Ghrelin's second life: From appetite stimulator to glucose regulator

World Journal of Gastroenterology

Volumn 18, Issue 25, 2012, Pages 3183-3195

  Verhulst, Pieter Jan ^a   Depoortere, Inge ^a  

^a UNIVERSITY OF LEUVEN   (Belgium)

Author keywords

Blood glucose; Diabetes; Ghrelin; Insulin; Pancreas

Indexed keywords

APPETITE STIMULANT; GHRELIN; GHRELIN RECEPTOR; GLUCAGON; GLUCOSE; IBUTAMOREN; INSULIN; MESSENGER RNA; TRANSCRIPTION FACTOR NKX2.2; TRANSCRIPTION FACTOR PAX4; UNCOUPLING PROTEIN 2;

ADIPOGENESIS; APOPTOSIS; CELL PROLIFERATION; CELL REGENERATION; CONCENTRATION (PARAMETERS); ENERGY BALANCE; GLUCOSE BLOOD LEVEL; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; GLUCOSE TOLERANCE; GROWTH HORMONE RELEASE; HUMAN; HYPERPHAGIA; INSULIN BLOOD LEVEL; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN RELEASE; INSULIN SENSITIVITY; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; ORAL GLUCOSE TOLERANCE TEST; PANCREAS; PANCREAS ISLET ALPHA CELL; PANCREAS ISLET BETA CELL; PHENOTYPE; PROTEIN EXPRESSION; PROTEIN PROCESSING; QUALITY OF LIFE; REVIEW; RNA SPLICING; SIGNAL TRANSDUCTION; STOMACH EMPTYING; STOMACH PARESIS; WEIGHT REDUCTION;

EID: 84863962816     PISSN: 10079327     EISSN: 22192840     Source Type: Journal    
DOI: 10.3748/wjg.v18.i25.3183     Document Type: Review

References (125)

1. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS,Suganuma T, Matsukura S, Kangawa K, Nakazato M. Ghre-lin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastroin-testinal tracts of rats and humans. Endocrinology 2000; 141: 4255-4261
2. Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP, Spedding M, Kojima M, Kangawa K. International Union of Pharmacology. LVI. Ghrelin receptor nomen-clature, distribution, and function. Pharmacol Rev 2005; 57: 541-546
3. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kan-gawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-660
4. Arvat E, Di Vito L, Broglio F, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E. Pre-liminary evidence that Ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest 2000; 23: 493-495
5. Shintani M, Ogawa Y, Ebihara K, Aizawa-Abe M, Miyanaga F, Takaya K, Hayashi T, Inoue G, Hosoda K, Kojima M, Kan-gawa K, Nakao K. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuro-peptide Y/Y1 receptor pathway. Diabetes 2001; 50: 227-232
6. 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
7. Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, Makino S, Fujimiya M, Niijima A, Fujino MA, Kasuga M. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 2001; 120: 337-345
8. Wren AM, Small CJ, Abbott CR, Dhillo WS, Seal LJ, Cohen MA, Batterham RL, Taheri S, Stanley SA, Ghatei MA, Bloom SR. Ghrelin causes hyperphagia and obesity in rats. Diabetes 2001; 50: 2540-2547
9. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Mur-phy KG, Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocri-nol Metab 2001; 86: 5992
10. Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, Ghatei MA, Small C, Bloom SR. Ghrelin increases food intake in obese as well as lean subjects. Int J Obes (Lond) 2005; 29: 1130-1136
11. Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, Bhattacharya S, Carpenter R, Grossman AB, Korbonits M. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endo-crinol Metab 2002; 87: 2988
12. Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000; 279: 909-913
13. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Iden-tification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 2008; 132: 387-396
14. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knier-man MD, Jin Z, Witcher DR, Luo S, Onyia JE, Hale JE. Ghre-lin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA 2008; 105: 6320-6325
15. Sakata I, Yang J, Lee CE, Osborne-Lawrence S, Rovinsky SA, Elmquist JK, Zigman JM. Colocalization of ghrelin O-acyl-transferase and ghrelin in gastric mucosal cells. Am J Physiol Endocrinol Metab 2009; 297: E134-E141
16. Stengel A, Keire D, Goebel M, Evilevitch L, Wiggins B, Ta-ché Y, Reeve JR. The RAPID method for blood processing yields new insight in plasma concentrations and molecular forms of circulating gut peptides. Endocrinology 2009; 150: 5113-5118
17. Liu J, Prudom CE, Nass R, Pezzoli SS, Oliveri MC, Johnson ML, Veldhuis P, Gordon DA, Howard AD, Witcher DR, Geysen HM, Gaylinn BD, Thorner MO. Novel ghrelin assays provide evidence for independent regulation of ghrelin ac-ylation and secretion in healthy young men. J Clin Endocrinol Metab 2008; 93: 1980-1987
18. Nishi Y, Hiejima H, Hosoda H, Kaiya H, Mori K, Fukue Y, Yanase T, Nawata H, Kangawa K, Kojima M. Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghrelin. Endocrinology 2005; 146: 2255-2264
19. Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, Schürmann A, Joost HG, Jandacek RJ, Hale JE, Heiman ML, Tschöp MH. GOAT links dietary lipids with the endocrine control of energy balance. Nat Med 2009; 15: 741-745
20. Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T, Mu-rakami N, Miyazato M, Kangawa K, Nakazato M. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology 2006; 147: 2306-2314
21. Filigheddu N, Gnocchi VF, Coscia M, Cappelli M, Porporato PE, Taulli R, Traini S, Baldanzi G, Chianale F, Cutrupi S, Ar-noletti E, Ghè C, Fubini A, Surico N, Sinigaglia F, Ponzetto C, Muccioli G, Crepaldi T, Graziani A. Ghrelin and des-acyl ghrelin promote differentiation and fusion of C2C12 skeletal muscle cells. Mol Biol Cell 2007; 18: 986-994
22. Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, Wells T. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism inde-pendent of the type 1a growth hormone secretagogue recep-tor. Endocrinology 2004; 145: 234-242
23. Baldanzi G, Filigheddu N, Cutrupi S, Catapano F, Bonissoni S, Fubini A, Malan D, Baj G, Granata R, Broglio F, Papotti M, Surico N, Bussolino F, Isgaard J, Deghenghi R, Sinigaglia F, Prat M, Muccioli G, Ghigo E, Graziani A. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endo-thelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002; 159: 1029-1037
24. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Ander-son J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rig-by M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974-977
