Table of Contents
International Journal of Peptides
Volume 2010, Article ID 234709, 25 pages
http://dx.doi.org/10.1155/2010/234709
Review Article

Effect of Ghrelin on Glucose-Insulin Homeostasis: Therapeutic Implications

1Department of Medicine, School of Health Science, University of A Coruña, Xubias de Arriba 84, 15006 A Coruña, Spain
2Institute of Biomedical Investigations (INIBIC), Group of Endocrinology, Xubias de Arriba, 84, 15006 A Coruña, Spain
3Department of Endocrinology, Complexo Hospitalario Universitario A Coruña, Xubias de Arriba, 84, 15006 A Coruña, Spain

Received 21 September 2009; Accepted 23 November 2009

Academic Editor: Akio Inui

Copyright © 2010 Susana Sangiao-Alvarellos and Fernando Cordido. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. E. E. Muller, V. Locatelli, and D. Cocchi, “Neuroendocrine control of growth hormone secretion,” Physiological Reviews, vol. 79, no. 2, pp. 511–607, 1999. View at Google Scholar · View at Scopus
  2. C. Y. Bowers, “Growth hormone-releasing peptide (GHRP),” Cellular and Molecular Life Sciences, vol. 54, no. 12, pp. 1316–1329, 1998. View at Publisher · View at Google Scholar · View at Scopus
  3. R. G. Smith, “Development of growth hormone secretagogues,” Endocrine Reviews, vol. 26, no. 3, pp. 346–360, 2005. View at Publisher · View at Google Scholar · View at Scopus
  4. R. G. Smith, K. Cheng, W. R. Schoen et al., “A nonpeptidyl growth hormone secretagogue,” Science, vol. 260, no. 5114, pp. 1640–1643, 1993. View at Google Scholar · View at Scopus
  5. R. G. Smith, R. Leonard, A. R. T. Bailey et al., “Growth hormone secretagogue receptor family members and ligands,” Endocrine, vol. 14, no. 1, pp. 9–14, 2001. View at Google Scholar · View at Scopus
  6. R. G. Smith, Y. Sun, L. Betancourt, and M. Asnicar, “Growth hormone secretagogues: prospects and potential pitfalls,” Best Practice and Research: Clinical Endocrinology and Metabolism, vol. 18, no. 3, pp. 333–347, 2004. View at Publisher · View at Google Scholar · View at Scopus
  7. M. L. Isidro and F. Cordido, “Growth hormone secretagogues,” Combinatorial Chemistry and High Throughput Screening, vol. 9, no. 3, pp. 175–180, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. R. G. Smith, S. Feighner, K. Prendergast, X. Guan, and A. Howard, “A new orphan receptor involved in pulsatile growth hormone release,” Trends in Endocrinology and Metabolism, vol. 10, no. 4, pp. 128–135, 1999. View at Publisher · View at Google Scholar · View at Scopus
  9. M. Kojima, H. Hosoda, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, “Ghrelin is a growth-hormone-releasing acylated peptide from stomach,” Nature, vol. 402, no. 6762, pp. 656–660, 1999. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Tschop, D. L. Smiley, and M. L. Heiman, “Ghrelin induces adiposity in rodents,” Nature, vol. 407, no. 6806, pp. 908–913, 2000. View at Publisher · View at Google Scholar · View at Scopus
  11. Y. Date, M. Kojima, H. Hosoda et al., “Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans,” Endocrinology, vol. 141, no. 11, pp. 4255–4261, 2000. View at Google Scholar · View at Scopus
  12. A. J. van der Lely, M. Tschöp, M. L. Heiman, and E. Ghigo, “Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin,” Endocrine Reviews, vol. 25, no. 3, pp. 426–457, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. A. D. Howard, S. D. Feighner, D. F. Cully et al., “A receptor in pituitary and hypothalamus that functions in growth hormone release,” Science, vol. 273, no. 5277, pp. 974–977, 1996. View at Google Scholar
  14. B. Holst, A. Cygankiewicz, T. H. Jensen, M. Ankersen, and T. W. Schwartz, “High constitutive signaling of the ghrelin receptor—identification of a potent inverse agonist,” Molecular Endocrinology, vol. 17, no. 11, pp. 2201–2210, 2003. View at Publisher · View at Google Scholar · View at Scopus
  15. S. Gnanapavan, B. Kola, S. A. Bustin et al., “The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 6, pp. 2988–2991, 2002. View at Publisher · View at Google Scholar · View at Scopus
  16. J. A. Gutierrez, P. J. Solenberg, D. R. Perkins et al., “Ghrelin octanoylation mediated by an orphan lipid transferase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 17, pp. 6320–6325, 2008. View at Publisher · View at Google Scholar · View at Scopus
  17. J. Yang, M. S. Brown, G. Liang, N. V. Grishin, and J. L. Goldstein, “Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone,” Cell, vol. 132, no. 3, pp. 387–396, 2008. View at Publisher · View at Google Scholar · View at Scopus
  18. A. P. Davenport, T. I. Bonner, S. M. Foord et al., “International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function,” Pharmacological Reviews, vol. 57, no. 4, pp. 541–546, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. H. Hosoda, M. Kojima, H. Matsuo, and K. Kangawa, “Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue,” Biochemical and Biophysical Research Communications, vol. 279, no. 3, pp. 909–913, 2000. View at Publisher · View at Google Scholar · View at Scopus
