Regulation of glucose metabolism by the ghrelin system: Multiple players and multiple actions

European Journal of Endocrinology

Volumn 171, Issue 1, 2014, Pages

  Heppner, Kristy M ^a   Tong, Jenny ^b  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACYL GHRELIN; ACYLTRANSFERASE; DES ACYL GHRELIN; GHRELIN; GHRELIN O ACYLTRANSFERASE; GHRELIN RECEPTOR; GLUCAGON LIKE PEPTIDE 1; UNCLASSIFIED DRUG; GLUCOSE;

BARIATRIC SURGERY; DIET RESTRICTION; DISEASE ASSOCIATION; GLUCOSE METABOLISM; GLUCOSE TOLERANCE; GLUCOSE TRANSPORT; HUMAN; IN VITRO STUDY; INSULIN RELEASE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; REGULATORY MECHANISM; REVIEW; ACYLATION; ANIMAL; ENDOCRINOLOGY; METABOLISM;

ACYLATION; ANIMALS; ENDOCRINOLOGY; GHRELIN; GLUCOSE; HUMANS; RECEPTORS, GHRELIN;

EID: 84903519847     PISSN: 08044643     EISSN: 1479683X     Source Type: Journal    
DOI: 10.1530/EJE-14-0183     Document Type: Review

References (113)

1. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H & Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999 402 656-660. (doi:10.1038/45230)
2. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, Witcher DR, Luo S, Onyia JE & Hale JE. Ghrelin octanoylation mediated by an orphan lipid transferase. PNAS 2008 105 6320-6325. (doi:10.1073/pnas.0800708105)
3. Yang J, Brown MS, Liang G, Grishin NV & Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 2008 132 387-396. (doi:10.1016/j.cell.2008.01.017)
4. Tschop M, Smiley DL & Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000 407 908-913. (doi:10.1038/35038090)
5. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K & Matsukura S. A role for ghrelin in the central regulation of feeding. Nature 2001 409 194-198. (doi:10.1038/35051587)
6. Kageyama H, Funahashi H, Hirayama M, Takenoya F, Kita T, Kato S, Sakurai J, Lee EY, Inoue S, Date Y et al. Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regulatory Peptides 2005 126 67-71. (doi:10.1016/j.regpep.2004.08.031)
7. Delhanty PJ, Neggers SJ & van der Lely AJ. Mechanisms in endocrinology: ghrelin: the differences between acyl-and des-acyl ghrelin. European Journal of Endocrinology 2012 167 601-608. (doi:10.1530/EJE-12-0456)
8. Delhanty PJ & van der Lely AJ. Ghrelin and glucose homeostasis. Peptides 2011 32 2309-2318. (doi:10.1016/j.peptides.2011.03.001)
9. Heppner KM, Piechowski CL, Muller A, Ottaway N, Sisley S, Smiley DL, Habegger KM, Pfluger PT, Dimarchi R, Biebermann H et al. Both acyl and des-acyl ghrelin regulate adiposity and glucose metabolism via central nervous system ghrelin receptors. Diabetes 2014 63 122-131. (doi:10.2337/db13-0414)
10. Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K & Nakazato M. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 2002 123 1120-1128. (doi:10.1053/gast.2002.35954)
11. Dezaki K, Hosoda H, Kakei M, Hashiguchi S, Watanabe M, Kangawa K & Yada T. Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2C signaling in β-cells: implication in the glycemic control in rodents. Diabetes 2004 53 3142-3151. (doi:10.2337/diabetes.53.12.3142)
12. Chanoine JP & Wong AC. Ghrelin gene expression is markedly higher in fetal pancreas compared with fetal stomach: effect of maternal fasting. Endocrinology 2004 145 3813-3820. (doi:10.1210/en.2004-0053)
13. Granata R, Settanni F, Biancone L, Trovato L, Nano R, Bertuzzi F, Destefanis S, Annunziata M, Martinetti M, Catapano F et al. Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic β-cells and human islets: involvement of 30,50-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. Endocrinology 2007 148 512-529. (doi:10.1210/en.2006-0266)
14. Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B & Sussel L. Ghrelin cells replace insulin-producing b cells in two mouse models of pancreas development. PNAS 2004 101 2924-2929. (doi:10.1073/pnas.0308604100)
15. Volante M, Allia E, Gugliotta P, Funaro A, Broglio F, Deghenghi R, Muccioli G, Ghigo E & Papotti M. Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. Journal of Clinical Endocrinology and Metabolism 2002 87 1300-1308. (doi:10.1210/jcem.87.3.8279)
16. Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H et al. Ghrelin is present in pancreatic a-cells of humans and rats and stimulates insulin secretion. Diabetes 2002 51 124-129. (doi:10.2337/diabetes.51.1.124)
17. Wierup N, Svensson H, Mulder H & Sundler F. The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas. Regulatory Peptides 2002 107 63-69. (doi:10.1016/S0167-0115(02)00067-8)
18. Wierup N, Yang S, McEvilly RJ, Mulder H & Sundler F. 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 2004 52 301-310. (doi:10.1177/002215540405200301)
19. Arnes L, Hill JT, Gross S,Magnuson MA & Sussel L. Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population. PLoS ONE 2012 7 e52026. (doi:10.1371/journal.pone.0052026)
20. Lim CT, Kola B, Grossman A & Korbonits M. The expression of ghrelin O-acyltransferase (GOAT) in human tissues. Endocrine Journal 2011 58 707-710. (doi:10.1507/endocrj.K11E-117)
21. Qader SS, Hakanson R, Rehfeld JF, Lundquist I & Salehi A. Proghrelinderived peptides influence the secretion of insulin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas. Regulatory Peptides 2008 146 230-237. (doi:10.1016/j.regpep. 2007.09.017)
22. ColomboM, Gregersen S, Xiao J & Hermansen K. 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 2003 27 161-166. (doi:10.1097/ 00006676-200308000-00009)
23. Adeghate E & Ponery AS. Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. Journal of Neuroendocrinology 2002 14 555-560. (doi:10.1046/j.1365-2826.2002.00811.x)
24. Dezaki K, Sone H, Koizumi M, Nakata M, Kakei M, Nagai H, Hosoda H, Kangawa K & Yada T. Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance. Diabetes 2006 55 3486-3493. (doi:10.2337/db06-0878)
25. Holst B, Cygankiewicz A, Jensen TH, Ankersen M & Schwartz TW. High constitutive signaling of the ghrelin receptor-identification of a potent inverse agonist. Molecular Endocrinology 2003 17 2201-2210. (doi:10.1210/me. 2003-0069)
26. Holst B, Holliday ND, Bach A, Elling CE, Cox HM & Schwartz TW. Common structural basis for constitutive activity of the ghrelin receptor family. Journal of Biological Chemistry 2004 279 53806-53817. (doi:10.1074/jbc. M407676200)
27. Petersen PS, Woldbye DP, Madsen AN, Egerod KL, Jin C, Lang M, Rasmussen M, Beck-Sickinger AG & Holst B. In vivo characterization of high basal signaling from the ghrelin receptor. Endocrinology 2009 150 4920-4930. (doi:10.1210/en.2008-1638)
28. Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, Bullock W, Daly M, Decarr L, Li Y et al. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology 2007 148 5175-5185. (doi:10.1210/en.2007-0239)
29. Feighner SD, Howard AD, Prendergast K, Palyha OC, Hreniuk DL, Nargund R, Underwood D, Tata JR, Dean DC, Tan CP et al. Structural requirements for the activation of the human growth hormone secretagogue receptor by peptide and nonpeptide secretagogues. Molecular Endocrinology 1998 12 137-145. (doi:10.1210/mend.12.1.0051)