25. McKee KK, Tan CP, Palyha OC, Liu J, Feighner SD, Hreniuk DL, Smith RG, Howard AD, Van der Ploeg LH. Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics 1997; 46: 426-434
26. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Siri-nathsinghji DJ, Smith RG, Van der Ploeg LH, Howard AD. Distribution of mRNA encoding the growth hormone secre-tagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 1997; 48: 23-29
27. Tannenbaum GS, Lapointe M, Beaudet A, Howard AD. Expression of growth hormone secretagogue-receptors by growth hormone-releasing hormone neurons in the medio-basal hypothalamus. Endocrinology 1998; 139: 4420-4423
28. Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK. Ex-pression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 2006; 494: 528-548
29. Willesen MG, Kristensen P, Rømer J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 1999; 70: 306-316
30. Xu L, Depoortere I, Tomasetto C, Zandecki M, Tang M, Tim-mermans JP, Peeters TL. Evidence for the presence of moti-lin, ghrelin, and the motilin and ghrelin receptor in neurons of the myenteric plexus. Regul Pept 2005; 124: 119-125
31. Dass NB, Munonyara M, Bassil AK, Hervieu GJ, Osbourne S, Corcoran S, Morgan M, Sanger GJ. Growth hormone secreta-gogue receptors in rat and human gastrointestinal tract and the effects of ghrelin. Neuroscience 2003; 120: 443-453
32. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Ta-heri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR. The novel hypothalamic peptide ghrelin stimu-lates food intake and growth hormone secretion. Endocrinol-ogy 2000; 141: 4325-4328
33. Lawrence CB, Snape AC, Baudoin FM, Luckman SM. Acute central ghrelin and GH secretagogues induce feeding and ac-tivate brain appetite centers. Endocrinology 2002; 143: 155-162
34. Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adipos-ity in rodents. Nature 2000; 407: 908-913
35. Trudel L, Tomasetto C, Rio MC, Bouin M, Plourde V, Eber-ling P, Poitras P. Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat. Am J Physiol Gastrointest Liver Physiol 2002; 282: G948-G952
36. Depoortere I, De Winter B, Thijs T, De Man J, Pelckmans P, Peeters T. Comparison of the gastroprokinetic effects of ghrelin, GHRP-6 and motilin in rats in vivo and in vitro. Eur J Pharmacol 2005; 515: 160-168
37. Dornonville de la Cour C, Lindström E, Norlén P, Håkan-son R. Ghrelin stimulates gastric emptying but is without ef-fect on acid secretion and gastric endocrine cells. Regul Pept 2004; 120: 23-32
38. Kitazawa T, De Smet B, Verbeke K, Depoortere I, Peeters TL. Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro. Gut 2005; 54: 1078-1084
39. Levin F, Edholm T, Schmidt PT, Grybäck P, Jacobsson H, Degerblad M, Höybye C, Holst JJ, Rehfeld JF, Hellström PM, Näslund E. Ghrelin stimulates gastric emptying and hunger in normal-weight humans. J Clin Endocrinol Metab 2006; 91: 3296-3302
40. Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J, Peeters T. Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis. Aliment Phar-macol Ther 2005; 22: 847-853
41. Murray CD, Martin NM, Patterson M, Taylor SA, Ghatei MA, Kamm MA, Johnston C, Bloom SR, Emmanuel AV. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 2005; 54: 1693-1698
42. Binn M, Albert C, Gougeon A, Maerki H, Coulie B, Lem-oyne M, Rabasa Lhoret R, Tomasetto C, Poitras P. Ghrelin gastrokinetic action in patients with neurogenic gastropare-sis. Peptides 2006; 27: 1603-1606
43. Tack J, Depoortere I, Bisschops R, Delporte C, Coulie B, Meulemans A, Janssens J, Peeters T. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut 2006; 55: 327-333
44. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y, Kangawa K. Hemodynamic and hor-monal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 2001; 280: R1483-R1487
45. Diano S, Farr SA, Benoit SC, McNay EC, da Silva I, Hor-vath B, Gaskin FS, Nonaka N, Jaeger LB, Banks WA, Morley JE, Pinto S, Sherwin RS, Xu L, Yamada KA, Sleeman MW, Tschöp MH, Horvath TL. Ghrelin controls hippocampal spine synapse density and memory performance. Nat Neuro-sci 2006; 9: 381-388
46. Carlini VP, Perez MF, Salde E, Schiöth HB, Ramirez OA, de Barioglio SR. Ghrelin induced memory facilitation implicates nitric oxide synthase activation and decrease in the threshold to promote LTP in hippocampal dentate gyrus. Physiol Behav 2010; 101: 117-123
47. Date Y, Nakazato M, Hashiguchi S, Dezaki K, Mondal MS, Hosoda H, Kojima M, Kangawa K, Arima T, Matsuo H, Yada T, Matsukura S. Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes 2002; 51: 124-129
48. Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, Tschöp MH, D'Alessio D. Ghrelin sup-presses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes 2010; 59: 2145-2151
49. Sun Y, Ahmed S, Smith RG. Deletion of ghrelin impairs nei-ther growth nor appetite. Mol Cell Biol 2003; 23: 7973-7981