  20. P. Alvarez-Castro, M. L. Isidro, J. Garcia-Buela et al., “Marked GH secretion after ghrelin alone or combined with GH-releasing hormone (GHRH) in obese patients,” Clinical Endocrinology, vol. 61, no. 2, pp. 250–255, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. G. Baldanzi, N. Filigheddu, S. Cutrupi et al., “Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT,” Journal of Cell Biology, vol. 159, no. 6, pp. 1029–1037, 2002. View at Publisher · View at Google Scholar · View at Scopus
  22. N. Filigheddu, V. F. Gnocchi, M. Coscia et al., “Ghrelin and des-acyl ghrelin promote differentiation and fusion of C2C12 skeletal muscle cells,” Molecular Biology of the Cell, vol. 18, no. 3, pp. 986–994, 2007. View at Publisher · View at Google Scholar · View at Scopus
  23. K. Nonogaki, K. Ohashi-Nozue, and Y. Oka, “Induction of hypothalamic serum- and glucocorticoid-induced protein kinase-1 gene expression and its relation to plasma des-acyl ghrelin in energy homeostasis in mice,” Biochemical and Biophysical Research Communications, vol. 344, no. 2, pp. 696–699, 2006. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Sato, K. Nakahara, S. Goto et al., “Effects of ghrelin and des-acyl ghrelin on neurogenesis of the rat fetal spinal cord,” Biochemical and Biophysical Research Communications, vol. 350, no. 3, pp. 598–603, 2006. View at Publisher · View at Google Scholar · View at Scopus
  25. K. Toshinai, H. Yamaguchi, Y. Sun et al., “Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor,” Endocrinology, vol. 147, no. 5, pp. 2306–2314, 2006. View at Publisher · View at Google Scholar · View at Scopus
  26. W. Zhang, B. Chai, J.-Y. Li, H. Wang, and M. W. Mulholland, “Effect of des-acyl ghrelin on adiposity and glucose metabolism,” Endocrinology, vol. 149, no. 9, pp. 4710–4716, 2008. View at Publisher · View at Google Scholar · View at Scopus
  27. H. Ariyasu, K. Takaya, H. Iwakura et al., “Transgenic mice overexpressing des-acyl ghrelin show small phenotype,” Endocrinology, vol. 146, no. 1, pp. 355–364, 2005. View at Publisher · View at Google Scholar · View at Scopus
  28. N. M. Thompson, D. A. Gill, R. Davies et al., “Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor,” Endocrinology, vol. 145, no. 1, pp. 234–242, 2004. View at Google Scholar
  29. P. J. D. Delhanty, B. C. J. van der Eerden, M. van der Velde et al., “Ghrelin and unacylated ghrelin stimulate human osteoblast growth via mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) pathways in the absence of GHS-R1a,” Journal of Endocrinology, vol. 188, no. 1, pp. 37–47, 2006. View at Publisher · View at Google Scholar · View at Scopus
  30. H. Ariyasu, K. Takaya, T. Tagami et al., “Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 10, pp. 4753–4758, 2001. View at Publisher · View at Google Scholar · View at Scopus
  31. D. E. Cummings, J. Q. Purnell, R. S. Frayo, K. Schmidova, B. E. Wisse, and D. S. Weigle, “A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans,” Diabetes, vol. 50, no. 8, pp. 1714–1719, 2001. View at Google Scholar · View at Scopus
  32. M. Tschöp, R. Wawarta, R. L. Riepl et al., “Post-prandial decrease of circulating human ghrelin levels,” Journal of Endocrinological Investigation, vol. 24, no. 6, pp. RC19–RC21, 2001. View at Google Scholar · View at Scopus
  33. K. A. Longo, S. Charoenthongtrakul, D. J. Giuliana et al., “Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice,” Regulatory Peptides, vol. 150, no. 1–3, pp. 55–61, 2008. View at Publisher · View at Google Scholar · View at Scopus
  34. Y. Sun, N. F. Butte, J. M. Garcia, and R. G. Smith, “Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance,” Endocrinology, vol. 149, no. 2, pp. 843–850, 2008. View at Publisher · View at Google Scholar · View at Scopus
  35. Y. Sun, S. Ahmed, and R. G. Smith, “Deletion of ghrelin impairs neither growth nor appetite,” Molecular and Cellular Biology, vol. 23, no. 22, pp. 7973–7981, 2003. View at Publisher · View at Google Scholar · View at Scopus
  36. Y. Sun, M. Asnicar, P. K. Saha, L. Chan, and R. G. Smith, “Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice,” Cell Metabolism, vol. 3, no. 5, pp. 379–386, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. P. T. Pfluger, H. Kirchner, S. Gunnel et al., “Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure,” American Journal of Physiology, vol. 294, no. 3, pp. G610–G618, 2008. View at Publisher · View at Google Scholar · View at Scopus
  38. A. Asakawa, A. Inui, M. Fujimiya et al., “Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin,” Gut, vol. 54, no. 1, pp. 18–24, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. H. Iwakura, K. Hosoda, C. Son et al., “Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice,” Journal of Biological Chemistry, vol. 280, no. 15, pp. 15247–15256, 2005. View at Publisher · View at Google Scholar · View at Scopus