30. Sharp GW. Mechanisms of inhibition of insulin release. American Journal of Physiology 1996 271 C1781-C1799.
31. Gilon P & Henquin JC. Mechanisms and physiological significance of the cholinergic control of pancreatic β-cell function. Endocrine Reviews 2001 22 565-604. (doi:10.1210/edrv.22.5.0440)
32. Dezaki K, Kakei M & Yada T. Ghrelin uses Gαi2 and activates voltagedependent K+ channels to attenuate glucose-induced Ca2+ signaling and insulin release in islet β-cells: novel signal transduction of ghrelin. Diabetes 2007 56 2319-2327. (doi:10.2337/db07-0345)
33. Park S, Jiang H, Zhang H & Smith RG. Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release. PNAS 2012 109 19003-19008. (doi:10.1073/pnas.1209590109)
34. Chuang JC, Sakata I, Kohno D, Perello M, Osborne-Lawrence S, Repa JJ & Zigman JM. Ghrelin directly stimulates glucagon secretion from pancreatic a-cells. Molecular Endocrinology 2011 25 1600-1611. (doi:10.1210/me.2011-1001)
35. Salehi A, Dornonville de la Cour C, Hakanson R & Lundquist I. Effectsof ghrelin on insulin and glucagon secretion: a study of isolated pancreatic islets and intact mice. Regulatory Peptides 2004 118 143-150. (doi:10.1016/j.regpep.2003.12.001)
36. Qader SS, Lundquist I, Ekelund M, Hakanson R & Salehi A. Ghrelin activates neuronal constitutive nitric oxide synthase in pancreatic islet cells while inhibiting insulin release and stimulating glucagon release. Regulatory Peptides 2005 128 51-56. (doi:10.1016/j.regpep.2004.12.018)
37. Gauna C, Delhanty PJ, van Aken MO, Janssen JA, Themmen AP, Hofland LJ, Culler M, Broglio F, Ghigo E & van der Lely AJ. Unacylated ghrelin is active on the INS-1E rat insulinoma cell line independently of the growth hormone secretagogue receptor type 1a and the corticotropin releasing factor 2 receptor. Molecular and Cellular Endocrinology 2006 251 103-111. (doi:10.1016/j.mce.2006. 03.040)
38. Gauna C, van de Zande B, van Kerkwijk A, Themmen AP, van der Lely AJ & Delhanty PJ. Unacylated ghrelin is not a functional antagonist but a full agonist of the type 1a growth hormone secretagogue receptor (GHS-R). Molecular and Cellular Endocrinology 2007 274 30-34. (doi:10.1016/j.mce.2007.05.010)
39. Lee HM, Wang G, Englander EW, Kojima M & Greeley GH Jr. Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology 2002 143 185-190. (doi:10.1210/endo.143.1.8602)
40. Reimer MK, Pacini G & Ahren B. Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology 2003 144 916-921. (doi:10.1210/en.2002-220819)
41. Cui C, Ohnuma H, Daimon M, Susa S, Yamaguchi H, Kameda W, Jimbu Y, Oizumi T & Kato T. Ghrelin infused into the portal vein inhibits glucose-stimulated insulin secretion in Wistar rats. Peptides 2008 29 1241-1246. (doi:10.1016/j.peptides.2008.02.022)
42. Barnett BP, Hwang Y, Taylor MS, Kirchner H, Pfluger PT, Bernard V, Lin YY, Bowers EM, Mukherjee C, Song WJ et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science 2010 330 1689-1692. (doi:10.1126/science.1196154)
43. Sun Y, Asnicar M, Saha PK, Chan L & Smith RG. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metabolism 2006 3 379-386. (doi:10.1016/j.cmet.2006.04.004)
44. Zhao TJ, Liang G, Li RL, Xie X, Sleeman MW, Murphy AJ, Valenzuela DM, Yancopoulos GD, Goldstein JL & Brown MS. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. PNAS 2010 107 7467-7472. (doi:10.1073/pnas.1002271107)
45. Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, Schurmann A, Joost HG, Jandacek RJ, Hale JE et al. GOAT links dietary lipids with the endocrine control of energy balance. Nature Medicine 2009 15 741-745. (doi:10.1038/nm.1997)
