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• W1972743455 abstract "The hormone ghrelin regulates secretion of growth hormone and energy homeostasis. Sun et al., 2006Sun Y. Asnicar M. Saha P.K. Chan L. Smith R.G. Cell Metab. 2006; 3 (this issue): 379-386Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, in this issue of Cell Metabolism, demonstrate that ghrelin inhibits insulin secretion. Deletion of ghrelin increased basal insulin level, enhanced glucose-stimulated insulin secretion, and improved peripheral insulin sensitivity. These effects were not related to changes in food intake or weight, suggesting ghrelin has unique actions on key components of glucose homeostasis. The hormone ghrelin regulates secretion of growth hormone and energy homeostasis. Sun et al., 2006Sun Y. Asnicar M. Saha P.K. Chan L. Smith R.G. Cell Metab. 2006; 3 (this issue): 379-386Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar, in this issue of Cell Metabolism, demonstrate that ghrelin inhibits insulin secretion. Deletion of ghrelin increased basal insulin level, enhanced glucose-stimulated insulin secretion, and improved peripheral insulin sensitivity. These effects were not related to changes in food intake or weight, suggesting ghrelin has unique actions on key components of glucose homeostasis. Blood glucose is tightly controlled by two key processes—insulin secretion by pancreatic β cells in response to a nutrient challenge and insulin action on major target organs, i.e., skeletal muscle, liver, and adipose tissue (Petersen and Shulman, 2006Petersen K.F. Shulman G.I. Am. J. Med. 2006; 119: S10-S16Abstract Full Text Full Text PDF PubMed Scopus (586) Google Scholar). The most common glucose disorder, type 2 diabetes, is often associated with obesity and results from insufficient insulin production/secretion and insulin resistance. Antidiabetic drugs include those that stimulate insulin synthesis and secretion, e.g., sulfonylureas and meglitinides; insulin sensitizers, e.g., thiazolidinedines; and biguanides, e.g., metformin, which decrease glucose production by the liver. Exenatide, a drug that mimics the action of the gut hormone glucagon-like peptide (GLP)-1 and augments insulin release, was recently approved for treatment of type 2 diabetes. When patients fail to respond to these drugs, insulin treatment is initiated to avoid diseases of the kidneys, eyes, cardiovascular and nervous systems. Ghrelin acts on the growth hormone secretagogue receptor (GHSR) and was named for its potent effect in stimulating growth hormone secretion (reviewed in Smith et al., 2005Smith R.G. Jiang H. Sun Y. Trends Endocrinol. Metab. 2005; 16: 436-442Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Subsequent studies found that ghrelin increased food intake when injected in the brain or peripherally, lowered energy expenditure and increased weight. Hence, it was proposed that ghrelin and GHSR could be targeted for obesity treatment. However, genetic manipulation of ghrelin and ghsr has not always produced the expected leanness in animals, leading to doubts about their importance in the physiological control of energy balance and weight (Sun et al., 2004Sun Y. Wang P. Zheng H. Smith R.G. Mol. Cell. Biol. 2004; 23: 7973-7981Crossref Scopus (518) Google Scholar, Wortley et al., 2004Wortley K.E. Anderson K.D. Garcia K. Murray J.D. Malinova L. Liu R. Moncrieffe M. Thabet K. Cox H.J. Yancopoulos G.D. et al.Proc. Natl. Acad. Sci. USA. 2004; 101: 8227-8232Crossref PubMed Scopus (377) Google Scholar, Wortley et al., 2005Wortley K.E. del Rincon J.P. Murray J.D. Garcia K. Iida K. Thorner M.O. Sleeman M.W. J. Clin. Invest. 2005; 115: 3573-3578Crossref PubMed Scopus (303) Google Scholar, Zigman et al., 2005Zigman J.M. Nakano Y. Coppari R. Balthasar N. Marcus J.N. Lee C.E. Jones J.E. Deysher A.E. Waxman A.R. White R.D. et al.J. Clin. Invest. 2005; 1115: 3564-3572Crossref Scopus (473) Google Scholar). Nonetheless, interest in the biology of ghrelin, in particular its role in glucose control, has persisted. The highest expression of ghrelin occurs in the stomach. Ghrelin-producing cells are also present in intestine, hypothalamus, and pancreatic islet. In the latter, ghrelin may play a developmental role, as well as modulate release of insulin and glucagon (reviewed in Smith et al., 2005Smith R.G. Jiang H. Sun Y. Trends Endocrinol. Metab. 2005; 16: 436-442Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). Deficiency of the adipocyte hormone leptin results in hyperphagia, obesity, and insulin resistance, and a variety of neuroendocrine deficits, notably hypogonadism. Lepob/ob mice initially maintain normal glucose levels by increasing islet size and insulin levels but eventually develop diabetes. Studies have shown that leptin and ghrelin act as mutual antagonists to affect energy homeostasis; hence, leptin blocks the ability of ghrelin to increase appetite or vice versa (Barazzoni et al., 2003Barazzoni R. Zanetti M. Stebel M. Biolo G. Cattin L. Guarnieri G. Gastroenterology. 2003; 124: 1188-1192Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar). In the current issue of Cell Metabolism, Sun et al., 2006Sun Y. Asnicar M. Saha P.K. Chan L. Smith R.G. Cell Metab. 