  40. I. M. Chapman, M. A. Bach, E. Van Cauter et al., “Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 12, pp. 4249–4257, 1996. View at Publisher · View at Google Scholar · View at Scopus
  41. I. M. Chapman, M. L. Hartman, S. S. Pezzoli, and M. O. Thorner, “Enhancement of pulsatile growth hormone secretion by continuous infusion of a growth hormone-releasing peptide mimetic, L-692,429, in older adults—a clinical research center study,” Journal of Clinical Endocrinology and Metabolism, vol. 81, no. 8, pp. 2874–2880, 1996. View at Publisher · View at Google Scholar · View at Scopus
  42. R. G. Clark, G. B. Thomas, D. L. Mortensen et al., “Growth hormone secretagogues stimulate the hypothalamic-pituitary-adrenal axis and are diabetogenic in the Zucker diabetic fatty rat,” Endocrinology, vol. 138, no. 10, pp. 4316–4323, 1997. View at Publisher · View at Google Scholar · View at Scopus
  43. A. F. Muller, J. A. Janssen, L. J. Hofland et al., “Blockade of the growth hormone (GH) receptor unmasks rapid GH-releasing peptide-6-mediated tissue-specific insulin resistance,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 2, pp. 590–593, 2001. View at Publisher · View at Google Scholar · View at Scopus
  44. M. B. Davidson, “Effect of growth hormone on carbohydrate and lipid metabolism,” Endocrine Reviews, vol. 8, no. 2, pp. 115–131, 1987. View at Google Scholar · View at Scopus
  45. C. Ameen, D. Linden, B.-M. Larsson, A. Mode, A. Holmang, and J. Oscarsson, “Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver,” American Journal of Physiology, vol. 287, no. 6, pp. E1039–E1048, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. A. J. Van der Lely, “Justified and unjustified use of growth hormone,” Postgraduate Medical Journal, vol. 80, no. 948, pp. 577–580, 2004. View at Publisher · View at Google Scholar · View at Scopus
  47. T. J. Roberts, M. J. Azain, G. J. Hausman, and R. J. Martin, “Interaction of insulin and somatotropin on body weight gain, feed intake, and body composition in rats,” American Journal of Physiology, vol. 267, no. 2, part 1, pp. E293–E299, 1994. View at Google Scholar · View at Scopus
  48. B.-A. Bengtsson, S. Eden, L. Lonn et al., “Treatment of adults with growth hormone (GH) deficiency with recombinant human GH,” Journal of Clinical Endocrinology and Metabolism, vol. 76, no. 2, pp. 309–317, 1993. View at Publisher · View at Google Scholar · View at Scopus
  49. R. D. Murray, J. E. Adams, and S. M. Shalet, “Adults with partial growth hormone deficiency have an adverse body composition,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 4, pp. 1586–1591, 2004. View at Publisher · View at Google Scholar · View at Scopus
  50. S. A. Beshyah, C. Freemantle, E. Thomas et al., “Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults,” Clinical Endocrinology, vol. 42, no. 2, pp. 179–189, 1995. View at Google Scholar · View at Scopus
  51. A. Balbis, A. Bartke, and D. Turyn, “Overexpression of bovine growth hormone in transgenic mice is associated with changes in hepatic insulin receptors and in their kinase activity,” Life Sciences, vol. 59, no. 16, pp. 1363–1371, 1996. View at Publisher · View at Google Scholar · View at Scopus
  52. Z. Wang, M. M. Masternak, K. A. Al-Regaiey, and A. Bartke, “Adipocytokines and the regulation of lipid metabolism in growth hormone transgenic and calorie-restricted mice,” Endocrinology, vol. 148, no. 6, pp. 2845–2853, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. D. E. Berryman, E. O. List, K. T. Coschigano, K. Behar, J. K. Kim, and J. J. Kopchick, “Comparing adiposity profiles in three mouse models with altered GH signaling,” Growth Hormone and IGF Research, vol. 14, no. 4, pp. 309–318, 2004. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. Date, M. Nakazato, S. Hashiguchi et al., “Ghrelin is present in pancreatic a-cells of humans and rats and stimulates insulin secretion,” Diabetes, vol. 51, no. 1, pp. 124–129, 2002. View at Google Scholar · View at Scopus
  55. M. Volante, E. Allia, P. Gugliotta et al., “Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 3, pp. 1300–1308, 2002. View at Publisher · View at Google Scholar · View at Scopus
  56. M. Colombo, S. Gregersen, J. Xiao, and K. Hermansen, “Effects of ghrelin and other neuropeptides (CART, MCH, orexin A and B, and GLP-1) on the release of insulin from isolated rat islets,” Pancreas, vol. 27, no. 2, pp. 161–166, 2003. View at Publisher · View at Google Scholar · View at Scopus
  57. N. Wierup, S. Yang, R. J. McEvilly, H. Mulder, and F. Sundler, “Ghrelin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells,” Journal of Histochemistry and Cytochemistry, vol. 52, no. 3, pp. 301–310, 2004. View at Google Scholar · View at Scopus
  58. K. Dezaki, H. Hosoda, M. Kakei et al., “Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in ß-cells: implication in the glycemic control in rodents,” Diabetes, vol. 53, no. 12, pp. 3142–3151, 2004. View at Publisher · View at Google Scholar · View at Scopus