46. Pfluger PT, Kirchner H, Gunnel S, Schrott B, Perez-Tilve D, Fu S, Benoit SC, Horvath T, Joost HG, Wortley KE et al. Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. American Journal of Physiology. Gastrointestinal and Liver Physiology 2008 294 G610-G618. (doi:10.1152/ajpgi.00321.2007)
47. Liu J, Prudom CE, Nass R, Pezzoli SS, Oliveri MC, Johnson ML, Veldhuis P, Gordon DA, Howard AD, Witcher DR et al. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. Journal of Clinical Endocrinology and Metabolism 2008 93 1980-1987. (doi:10.1210/jc.2007-2235)
48. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE & Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001 50 1714-1719. (doi:10.2337/diabetes.50.8.1714)
49. Longo KA, Charoenthongtrakul S, Giuliana DJ, Govek EK, McDonagh T, Qi Y, DiStefano PS & Geddes BJ. Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice. Regulatory Peptides 2008 150 55-61. (doi:10.1016/j.regpep.2008.03.011)
50. Lin L, Saha PK, Ma X, Henshaw IO, Shao L, Chang BH, Buras ED, Tong Q, Chan L, McGuinness OP et al. Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell 2012 10 996-1010. (doi:10.1111/j.1474- 9726.2011.00740.x)
51. Qi Y, Longo KA, Giuliana DJ, Gagne S, McDonagh T, Govek E, Nolan A, Zou C, Morgan K, Hixon J et al. Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps. BMC Physiology 2011 11 1. (doi:10.1186/1472-6793-11-1)
52. Kirchner H, Heppner KM, Holland J, Kabra D, Tschop MH & Pfluger PT. Ablation of ghrelin O-acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background. PLoS ONE 2013 8 e61822. (doi:10.1371/journal.pone.0061822)
53. Gauna C, Kiewiet RM, Janssen JA, van de Zande B, Delhanty PJ, Ghigo E, Hofland LJ, Themmen AP & van der Lely AJ. Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions. American Journal of Physiology. Endocrinology and Metabolism 2007 293 E697-E704. (doi:10.1152/ajpendo.00219.2007)
54. Delhanty PJ, Huisman M, Baldeon-Rojas LY, van den Berge I, Grefhorst A, Abribat T, Leenen PJ, Themmen AP & van der Lely AJ. Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis. FASEB Journal 2013 27 1690-1700. (doi:10.1096/fj.12-221143)
55. Zhang W, Chai B, Li JY, Wang H & Mulholland MW. Effect of des-acyl ghrelin on adiposity and glucose metabolism. Endocrinology 2008 149 4710-4716. (doi:10.1210/en.2008-0263)
56. Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, Tschop MH & D'Alessio D. Ghrelin suppresses glucosestimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes 2010 59 2145-51. (doi:10.2337/db10-0504)
57. Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Tschop MH & D'Alessio D. Physiologic concentrations of exogenously infused ghrelin reduces insulin secretion without affecting insulin sensitivity in healthy humans. Journal of Clinical Endocrinology and Metabolism 2013 98 2536-43. (doi:10.1210/jc.2012- 4162)
58. Lucidi P, Murdolo G, Di Loreto C, Parlanti N, De Cicco A, Fatone C, Taglioni C, Fanelli C, Broglio F, Ghigo E et al.Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations. Nutrition, Metabolism, and Cardiovascular Diseases 2005 15 410-417. (doi:10.1016/j.numecd. 2005.02.006)
59. Broglio F, Benso A, Gottero C, Prodam F, Gauna C, Filtri L, Arvat E, van der Lely AJ, Deghenghi R & Ghigo E. Non-acylated ghrelin does not possess the pituitaric and pancreatic endocrine activity of acylated ghrelin in humans. Journal of Endocrinological Investigation 2003 26 192-196. (doi:10.1007/ BF03345156)
60. Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, van der Lely AJ, Deghenghi R & Ghigo E. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. Journal of Clinical Endocrinology and Metabolism 2001 86 5083-5086. (doi:10.1210/jcem.86.10.8098)
61. Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, Abribat T, Van Der Lely AJ & Ghigo E. Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. Journal of Clinical Endocrinology and Metabolism 2004 89 3062-3065. (doi:10.1210/jc.2003- 031964)
62. Vestergaard ET, Djurhuus CB, Gjedsted J, Nielsen S, Moller N, Holst JJ, Jorgensen JO & Schmitz O. Acute effects of ghrelin administration on glucose and lipid metabolism. Journal of Clinical Endocrinology and Metabolism 2008 93 438-444. (doi:10.1210/jc.2007-2018)
63. Vestergaard ET, Gormsen LC, Jessen N, Lund S, Hansen TK, Moller N & Jorgensen JO. Ghrelin infusion in humans induces acute insulin resistance and lipolysis independent of growth hormone signaling. Diabetes 2008 57 3205-3210. (doi:10.2337/db08-0025)
64. Damjanovic SS, Lalic NM, Pesko PM, Petakov MS, Jotic A, Miljic D, Lalic KS, Lukic L, Djurovic M & Djukic VB. Acute effects of ghrelin on insulin secretion and glucose disposal rate in gastrectomized patients. Journal of Clinical Endocrinology and Metabolism 2006 91 2574-2581. (doi:10.1210/jc.2005- 1482)
65. Vestergaard ET, Buhl M, Gjedsted J, Madsen M, Jessen N, Nielsen S, Gaylinn BD, Liu J, Thorner MO, Moller N et al. Acute peripheral metabolic effects of intraarterial ghrelin infusion in healthy young men. Journal of Clinical Endocrinology and Metabolism 2011 96 468-477. (doi:10.1210/jc.2010- 1995)
66. Vestergaard ET, Moller N & Jorgensen JO. Acute peripheral tissue effects of ghrelin on interstitial levels of glucose, glycerol, and lactate: a Microdialysis Study in Healthy Human Subjects. American Journal of Physiology. Endocrinology and Metabolism 2013 304 E1273-E1280. (doi:10.1152/ajpendo.00662. 2012)
67. Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, Heymsfield SB, Bach MA, Vance ML & Thorner MO. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Annals of Internal Medicine 2008 149 601-611. (doi:10.7326/0003-4819-149-9-200811040-00003)
68. Tong J, Dave N, Mugundu GM, Davis HW, Gaylinn BD, Thorner MO, Tschop MH, D'Alessio D & Desai PB. The pharmacokinetics of acyl, des-acyl, and total ghrelin in healthy human subjects. European Journal of Endocrinology 2013 168 821-828. (doi:10.1530/EJE-13-0072)
69. Kiewiet RM, van Aken MO, van der Weerd K, Uitterlinden P, Themmen AP, Hofland LJ, de Rijke YB, Delhanty PJ, Ghigo E, Abribat T et al. Effects of acute administration of acylated and unacylated ghrelin on glucose and insulin concentrations in morbidly obese subjects without overt diabetes. European Journal of Endocrinology 2009 161 567-573. (doi:10.1530/EJE-09-0339)
70. Tong J, Davis HW, Summer S, Benoit SC, Haque A, Bidlingmaier M, Tschop MH& D'Alessio D. Acute administration of unacylated ghrelin has no effect on basal or stimulated insulin secretion in healthy humans. Diabetes 2014. In Press. (doi:10.2337/db13-1598 1939-327X)
71. Benso A, St-Pierre DH, Prodam F, Gramaglia E, Granata R, van der Lely AJ, Ghigo E& Broglio F. Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans. European Journal of Endocrinology 2012 166 911-916. (doi:10.1530/EJE-11-0982)
