G hrelin, a 28 -amino acid hormone, was recently identified in the stomach as the endogenous ligand for the growth hormone (GH) secretagogue receptor (1). Ghrelin is a potent stimulator of GH secretion (2); promotes ACTH, cortisol (2,3), and epinephrine (3) release; increases food intake, possibly by augmenting hypothalamic mRNA levels of neuropeptide Y and agouti gene-related protein (4); and increases plasma glucose in normal subjects (5). Recently, it was shown in humans that circulating ghrelin levels rise shortly before and fall shortly after every meal (6,7) and that ghrelin administration increases subjective hunger and voluntary food intake (8). All of these data suggest that ghrelin works as a hormone signaling the need to conserve energy (9). Therefore, ghrelin secretion might be triggered by an acute decrease of plasma glucose concentrations. The hypoglycemia alarm symptom of hunger and the responses of GH and cortisol play an important role in the defense against insulin-induced hypoglycemia (10,11). Ghrelin might act, at least in part, as a physiological mediator of these protective mechanisms. In addition, ghrelin could directly contribute to glucose counterregulation by stimulating hepatic glucose production. The prompt increase of plasma glucose after an intravenous bolus of ghrelin in healthy humans suggests a direct glycogenolytic activity (5), whereas recent data show that ghrelin upregulates markers of gluconeogenesis and downregulates markers of glycogen synthesis in hepatoma cells (12).For demonstrating that ghrelin is required for glucose counterregul...

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Meal suppression of circulating ghrelin is normalized in obese individuals following gastric bypass surgery

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