  59. N. Wierup, H. Svensson, H. Mulder, and F. Sundler, “The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas,” Regulatory Peptides, vol. 107, no. 1–3, pp. 63–69, 2002. View at Publisher · View at Google Scholar · View at Scopus
  60. C. L. Prado, A. E. Pugh-Bernard, L. Elghazi, B. Sosa-Pineda, and L. Sussel, “Ghrelin cells replace insulin-producing β cells in two mouse models of pancreas development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 2924–2929, 2004. View at Publisher · View at Google Scholar · View at Scopus
  61. Y. Date, M. Nakazato, N. Murakami, M. Kojima, K. Kangawa, and S. Matsukura, “Ghrelin acts in the central nervous system to stimulate gastric acid secretion,” Biochemical and Biophysical Research Communications, vol. 280, no. 3, pp. 904–907, 2001. View at Publisher · View at Google Scholar · View at Scopus
  62. Y. Masuda, T. Tanaka, N. Inomata et al., “Ghrelin stimulates gastric acid secretion and motility in rats,” Biochemical and Biophysical Research Communications, vol. 276, no. 3, pp. 905–908, 2000. View at Publisher · View at Google Scholar · View at Scopus
  63. M. G. Latour and W. W. Lautt, “The hepatic vagus nerve in the control of insulin sensitivity in the rat,” Autonomic Neuroscience, vol. 95, no. 1-2, pp. 125–130, 2002. View at Publisher · View at Google Scholar · View at Scopus
  64. M. Matsuhisa, Y. Yamasaki, Y. Shiba et al., “Important role of the hepatic vagus nerve in glucose uptake and production by the liver,” Metabolism, vol. 49, no. 1, pp. 11–16, 2000. View at Google Scholar · View at Scopus
  65. F. Broglio, E. Arvat, A. Benso et al., “Ghrelin, a natural gh secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 10, pp. 5083–5086, 2001. View at Publisher · View at Google Scholar · View at Scopus
  66. F. Broglio, A. Benso, C. Gottero et al., “Non-acylated ghrelin does not possess the pituitaric and pancreatic endocrine activity of acylated ghrelin in humans,” Journal of Endocrinological Investigation, vol. 26, no. 3, pp. 192–196, 2003. View at Google Scholar · View at Scopus
  67. F. Broglio, C. Gottero, F. Prodam et al., “Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 6, pp. 3062–3065, 2004. View at Publisher · View at Google Scholar · View at Scopus
  68. M. Arosio, C. L. Ronchi, C. Gebbia, V. Cappiello, P. Beck-Peccoz, and M. Peracchi, “Stimulatory effects of ghrelin on circulating somatostatin and pancreatic polypeptide levels,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 2, pp. 701–704, 2003. View at Publisher · View at Google Scholar · View at Scopus
  69. P. Nieminen and A.-M. Mustonen, “Effects of peripheral ghrelin on the carbohydrate and lipid metabolism of the tundra vole (Microtus oeconomus),” General and Comparative Endocrinology, vol. 138, no. 2, pp. 182–187, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. C. Cui, H. Ohnuma, M. Daimon et al., “Ghrelin infused into the portal vein inhibits glucose-stimulated insulin secretion in Wistar rats,” Peptides, vol. 29, no. 7, pp. 1241–1246, 2008. View at Publisher · View at Google Scholar · View at Scopus
  71. E. T. Vestergaard, C. B. Djurhuus, J. Gjedsted et al., “Acute effects of ghrelin administration on glucose and lipid metabolism,” Journal of Clinical Endocrinology and Metabolism, vol. 93, no. 2, pp. 438–444, 2008. View at Publisher · View at Google Scholar · View at Scopus
  72. P. Alvarez-Castro, M. L. Isidro, J. Garcia-Buela, C. Dieguez, F. F. Casanueva, and F. Cordido, “Effect of acute ghrelin administration on glycaemia and insulin levels in obese patients,” Diabetes, Obesity and Metabolism, vol. 8, no. 5, pp. 555–560, 2006. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Murata, Y. Okimura, K. Iida et al., “Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells,” Journal of Biological Chemistry, vol. 277, no. 7, pp. 5667–5674, 2002. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Papotti, C. Ghe, P. Cassoni et al., “Growth hormone secretagogue binding sites in peripheral human tissues,” Journal of Clinical Endocrinology and Metabolism, vol. 85, no. 10, pp. 3803–3807, 2000. View at Google Scholar · View at Scopus
  75. A. Asakawa, A. Inui, T. Kaga et al., “Antagonism of ghrelin receptor reduces food intake and body weight gain in mice,” Gut, vol. 52, no. 7, pp. 947–952, 2003. View at Publisher · View at Google Scholar · View at Scopus
  76. G. Perseghin, A. Caumo, M. Caloni, G. Testolin, and L. Luzi, “Incorporation of the fasting plasma FFA concentration into QUICKI improves its association with insulin sensitivity in nonobese individuals,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 10, pp. 4776–4781, 2001. View at Publisher · View at Google Scholar · View at Scopus
  77. E. T. Vestergaard, T. K. Hansen, L. C. Gormsen et al., “Constant intravenous ghrelin infusion in healthy young men: clinical pharmacokinetics and metabolic effects,” American Journal of Physiology, vol. 292, no. 6, pp. E1829–E1836, 2007. View at Publisher · View at Google Scholar · View at Scopus