72. Ozcan B, Neggers SJ, Miller AR, Yang HC, Lucaites V, Abribat T, Allas S, Huisman M, Visser JA, Themmen AP et al. Does des-acyl ghrelin improve glycemic control in obese diabetic subjects by decreasing acylated ghrelin levels? European Journal of Endocrinology 2014 170 799-807. (doi:10.1530/EJE-13-0347)
73. Sun Y, Butte NF, Garcia JM & Smith RG. Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology 2008 149 843-850. (doi:10.1210/en.2007-0271)
74. Li RL, Sherbet DP, Elsbernd BL, Goldstein JL, Brown MS & Zhao TJ. Profound hypoglycemia in starved, ghrelin-deficient mice is caused by decreased gluconeogenesis and revrsed by lactate or fatty acids. Journal of Biological Chemistry 2012 287 17942-17950. (doi:10.1074/jbc.M112.358051)
75. Gahete MD, Cordoba-Chacon J, Luque RM & Kineman RD. The rise in growth hormone during starvation does not serve tomaintain glucose levels or lean mass but is required for appropriate adipose tissue response in female mice. Endocrinology 2012 154 263-269. (doi:10.1210/en.2012-1849)
76. Yi CX, Heppner KM, Kirchner H, Tong J, Bielohuby M, Gaylinn BD, Muller TD, Bartley E, Davis HW, Zhao Y et al. The GOAT-ghrelin system is not essential for hypoglycemia prevention during prolonged calorie restriction. PLoS ONE 2012 7 e32100. (doi:10.1371/journal.pone.0032100)
77. Liu YL, Yakar S, Otero-Corchon V, Low MJ & Liu JL. Ghrelin gene expression is age-dependent and influenced by gender and the level of circulating IGF-I. Molecular and Cellular Endocrinology 2002 189 97-103. (doi:10.1016/S0303-7207(01)00742-0)
78. Schwartz MW & Porte D Jr. Diabetes, obesity, and the brain. Science 2005 307 375-379. (doi:10.1126/science.1104344)
79. Sandoval DA, Obici S & Seeley RJ. Targeting the CNS to treat type 2 diabetes. Nature Reviews. Drug Discovery 2009 8 386-398. (doi:10.1038/nrd2874)
80. Thorens B. Brain glucose sensing and neural regulation of insulin and glucagon secretion. Diabetes, Obesity & Metabolism 2011 13 (Suppl 1) 82-88. (doi:10.1111/j.1463-1326.2011.01453.x)
81. Duangtep Y, Narksawat K, Chongsuwat R & Rojanavipart P. Association between an unhealthy lifestyle and other factors with hypertension among hill tribe populations of Mae Fah Luang District, Chiang Rai Province, Thailand. Southeast Asian Journal of Tropical Medicine and Public Health 2010 41 726-734.
82. Ahren B. Autonomic regulation of islet hormone secretion-implications for health and disease. Diabetologia 2000 43 393-410. (doi:10.1007/s001250051322)
83. Zigman JM, Jones JE, Lee CE, Saper CB & Elmquist JK. Expression of ghrelin receptor mRNA in the rat and the mouse brain. Journal of Comparative Neurology 2006 494 528-548. (doi:10.1002/cne.20823)
84. Faulconbridge LF, Cummings DE, Kaplan JM & Grill HJ. Hyperphagic effects of brainstem ghrelin administration. Diabetes 2003 52 2260-2265. (doi:10.2337/diabetes.52.9.2260)
85. Tsubota Y, Owada-Makabe K, Yukawa K & Maeda M. Hypotensive effect of des-acyl ghrelin at nucleus tractus solitarii of rat. Neuroreport 2005 16 163-166. (doi:10.1097/00001756-200502080-00019)
86. Lin Y, Matsumura K, Fukuhara M, Kagiyama S, Fujii K & Iida M. Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension 2004 43 977-982. (doi:10.1161/01.HYP.0000122803.91559.55)
87. Meyer C. Final answer: ghrelin can suppress insulin secretion in humans, but is it clinically relevant? Diabetes 2010 59 2726-2728. (doi:10.2337/db10- 1088)
88. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y & Kangawa K. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 2001 280 R1483-R1487.