50. Wortley KE, Anderson KD, Garcia K, Murray JD, Malinova L, Liu R, Moncrieffe M, Thabet K, Cox HJ, Yancopoulos GD, Wiegand SJ, Sleeman MW. Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel pref-erence. Proc Natl Acad Sci USA 2004; 101: 8227-8232
51. De Smet B, Depoortere I, Moechars D, Swennen Q, Moreaux B, Cryns K, Tack J, Buyse J, Coulie B, Peeters TL. Energy ho-meostasis and gastric emptying in ghrelin knockout mice. J Pharmacol Exp Ther 2006; 316: 431-439
52. Sun Y, Wang P, Zheng H, Smith RG. Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA 2004; 101: 4679-4684
53. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, Wil-liams TD, Lachey JL, Seeley RJ, Lowell BB, Elmquist JK. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 2005; 115: 3564-3572
54. Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, Sleeman MW. Absence of ghrelin protects against early-onset obesity. J Clin Invest 2005; 115: 3573-3578
55. 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 Metab 2006; 3: 379-386
56. 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
57. 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. Proc Natl Acad Sci USA 2010; 107: 7467-7472
58. Dezaki K, Hosoda H, Kakei M, Hashiguchi S, Watanabe M, Kangawa K, Yada T. Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in beta-cells: implication in the glycemic control in rodents. Diabetes 2004; 53: 3142-3151
59. Volante M, Allìa E, Gugliotta P, Funaro A, Broglio F, Degh-enghi R, Muccioli G, Ghigo E, Papotti M. Expression of ghre-lin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. J Clin Endocrinol Metab 2002; 87: 1300-1308
60. Wierup N, Svensson H, Mulder H, Sundler F. The ghrelin cell: a novel developmentally regulated islet cell in the hu-man pancreas. Regul Pept 2002; 107: 63-69
61. Andralojc KM, Mercalli A, Nowak KW, Albarello L, Calc-agno R, Luzi L, Bonifacio E, Doglioni C, Piemonti L. Ghrelin-producing epsilon cells in the developing and adult human pancreas. Diabetologia 2009; 52: 486-493
62. Wierup N, Yang S, McEvilly RJ, Mulder H, Sundler F. Ghre-lin is expressed in a novel endocrine cell type in developing rat islets and inhibits insulin secretion from INS-1 (832/13) cells. J Histochem Cytochem 2004; 52: 301-310
63. Chanoine JP, Wong AC. Ghrelin gene expression is mark-edly higher in fetal pancreas compared with fetal stomach: effect of maternal fasting. Endocrinology 2004; 145: 3813-3820
64. Prado CL, Pugh-Bernard AE, Elghazi L, Sosa-Pineda B, Sus-sel L. Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development. Proc Natl Acad Sci USA 2004; 101: 2924-2929
65. Ueberberg B, Unger N, Saeger W, Mann K, Petersenn S. Ex-pression of ghrelin and its receptor in human tissues. Horm Metab Res 2009; 41: 814-821
66. Kageyama H, Funahashi H, Hirayama M, Takenoya F, Kita T, Kato S, Sakurai J, Lee EY, Inoue S, Date Y, Nakazato M, Kangawa K, Shioda S. Morphological analysis of ghrelin and its receptor distribution in the rat pancreas. Regul Pept 2005; 126: 67-71
67. Granata R, Settanni F, Biancone L, Trovato L, Nano R, Bertuzzi F, Destefanis S, Annunziata M, Martinetti M, Cata-pano F, Ghè C, Isgaard J, Papotti M, Ghigo E, Muccioli G. Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3',5'-cyclic adenosine monophosphate/pro-tein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. Endocrinology 2007; 148: 512-529
68. 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
69. Flanagan DE, Evans ML, Monsod TP, Rife F, Heptulla RA, Tamborlane WV, Sherwin RS. The influence of insulin on circulating ghrelin. Am J Physiol Endocrinol Metab 2003; 284: E313-E316
70. Lucidi P, Murdolo G, Di Loreto C, De Cicco A, Parlanti N, Fanelli C, Santeusanio F, Bolli GB, De Feo P. Ghrelin is not necessary for adequate hormonal counterregulation of insu-lin-induced hypoglycemia. Diabetes 2002; 51: 2911-2914
71. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Oika-wa S. Effects of insulin, leptin, and glucagon on ghrelin se-cretion from isolated perfused rat stomach. Regul Pept 2004; 119: 77-81
72. Saad MF, Bernaba B, Hwu CM, Jinagouda S, Fahmi S, Kogosov E, Boyadjian R. Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab 2002; 87: 3997-4000
73. Möhlig M, Spranger J, Otto B, Ristow M, Tschöp M, Pfeiffer AF. Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans. J Endocrinol Invest 2002; 25: RC36-RC38
74. Caixás A, Bashore C, Nash W, Pi-Sunyer F, Laferrère B. Insu-lin, unlike food intake, does not suppress ghrelin in human subjects. J Clin Endocrinol Metab 2002; 87: 1902
75. Schaller G, Schmidt A, Pleiner J, Woloszczuk W, Wolzt M, Luger A. Plasma ghrelin concentrations are not regulated by glucose or insulin: a double-blind, placebo-controlled cross-over clamp study. Diabetes 2003; 52: 16-20
76. Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, van der Lely AJ, Deghenghi R, Ghigo E. Ghrelin, a natu-ral GH secretagogue produced by the stomach, induces hy-perglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 2001; 86: 5083-5086