  78. E. T. Vestergaard, L. C. Gormsen, N. Jessen et al., “Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling,” Diabetes, vol. 57, no. 12, pp. 3205–3210, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. T. Sudo, K. Ishiyama, M. Takemoto et al., “Pancreatic endocrine function after total gastrectomy and truncal vagotomy,” American Journal of Surgery, vol. 144, no. 5, pp. 539–544, 1982. View at Google Scholar · View at Scopus
  80. S. S. Damjanovic, N. M. Lalic, P. M. Pesko et al., “Acute effects of ghrelin on insulin secretion and glucose disposal rate in gastrectomized patients,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 7, pp. 2574–2581, 2006. View at Publisher · View at Google Scholar · View at Scopus
  81. F. Broglio, C. Gottero, A. Benso et al., “Effects of ghrelin on the insulin and glycemic responses to glucose, arginine, or free fatty acids load in humans,” The Journal of clinical endocrinology and metabolism, vol. 88, no. 9, pp. 4268–4272, 2003. View at Google Scholar
  82. C. Gauna, F. M. Meyler, J. A. M. J. L. Janssen et al., “Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 10, pp. 5035–5042, 2004. View at Publisher · View at Google Scholar · View at Scopus
  83. C. Gauna, R. M. Kiewiet, J. A. M. J. L. Janssen et al., “Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions,” American Journal of Physiology, vol. 293, no. 3, pp. E697–E704, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. M. K. Reimer, G. Pacini, and B. Ahren, “Dose-dependent inhibition by ghrelin of insulin secretion in the mouse,” Endocrinology, vol. 144, no. 3, pp. 916–921, 2003. View at Publisher · View at Google Scholar · View at Scopus
  85. R. Barazzoni, A. Bosutti, M. Stebel et al., “Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle,” American Journal of Physiology, vol. 288, no. 1, pp. E228–E235, 2005. View at Publisher · View at Google Scholar · View at Scopus
  86. R. Barazzoni, M. Zanetti, M. R. Cattin et al., “Ghrelin enhances in vivo skeletal muscle but not liver AKT signaling in rats,” Obesity, vol. 15, no. 11, pp. 2614–2623, 2007. View at Publisher · View at Google Scholar · View at Scopus
  87. C. Theander-Carrillo, P. Wiedmer, P. Cettour-Rose et al., “Ghrelin action in the brain controls adipocyte metabolism,” Journal of Clinical Investigation, vol. 116, no. 7, pp. 1983–1993, 2006. View at Publisher · View at Google Scholar · View at Scopus
  88. J. Kamegai, H. Tamura, T. Shimizu, S. Ishii, H. Sugihara, and I. Wakabayashi, “Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats,” Diabetes, vol. 50, no. 11, pp. 2438–2443, 2001. View at Google Scholar · View at Scopus
  89. D. Stevanović, D. Nešić, V. Milošević, V. Starčević, and W. B. Severs, “Consummatory behavior and metabolic indicators after central ghrelin injections in rats,” Regulatory Peptides, vol. 147, no. 1–3, pp. 52–59, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. E. M. Egido, J. Rodriguez-Gallardo, R. A. Silvestre, and J. Marco, “Inhibitory effect of ghrelin on insulin and pancreatic somatostatin secretion,” European Journal of Endocrinology, vol. 146, no. 2, pp. 241–244, 2002. View at Google Scholar · View at Scopus
  91. K. Dezaki, H. Sone, M. Koizumi et al., “Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance,” Diabetes, vol. 55, no. 12, pp. 3486–3493, 2006. View at Publisher · View at Google Scholar · View at Scopus
  92. W. P. Esler, J. Rudolph, T. H. Claus et al., “Small-molecule Ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss,” Endocrinology, vol. 148, no. 11, pp. 5175–5185, 2007. View at Publisher · View at Google Scholar · View at Scopus
  93. A. Doi, T. Shono, M. Nishi, H. Furuta, H. Sasaki, and K. Nanjo, “IA-2β, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 4, pp. 885–890, 2006. View at Publisher · View at Google Scholar · View at Scopus
  94. L. Sussel, J. Kalamaras, D. J. Hartigan-O'Connor et al., “Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic ß cells,” Development, vol. 125, no. 12, pp. 2213–2221, 1998. View at Google Scholar · View at Scopus
  95. C. Wasmeier and J. C. Hutton, “Molecular cloning of phogrin, a protein-tyrosine phosphatase homologue localized to insulin secretory granule membranes,” Journal of Biological Chemistry, vol. 271, no. 30, pp. 18161–18170, 1996. View at Publisher · View at Google Scholar · View at Scopus
  96. C. Gauna, P. J. D. Delhanty, L. J. Hofland et al., “Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 2, pp. 1055–1060, 2005. View at Publisher · View at Google Scholar · View at Scopus
  97. P. Cassoni, C. Ghe, T. Marrocco et al., “Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines,” European Journal of Endocrinology, vol. 150, no. 2, pp. 173–184, 2004. View at Publisher · View at Google Scholar · View at Scopus