89. Huda MS, Mani H, Dovey T, Halford JC, Boyland E, Daousi C, Wilding JP & Pinkney J. Ghrelin inhibits autonomic function in healthy controls, but has no effect on obese and vagotomized subjects. Clinical Endocrinology 2010 73 678-685. (doi:10.1111/j.1365-2265.2010.03865.x)
90. le Roux CW, Neary NM, Halsey TJ, Small CJ, Martinez-Isla AM, Ghatei MA, Theodorou NA & Bloom SR. Ghrelin does not stimulate food intake in patients with surgical procedures involving vagotomy. Journal of Clinical Endocrinology and Metabolism 2005 90 4521-4524. (doi:10.1210/jc.2004-2537)
91. Kim MS, Namkoong C, Kim HS, Jang PG, Kim Pak YM, Katakami H, Park JY & Lee KU. Chronic central administration of ghrelin reverses the effects of leptin. International Journal of Obesity and Related Metabolic Disorders 2004 28 1264-1271. (doi:10.1038/sj.ijo.0802647)
92. Yada T, Itoh K & Nakata M. Glucagon-like peptide-1-(7-36)amide and a rise in cyclic adenosine 3′,5′-monophosphate increase cytosolic free Ca2+ in rat pancreatic β-cells by enhancing Ca2+ channel activity. Endocrinology 1993 133 1685-1692. (doi:10.1210/endo.133.4.8404610)
93. Damdindorj B, Dezaki K, Kurashina T, Sone H, Rita R, Kakei M & Yada T. Exogenous and endogenous ghrelin counteracts GLP-1 action to stimulate cAMP signaling and insulin secretion in islet β-cells. FEBS Letters 2012 586 2555-2562. (doi:10.1016/j.febslet.2012.06.034)
94. Senda M, Ogawa S, Nako K, Okamura M, Sakamoto T & Ito S. The glucagon-like peptide-1 analog liraglutide suppresses ghrelin and controls diabetes in a patient with Prader-Willi syndrome. Endocrine Journal 2012 59 889-894. (doi:10.1507/endocrj.EJ12-0074)
95. Daousi C, Pinkney JH, Cleator J, Wilding JP & Ranganath LR. Acute peripheral administration of synthetic human GLP-1 (7-36 amide) decreases circulating IL-6 in obese patients with type 2 diabetes mellitus: a potential role for GLP-1 in modulation of the diabetic pro-inflammatory state? Regulatory Peptides 2013 183C 54-61. (doi:10.1016/j.regpep.2013.03.004)
96. Falken Y, Hellstrom PM, Sanger GJ, Dewit O, Dukes G, Gryback P, Holst JJ & Naslund E. Actions of prolonged ghrelin infusion on gastrointestinal transit and glucose homeostasis in humans. Neurogastroenterology and Motility 2010 22 e192-e200. (doi:10.1111/j.1365-2982.2009.01463.x)
97. Santry HP, Gillen DL & Lauderdale DS. Trends in bariatric surgical procedures. Journal of the American Medical Association 2005 294 1909-1917. (doi:10.1001/jama.294.15.1909)
98. Cutolo PP, Nosso G, Vitolo G, Brancato V, Capaldo B & Angrisani L. Clinical efficacy of laparoscopic sleeve gastrectomy vs laparoscopic gastric bypass in obese type 2 diabetic patients: a retrospective comparison. Obesity Surgery 2012 22 1535-1539. (doi:10.1007/s11695-012-0657-5)
99. Roslin MS, Dudiy Y, Weiskopf J, Damani T & Shah P. Comparison between RYGB, DS, and VSG effect on glucose homeostasis. Obesity Surgery 2012 22 1281-1286. (doi:10.1007/s11695-012-0686-0)
100. Woelnerhanssen B, Peterli R, Steinert RE, Peters T, Borbely Y & Beglinger C. Effects of postbariatric surgery weight loss on adipokines and metabolic parameters: comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy-A prospective randomized trial. Surgery for Obesity and Related Diseases 2011 7 561-568. (doi:10.1016/j.soard.2011.01.044)