2006; 3 (this issue): 379-386Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar examined the interaction between ghrelin and leptin using a genetic approach. To their surprise, ablation of ghrelin in leptin-deficient mice did not reverse hyperphagia and obesity. There was slight improvement in thermoregulation, but mice deficient in leptin or both ghrelin and leptin had a rapid drop in temperature when exposed to cold. The major finding was a reduction in blood glucose and increase in insulin secretion and action when ghrelin was deleted. Ghrelin deficiency augmented insulin secretion in response to glucose load (Figure 1). Importantly, ghrelin deficiency preserved the early-phase insulin secretion, a feature that is lost in type 2 diabetes. In contrast, acute ghrelin treatment blunted insulin secretion. Glucose and insulin tolerance were both increased in the absence of ghrelin. In order to address the mechanisms underlying ghrelin's effect on peripheral insulin sensitivity, the authors performed a hyperinsulinemic euglycemic clamp study on ghrelin knockout mice. The loss of ghrelin increased insulin's ability to suppress glucose production. In contrast, the rate of glucose infusion to attain euglycemia and rate of glucose disposal were significantly increased in the absence of ghrelin, confirming improvement in peripheral insulin sensitivity (Figure 1). The ability of ghrelin deficiency to improve glucose homeostasis did not depend on resistin, a hormone associated with insulin resistance (Steppan et al., 2001Steppan C.M. Bailey S.T. Bhat S. Brown E.J. Banerjee R.R. Wright C.M. Patel H.R. Ahima R.S. Lazar M.A. Nature. 2001; 409: 307-312Crossref PubMed Scopus (3775) Google Scholar). Resistin was elevated in leptin-deficient mice with or without ghrelin. Because deletion of uncoupling protein 2 (Ucp2) has previously been shown to increase insulin secretion and glucose tolerance in Lepob/ob mice, the authors examined its regulation in the current model (Zhang et al., 2001Zhang C.Y. Baffy G. Perret P. Krauss S. Peroni O. Grujic D. Hagen T. Vidal-Puig A.J. Boss O. Kim Y.B. et al.Cell. 2001; 105: 745-755Abstract Full Text Full Text PDF PubMed Scopus (793) Google Scholar). UCP2 was drastically suppressed in the pancreas of ghrelin-deficient mice, consistent with a role in the observed phenotype. Because these studies were done in a global ghrelin knockout, the organs mediating the dual effects on insulin secretion and insulin sensitivity are unknown. Ghrelin could act directly on β cells via paracrine or endocrine mechanisms (Figure 1). Likewise, the reasons for improvement in insulin sensitivity are unknown. These new data offer insights into how ghrelin affects key components of glucose homeostasis, i.e., β cell function and organ response to insulin. However, the degree to which muscle and adipose tissue contribute to the increase in “glucose disposal” is not known. Since the use of Lepob/ob mice could be confounded by neuroendocrine and metabolic abnormalities due to leptin deficiency, e.g., steatosis, the role of ghrelin in glucose metabolism remains to be tested in other experimental models of “common” (polygenic) obesity and type 2 diabetes, e.g., diet-induced obese mice. While UCP2 is a potential culprit, a causal role for it in insulin secretion remains to be determined, as does the mechanism through which ghrelin acts on UCP2 in various peripheral tissues to regulate glucose metabolism. Still unanswered is why pharmacological treatment with ghrelin increases feeding and weight, while deletion of ghrelin does not affect these parameters. The results of this study are in agreement with Dezaki et al., 2004Dezaki K. Hosoda H. Kakei M. Hashiguchi S. Watanabe M. Kangawa K. Yada T. Diabetes. 2004; 53: 3142-3151Crossref PubMed Scopus (278) Google Scholar, who reported ghrelin administration inhibited glucose-induced insulin secretion, but neither ghrelin nor ghrelin antagonists affected insulin sensitivity. In contrast, low ghrelin level inhibited while high levels stimulated insulin from mouse islets (Salehi et al., 2004Salehi A. Dornonville de la Cour C. Hakanson R. Lundquist I. Regul. Pept. 2004; 118: 143-150Crossref PubMed Scopus (109) Google Scholar). Furthermore, Heijboer et al., 2006Heijboer A.C. van den Hoek A.M. Parlevliet E.T. Havekes L.M. Romijn J.A. Pijl H. Corssmit E.P. Diabetologia. 2006; 49: 732-738Crossref PubMed Scopus (59) Google Scholar reported that ghrelin treatment hampered insulin's ability to suppress glucose production and increased glucose disposal, actions opposite to the current study. These discrepancies may arise from additional effects of ghrelin treatment on endogenous ghrelin levels, glucocorticoids, and various hormones. Overall, the studies provide compelling evidence that ghrelin has unique dual effects on glucose homeostasis, at least in a genetic model. Ghrelin antagonism may be a new approach for treating type 2 diabetes by increasing insulin secretion and enhancing peripheral insulin action. The challenge is to ascertain if these results in rodents can be translated to patients. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob miceSun et al.Cell MetabolismMay, 2006In BriefGhrelin and leptin are suggested to regulate energy homeostasis as mutual antagonists on hypothalamic neurons that regulate feeding behavior. We employed reverse genetics to investigate the interplay between ghrelin and leptin. Leptin-deficient mice (ob/ob) are hyperphagic, obese, and hyperglycemic. Unexpectedly, ablation of ghrelin in ob/ob mice fails to rescue the obese hyperphagic phenotype, indicating that the ob/ob phenotype is not a consequence of ghrelin unopposed by leptin. Remarkably, deletion of ghrelin augments insulin secretion in response to glucose challenge and increases peripheral insulin sensitivity; indeed, the hyperglycemia exhibited by ob/ob mice is markedly reduced when ob/ob mice are bred onto the ghrelin−/− background. Full-Text PDF Open Archive" @default.
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• W1972743455 title "Ghrelin—a new player in glucose homeostasis?" @default.
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