  98. P. Cassoni, M. Papotti, C. Ghe et al., “Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 4, pp. 1738–1745, 2001. View at Publisher · View at Google Scholar · View at Scopus
  99. I. Bedendi, G. Alloatti, A. Marcantoni et al., “Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin,” European Journal of Pharmacology, vol. 476, no. 1-2, pp. 87–95, 2003. View at Publisher · View at Google Scholar · View at Scopus
  100. G. Muccioli, M. Tschöp, M. Papotti, R. Deghenghi, M. Heiman, and E. Ghigo, “Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity,” European Journal of Pharmacology, vol. 440, no. 2-3, pp. 235–254, 2002. View at Publisher · View at Google Scholar · View at Scopus
  101. M. T. Diz-Lois, J. Garcia-Buela, F. Suarez, S. Sangiao-Alvarellos, O. Vidal, and F. Cordido, “Fasting and postprandial plasma ghrelin levels are decreased in patients with liver failure previous to liver transplantation,” Endocrine, vol. 35, no. 3, pp. 467–476, 2009. View at Publisher · View at Google Scholar · View at Scopus
  102. M. Tschop, C. Weyer, P. A. Tataranni, V. Devanarayan, E. Ravussin, and M. L. Heiman, “Circulating ghrelin levels are decreased in human obesity,” Diabetes, vol. 50, no. 4, pp. 707–709, 2001. View at Google Scholar · View at Scopus
  103. K. E. Wortley, K. D. Anderson, K. Garcia et al., “Genetic deletion of ghrelin does decrease food intake but influences metabolic fuel preference,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 21, pp. 8227–8232, 2004. View at Publisher · View at Google Scholar · View at Scopus
  104. J. M. Zigman, Y. Nakano, R. Coppari et al., “Mice lacking ghrelin receptors resist the development of diet-induced obesity,” Journal of Clinical Investigation, vol. 115, no. 12, pp. 3564–3572, 2005. View at Publisher · View at Google Scholar · View at Scopus
  105. E. Egecioglu, M. Bjursell, A. Ljungberg et al., “Growth hormone receptor deficiency results in blunted ghrelin feeding response, obesity, and hypolipidemia in mice,” American Journal of Physiology, vol. 290, no. 2, pp. E317–E325, 2006. View at Publisher · View at Google Scholar · View at Scopus
  106. Y. Sun, P. Wang, H. Zheng, and R. G. Smith, “Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 13, pp. 4679–4684, 2004. View at Publisher · View at Google Scholar · View at Scopus
  107. K. E. Wortley, J.-P. del Rincon, J. D. Murray et al., “Absence of ghrelin protects against early-onset obesity,” Journal of Clinical Investigation, vol. 115, no. 12, pp. 3573–3578, 2005. View at Publisher · View at Google Scholar · View at Scopus
  108. J. V. Zhang, P.-G. Ren, O. Avsian-Kretchmer et al., “Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake,” Science, vol. 310, no. 5750, pp. 996–999, 2005. View at Publisher · View at Google Scholar · View at Scopus
  109. R. D. Kineman, M. D. Gahete, and R. M. Luque, “Identification of a mouse ghrelin gene transcipt that contains intron 2 and is regulated in the pituitary and hypothalamus in responce to metabolic stress,” Journal of Molecular Endocrinology, vol. 38, no. 5, pp. 511–521, 2007. View at Publisher · View at Google Scholar · View at Scopus
  110. B. Holst and T. W. Schwartz, “Ghrelin receptor mutations—too little height and too much hunger,” Journal of Clinical Investigation, vol. 116, no. 3, pp. 637–641, 2006. View at Publisher · View at Google Scholar · View at Scopus
  111. V. Poitout and R. P. Robertson, “An integrated view of β-cell dysfunction in type-II diabetes,” Annual Review of Medicine, vol. 47, pp. 69–83, 1996. View at Google Scholar · View at Scopus
  112. L. Storlien, N. D. Oakes, and D. E. Kelley, “Metabolic flexibility,” Proceedings of the Nutrition Society, vol. 63, no. 2, pp. 363–368, 2004. View at Publisher · View at Google Scholar · View at Scopus
  113. G. A. Bewick, A. Kent, D. Campbell et al., “Mice with hyperghrelinemia are hyperphagic and glucose intolerant and have reduced leptin sensitivity,” Diabetes, vol. 58, no. 4, pp. 840–846, 2009. View at Publisher · View at Google Scholar · View at Scopus
  114. J. A. Reed, S. C. Benoit, P. T. Pfluger, M. H. Tschop, D. A. D'Alessio, and R. J. Seeley, “Mice with chronically increased circulating ghrelin develop age-related glucose intolerance,” American Journal of Physiology, vol. 294, no. 4, pp. E752–E760, 2008. View at Publisher · View at Google Scholar · View at Scopus
  115. S. J. Pilkis and D. K. Granner, “Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis,” Annual Review of Physiology, vol. 54, pp. 885–909, 1992. View at Google Scholar · View at Scopus
  116. R. M. O'Brien, R. S. Streeper, J. E. Ayala, B. T. Stadelmaier, and L. A. Hornbuckle, “Insulin-regulated gene expression,” Biochemical Society Transactions, vol. 29, part 4, pp. 552–558, 2001. View at Publisher · View at Google Scholar · View at Scopus
  117. A. Brunet, A. Bonni, M. J. Zigmond et al., “Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor,” Cell, vol. 96, no. 6, pp. 857–868, 1999. View at Google Scholar · View at Scopus