101. Rubino F, Gagner M, Gentileschi P, Kini S, Fukuyama S, Feng J & Diamond E. The early effect of the Roux-en-Y gastric bypass on hormones involved in body weight regulation and glucose metabolism. Annals of Surgery 2004 240 236-242. (doi:10.1097/ 01.sla.0000133117.12646.48)
102. Wickremesekera K, Miller G, Naotunne TD, Knowles G & Stubbs RS. Loss of insulin resistance after Roux-en-Y gastric bypass surgery: a time course study. Obesity Surgery 2005 15 474-481. (doi:10.1381/0960892053723402)
103. Rizzello M, Abbatini F, Casella G, Alessandri G, Fantini A, Leonetti F & Basso N. Early postoperative insulin-resistance changes after sleeve gastrectomy. Obesity Surgery 2010 20 50-55. (doi:10.1007/s11695-009-0017-2)
104. Chambers AP, Jessen L, Ryan KK, Sisley S, Wilson-Perez HE, Stefater MA, Gaitonde SG, Sorrell JE, Toure M, Berger J et al. Weight-independent changes in blood glucose homeostasis after gastric bypass or vertical sleeve gastrectomy in rats. Gastroenterology 2011 141 950-958. (doi:10.1053/j.gastro.2011.05.050)
105. Chambers AP, Stefater MA, Wilson-Perez HE, Jessen L, Sisley S, Ryan KK, Gaitonde S, Sorrell JE, Toure M, Berger J et al. Similar effects of Roux-en-Y gastric bypass and vertical sleeve gastrectomy on glucose regulation in rats. Physiology & Behavior 2011 105 120-123. (doi:10.1016/j.physbeh.2011.05.026)
106. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP & Purnell JQ. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. New England Journal of Medicine 2002 346 1623-1630. (doi:10.1056/NEJMoa012908)
107. Pournaras DJ & le Roux CW. Ghrelin and metabolic surgery. International Journal of Peptides 2010 2010. Article ID 217267. (doi:10.1155/2010/217267)
108. Karamanakos SN, Vagenas K, Kalfarentzos F & Alexandrides TK. Weight loss, appetite suppression, and changes in fasting and postprandial ghrelin and peptide-YY levels after Roux-en-Y gastric bypass and sleeve gastrectomy: a prospective, double blind study. Annals of Surgery 2008 247 401-407. (doi:10.1097/SLA.0b013e318156f012)
109. Wang Y & Liu J. Plasma ghrelin modulation in gastric band operation and sleeve gastrectomy. Obesity Surgery 2009 19 357-362. (doi:10.1007/s11695- 008-9688-3)
110. Cohen R, Uzzan B, Bihan H, Khochtali I, Reach G & Catheline JM. Ghrelin levels and sleeve gastrectomy in super-super-obesity. Obesity Surgery 2005 15 1501-1502. (doi:10.1381/096089205774859335)
111. Langer FB, Reza Hoda MA, Bohdjalian A, Felberbauer FX, Zacherl J, Wenzl E, Schindler K, Luger A, Ludvik B & Prager G. Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels. Obesity Surgery 2005 15 1024-1029. (doi:10.1381/0960892054621125)
112. Yousseif A, Emmanuel J, Karra E, Millet Q, Elkalaawy M, Jenkinson AD, Hashemi M, Adamo M, Finer N, Fiennes AG et al. Differential effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circulating acylghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans. Obesity Surgery 2014 24 241-252. (doi:10.1007/s11695-013-1066-0)
113. Chambers AP, Kirchner H, Wilson-Perez HE, Willency JA, Hale JE, Gaylinn BD, Thorner MO, Pfluger PT, Gutierrez JA, Tschop MH et al. The effects of vertical sleeve gastrectomy in rodents are ghrelin independent. Gastroenterology 2013 144 50-52 e55. (doi:10.1053/j.gastro.2012.09.009)