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University of Pennsylvania School of Medicine Department of Medicine Division of Endocrinology, Diabetes and Metabolism Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Rexford S. Ahima, M.D., Ph.D., University of Pennsylvania School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Philadelphia, Pennsylvania 19104. E-mail: ahima{at}mail.med.upenn.edu.
The worldwide increase in the incidence of type 2 diabetes and the recognition that intensive glycemic control reduces long-term complications have spurred the development of newer drugs (1). Exenatide, a glucagon-like peptide-1 mimetic, enhances insulin secretion, suppresses glucagon, promotes satiety, and decreases weight. Inhibition of dipeptidyl peptidase-IV prevents the breakdown of endogenous glucagon-like peptide-1, thereby augmenting the action of this incretin. The amylin analog pramlintide acts in concert with insulin to suppress glucagon and delay gastric emptying. These newer drugs do not typically provoke hypoglycemia or weight gain as did the older antidiabetic drugs, but they are not more effective and are certainly more expensive (2).
Esler et al. (3) in the current issue of Endocrinology have demonstrated antidiabetic properties of GH secretagogue receptor (GHS-R)-1a antagonists in rodents. Ghrelin, the natural ligand of GHS-R1a, is an acylated peptide consisting of 28 amino acids and uniquely esterified with an octanoic acid on the hydroxyl group of serine at position 3 (4). The stomach is the main source of ghrelin, although expression of ghrelin has been detected in the pancreas, pituitary, and hypothalamus. Ghrelin is secreted in a pulsatile manner and also in relation to feeding. In humans, ghrelin peaks before meals, suggesting a role as a hunger signal (4). Circulating ghrelin concentration is inversely associated with the body mass index; thus, obese individuals have lower levels than lean individuals. An exception is the Prader-Willi syndrome where morbid obesity is associated with hypersecretion of ghrelin. Ghrelin is nutritionally regulated. Food intake, especially ingestion of glucose and to a lesser extent fat, suppresses ghrelin. Conversely, calorie restriction increases ghrelin (4). GHS-R1a is highly expressed in the hypothalamus and pituitary where it mediates the effects of acylated ghrelin on feeding, energy balance, and hormone secretion (4, 5). Peripheral and particularly intracerebroventricular injection of acylated ghrelin stimulates feeding, reduces energy expenditure, and increases adiposity in rodents (6). Subcutaneous injection of ghrelin stimulates appetite in humans (7). Studies in rodents indicate that ghrelin exerts its anorexigenic action by targeting the hypothalamus and brain stem (8). In contrast to the strong pharmacological evidence, deletion of Ghrelin or Ghsr in mice resulted in a normal or mild metabolic phenotype (9, 10, 11). Nonetheless, interest in the role of ghrelin in glucose homeostasis has persisted.
Ghrelin and GHS-R1a are expressed in pancreatic islets, and ghrelin inhibits glucose-induced insulin release via a paracrine mechanism (12). Treatment with GHS-R1a antagonist or immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed insulin (13). Furthermore, deletion of Ghrelin enhanced insulin release and glucose tolerance. Ghrelin deficiency in Lepob/ob mice did not reverse hyperphagia or obesity but augmented insulin secretion and peripheral insulin sensitivity (14). Thus, antagonism of ghrelin may provide a potential therapeutic option for type 2 diabetes. As predicted, Esler et al. (3) observed that acylated but not des-acylated ghrelin inhibited insulin secretion from rat islets in a dose-dependent manner, and this effect was fully blocked by a novel GHS-R1a antagonist. Oral administration of GHS-R1a antagonist improved glucose tolerance by stimulating insulin secretion. However, unlike nateglinide, GHS-R1a antagonist did not induce hypoglycemia. Moreover, GHS-R1a antagonist had no apparent effect on insulin sensitivity. Interestingly, GHS-R1a antagonist decreased food intake and adiposity in obese mice and was more potent than the cannabinoid receptor-1 antagonist rimonabant. GHS-1Ra antagonist treatment resulted in similar reductions in food intake and weight as pair-feeding, suggesting that these compounds mainly inhibit food intake. The anorexigenic action of GHS-R1a antagonist was related to the concentration in the brain, suggesting a central effect on energy balance. Because ghrelin stimulates gastric emptying (15), the effect of GHS-1Ra antagonist on gastric motility was studied. Although there was a mild delay in gastric emptying, the dose of GHS-R1a antagonist was much higher than required for weight loss or improvement in glucose homeostasis.
Overall, these studies demonstrate that oral administration of GHS-R1a antagonist stimulates insulin release, inhibits feeding, and decreases body weight in rodents. However, questions remain as to how these novel compounds specifically regulate insulin and energy balance. How GHS-1Ra antagonist would affect the kinetics of insulin after an oral glucose load was not determined. The cellular mechanisms linking GHS-1Ra antagonist to insulin production and coupling of glucose to insulin were not examined. Furthermore, whether GHS-1Ra antagonist influences the response of pancreatic β-cells to other secretagogues besides glucose was not studied. The anorexigenic action of GHS-1Ra antagonist is an advantage, given that commonly used antidiabetics, e.g. insulin, sulfonylureas, glinides, and thiazolidinediones, increase weight. However, whether GHS-1Ra antagonist decreases food intake through taste aversion or illness was not determined. The transport of GHR-1Ra antagonist across the blood-brain barrier and the targets in the hypothalamus and other regions of the brain were not studied. Moreover, the elucidation of effects of GHS-1Ra antagonist on energy expenditure and fuel oxidation is necessary.
Despite these shortcomings, the new data by Esler et al. (3) provide compelling evidence that GHS-1Ra antagonists enhance insulin secretion. Moreover, these novel compounds have therapeutic advantages, such as not provoking hypoglycemia even under fasted conditions, and avoiding weight gain typical of antidiabetic medications. The challenge is whether these results in rodents can be translated to primates and, ultimately, humans.
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Abbreviation: GHS-R, GH secretagogue receptor.
Received August 10, 2007.
Accepted for publication August 21, 2007.
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