  118. D. A. E. Cross, D. R. Alessi, P. Cohen, M. Andjelkovich, and B. A. Hemmings, “Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B,” Nature, vol. 378, no. 6559, pp. 785–789, 1995. View at Publisher · View at Google Scholar · View at Scopus
  119. A. D. Kohn, S. A. Summers, M. J. Birnbaum, and R. A. Roth, “Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation,” Journal of Biological Chemistry, vol. 271, no. 49, pp. 31372–31378, 1996. View at Publisher · View at Google Scholar · View at Scopus
  120. J. Nakae, W. H. Biggs III, T. Kitamura et al., “Regulation of insulin action and pancreatic ß-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1,” Nature Genetics, vol. 32, no. 2, pp. 245–253, 2002. View at Publisher · View at Google Scholar · View at Scopus
  121. D. Schmoll, K. S. Walker, D. R. Alessi et al., “Regulation of glucose-6-phosphatase gene expression by protein kinase Ba and the Forkhead transcription factor FKHR: evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity,” Journal of Biological Chemistry, vol. 275, no. 46, pp. 36324–36333, 2000. View at Publisher · View at Google Scholar · View at Scopus
  122. R. K. Hall, T. Yamasaki, T. Kucera, M. Waltner-Law, R. O'Brien, and D. K. Granner, “Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/Forkhead proteins,” Journal of Biological Chemistry, vol. 275, no. 39, pp. 30169–30175, 2000. View at Google Scholar · View at Scopus
  123. J. C. Yoon, P. Puigserver, G. Chen et al., “Control of hepatic gluconeogenesis through the transcriptional coaotivator PGC-1,” Nature, vol. 413, no. 6852, pp. 131–138, 2001. View at Publisher · View at Google Scholar · View at Scopus
  124. P. Puigserver, J. Rhee, J. Donovan et al., “Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1a interaction,” Nature, vol. 423, no. 6939, pp. 550–555, 2003. View at Publisher · View at Google Scholar · View at Scopus
  125. C. J. Hedeskov, “Mechanism of glucose-induced insulin secretion,” Physiological Reviews, vol. 60, no. 2, pp. 442–509, 1980. View at Google Scholar · View at Scopus
  126. G. A. Rutter, “Nutrient-secretion coupling in the pancreatic islet β-cell: recent advances,” Molecular Aspects of Medicine, vol. 22, no. 6, pp. 247–284, 2001. View at Publisher · View at Google Scholar · View at Scopus
  127. F. C. Schuit, “Is GLUT2 required for glucose sensing?” Diabetologia, vol. 40, no. 1, pp. 104–111, 1997. View at Publisher · View at Google Scholar · View at Scopus
  128. A. Valera, G. Solanes, J. Fernandez-Alvarez et al., “Expression of GLUT-2 antisense RNA in ß cells of transgenic mice leads to diabetes,” Journal of Biological Chemistry, vol. 269, no. 46, pp. 28543–28546, 1994. View at Google Scholar · View at Scopus
  129. M.-T. Guillam, E. Hummler, E. Schaerer et al., “Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2,” Nature Genetics, vol. 17, no. 3, pp. 327–330, 1997. View at Publisher · View at Google Scholar · View at Scopus
  130. M. D. Meglasson and F. M. Matschinsky, “Pancreatic islet glucose metabolism and regulation of insulin secretion,” Diabetes/Metabolism Reviews, vol. 2, no. 3-4, pp. 163–214, 1986. View at Google Scholar · View at Scopus
  131. J. Bryan, A. Crane, W. H. Vila-Carriles, A. P. Babenko, and L. Aguilar-Bryan, “Insulin secretagogues, sulfonylurea receptors and KATP channels,” Current Pharmaceutical Design, vol. 11, no. 21, pp. 2699–2716, 2005. View at Publisher · View at Google Scholar · View at Scopus
  132. P. E. MacDonald, J. W. Joseph, and P. Rorsman, “Glucose-sensing mechanisms in pancreatic β-cells,” Philosophical Transactions of the Royal Society B, vol. 360, no. 1464, pp. 2211–2225, 2005. View at Publisher · View at Google Scholar · View at Scopus
  133. P. E. MacDonald, A. M. F. Salapatek, and M. B. Wheeler, “Temperature and redox state dependence of native Kv2.1 currents in rat pancreatic β-cells,” Journal of Physiology, vol. 546, no. 3, pp. 647–653, 2003. View at Publisher · View at Google Scholar · View at Scopus
  134. M. V. Jensen, J. W. Joseph, S. M. Ronnebaum, S. C. Burgess, A. D. Sherry, and C. B. Newgard, “Metabolic cycling in control of glucose-stimulated insulin secretion,” American Journal of Physiology, vol. 295, no. 6, pp. E1287–E1297, 2008. View at Publisher · View at Google Scholar · View at Scopus
  135. K. Dezaki, H. Sone, and T. Yada, “Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis,” Pharmacology and Therapeutics, vol. 118, no. 2, pp. 239–249, 2008. View at Publisher · View at Google Scholar · View at Scopus
  136. K. Dezaki, M. Kakei, and T. Yada, “Ghrelin uses Gαi2 and activates voltage-dependent K+ channels to attenuate glucose-induced Ca2+ signaling and insulin release in islet β-cells: novel signal transduction of ghrelin,” Diabetes, vol. 56, no. 9, pp. 2319–2327, 2007. View at Publisher · View at Google Scholar · View at Scopus
  137. D. L. Burns, S. Z. Hausman, M. H. Witvliet, M. J. Brennan, J. T. Poolman, and C. R. Manclark, “Biochemical properties of pertussis toxin,” Tokai Journal of Experimental and Clinical Medicine, vol. 13, supplement, pp. 181–185, 1988. View at Google Scholar · View at Scopus
  138. R. M. Smith, M. J. Charron, N. Shah, H. F. Lodish, and L. Jarett, “Immunoelectron microscopic demonstration of insulin-stimulated translocation of glucose transporters to the plasma membrane of isolated rat adipocytes and masking of the carboxyl-terminal epitope of intracellular GLUT4,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 15, pp. 6893–6897, 1991. View at Publisher · View at Google Scholar · View at Scopus
  139. A. R. Saltiel, “New perspectives into the molecular pathogenesis and treatment of type 2 diabetes,” Cell, vol. 104, no. 4, pp. 517–529, 2001. View at Publisher · View at Google Scholar · View at Scopus
  140. E. U. Frevert and B. B. Kahn, “Differential effects of constitutively active phosphatidylinositol 3-kinase on glucose transport, glycogen synthase activity, and DNA synthesis in 3T3-L1 adipocytes,” Molecular and Cellular Biology, vol. 17, no. 1, pp. 190–198, 1997. View at Google Scholar · View at Scopus
  141. M. M. Hill, S. F. Clark, D. F. Tucker, M. J. Birnbaum, D. E. James, and S. L. Macaulay, “A role for protein kinase Bβ/Akt2 in insulin-stimulated GLUT4 translocation in adipocytes,” Molecular and Cellular Biology, vol. 19, no. 11, pp. 7771–7781, 1999. View at Google Scholar · View at Scopus
  142. F. Tremblay, M.-J. Dubois, and A. Marette, “Regulation of GLUT4 traffic and function by insulin and contraction in skeletal muscle,” Frontiers in Bioscience, vol. 8, pp. d1072–d1084, 2003. View at Google Scholar · View at Scopus
  143. J. E. Pessin and A. R. Saltiel, “Signaling pathways in insulin action: molecular targets of insulin resistance,” Journal of Clinical Investigation, vol. 106, no. 2, pp. 165–169, 2000. View at Google Scholar · View at Scopus
  144. A. H. Khan and J. E. Pessin, “Insulin regulation of glucose uptake: a complex interplay of intracellular signalling pathways,” Diabetologia, vol. 45, no. 11, pp. 1475–1483, 2002. View at Publisher · View at Google Scholar · View at Scopus
  145. A. D. Patel, S. A. Stanley, K. G. Murphy et al., “Ghrelin stimulates insulin-induced glucose uptake in adipocytes,” Regulatory Peptides, vol. 134, no. 1, pp. 17–22, 2006. View at Publisher · View at Google Scholar · View at Scopus
  146. M. S. Kim, C. Y. Yoon, P. G. Jang et al., “The mitogenic and antiapoptotic actions of ghrelin in 3T3-L1 adipocytes,” Molecular Endocrinology, vol. 18, no. 9, pp. 2291–2301, 2004. View at Publisher · View at Google Scholar · View at Scopus
  147. P. R. Shepherd and B. B. Kahn, “Glucose transporters and insulin action: implications for insulin resistance and diabetes mellitus,” New England Journal of Medicine, vol. 341, no. 4, pp. 248–257, 1999. View at Publisher · View at Google Scholar · View at Scopus
  148. A. Neu, A. Willasch, S. Ehehalt, M. Kehrer, R. Hub, and M. B. Ranke, “Diabetes incidence in children of different nationalities: an epidemiological approach to the pathogenesis of diabetes,” Diabetologia, vol. 44, supplement 3, pp. B21–B26, 2001. View at Google Scholar · View at Scopus
  149. A. H. Mokdad, E. S. Ford, B. A. Bowman et al., “Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001,” Journal of the American Medical Association, vol. 289, no. 1, pp. 76–79, 2003. View at Publisher · View at Google Scholar · View at Scopus
  150. A. Ikezaki, H. Hosoda, K. Ito et al., “Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin, in obese children and adolescents,” Diabetes, vol. 51, no. 12, pp. 3408–3411, 2002. View at Google Scholar · View at Scopus
  151. S. M. Poykko, E. Kellokoski, S. Horkko, H. Kauma, Y. A. Kesaniemi, and O. Ukkola, “Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes,” Diabetes, vol. 52, no. 10, pp. 2546–2553, 2003. View at Publisher · View at Google Scholar · View at Scopus
  152. F. Cordido, M. L. Isidro, R. Nemina, and S. Sangiao-Alvarellos, “Ghrelin and growth hormone secretagogues, physiological and pharmacological aspect,” Current Drug Discovery Technologies, vol. 6, no. 1, pp. 34–42, 2009. View at Publisher · View at Google Scholar · View at Scopus
  153. A. J. Van der Lely, “Ghrelin and new metabolic frontiers,” Hormone Research, vol. 71, supplement 1, pp. 129–133, 2009. View at Publisher · View at Google Scholar · View at Scopus
  154. M. L. Isidro and F. Cordido, “Drug treatment of obesity: established and emerging therapies,” Mini-Reviews in Medicinal Chemistry, vol. 9, no. 6, pp. 664–673, 2009. View at Publisher · View at Google Scholar · View at Scopus
  155. M. Perez-Fontan, F. Cordido, A. Rodriguez-Carmona et al., “Acute plasma ghrelin and leptin responses to oral feeding or intraperitoneal hypertonic glucose-based dialysate in patients with chronic renal failure,” Kidney International, vol. 68, no. 6, pp. 2877–2885, 2005. View at Publisher · View at Google Scholar · View at Scopus