77. 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
78. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tana-ka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002; 87: 240-244
79. Colombo M, 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
80. Qader SS, Håkanson R, Rehfeld JF, Lundquist I, Salehi A. Proghrelin-derived peptides influence the secretion of insu-lin, glucagon, pancreatic polypeptide and somatostatin: a study on isolated islets from mouse and rat pancreas. Regul Pept 2008; 146: 230-237
81. Reimer MK, Pacini G, Ahrén B. Dose-dependent inhibition by ghrelin of insulin secretion in the mouse. Endocrinology 2003; 144: 916-921
82. Ni H, De Waele K, Walia P, Chanoine JP. In vitro and in vivo effect of acylated and unacylated ghrelin on neonatal glucose homeostasis. Pediatr Res 2010; 67: 609-613
83. Doi A, Shono T, Nishi M, Furuta H, Sasaki H, Nanjo K. IA-2beta, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion. Proc Natl Acad Sci USA 2006; 103: 885-890
84. Wang Y, Nishi M, Doi A, Shono T, Furukawa Y, Shimada T, Furuta H, Sasaki H, Nanjo K. Ghrelin inhibits insulin secre-tion through the AMPK-UCP2 pathway in beta cells. FEBS Lett 2010; 584: 1503-1508
85. Egido EM, Rodriguez-Gallardo J, Silvestre RA, Marco J. Inhibitory effect of ghrelin on insulin and pancreatic soma-tostatin secretion. Eur J Endocrinol 2002; 146: 241-244
86. Adeghate E, Ponery AS. Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. J Neuroendo-crinol 2002; 14: 555-560
87. 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 re-ceptor. Mol Cell Endocrinol 2006; 251: 103-111
88. Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, Bullock W, Daly M, Decarr L, Li Y, Milardo L, Molstad D, Zhu J, Gardell SJ, Livingston JN, Sweet LJ. Small-molecule ghrelin receptor antagonists improve glucose tolerance, sup-press appetite, and promote weight loss. Endocrinology 2007; 148: 5175-5185
89. Cui C, Ohnuma H, Daimon M, Susa S, Yamaguchi H, Kam-eda 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
90. Gauna C, Kiewiet RM, Janssen JA, van de Zande B, Delhan-ty PJ, Ghigo E, Hofland LJ, Themmen AP, van der Lely AJ. Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions. Am J Physiol Endocrinol Metab 2007; 293: E697-E704
91. Akamizu T, Takaya K, Irako T, Hosoda H, Teramukai S, Matsuyama A, Tada H, Miura K, Shimizu A, Fukushima M, Yokode M, Tanaka K, Kangawa K. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur J Endocrinol 2004; 150: 447-455
92. Lucidi P, Murdolo G, Di Loreto C, Parlanti N, De Cicco A, Fatone C, Taglioni C, Fanelli C, Broglio F, Ghigo E, Bolli GB, Santeusanio F, De Feo P. Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations. Nutr Metab Cardiovasc Dis 2005; 15: 410-417
93. Gauna C, Meyler FM, Janssen JA, Delhanty PJ, Abribat T, van Koetsveld P, Hofland LJ, Broglio F, Ghigo E, van der Lely AJ. Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unac-ylated ghrelin strongly improves insulin sensitivity. J Clin Endocrinol Metab 2004; 89: 5035-5042
94. Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Pa-potti 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. J Clin Endocrinol Metab 2004; 89: 3062-3065
95. Barazzoni R, Zanetti M, Ferreira C, Vinci P, Pirulli A, Mucci M, Dore F, Fonda M, Ciocchi B, Cattin L, Guarnieri G. Rela-tionships between desacylated and acylated ghrelin and in-sulin sensitivity in the metabolic syndrome. J Clin Endocrinol Metab 2007; 92: 3935-3940
96. Longo KA, Charoenthongtrakul S, Giuliana DJ, Govek EK, McDonagh T, Qi Y, DiStefano PS, Geddes BJ. Improved in-sulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice. Regul Pept 2008; 150: 55-61
97. Barnett BP, Hwang Y, Taylor MS, Kirchner H, Pfluger PT, Bernard V, Lin YY, Bowers EM, Mukherjee C, Song WJ, Longo PA, Leahy DJ, Hussain MA, Tschöp MH, Boeke JD, Cole PA. Glucose and weight control in mice with a de-signed ghrelin O-acyltransferase inhibitor. Science 2010; 330: 1689-1692
98. Lu J, Li Q, Xie H, Chen ZJ, Borovitskaya AE, Maclaren NK, Notkins AL, Lan MS. Identification of a second transmem-brane protein tyrosine phosphatase, IA-2beta, as an autoan-tigen in insulin-dependent diabetes mellitus: precursor of the 37-kDa tryptic fragment. Proc Natl Acad Sci USA 1996; 93: 2307-2311
99. Lan MS, Wasserfall C, Maclaren NK, Notkins AL. IA-2, a transmembrane protein of the protein tyrosine phosphatase family, is a major autoantigen in insulin-dependent diabetes mellitus. Proc Natl Acad Sci USA 1996; 93: 6367-6370
100. Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, Tschöp MH, Shanabrough M, Cline G, Shul-man GI, Coppola A, Gao XB, Horvath TL, Diano S. UCP2 mediates ghrelin's action on NPY/AgRP neurons by lower-ing free radicals. Nature 2008; 454: 846-851
101. Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB, Zheng XX, Wheeler MB, Shulman GI, Chan CB, Lowell BB. Uncoupling protein-2 negatively regulates insulin secretion and is a ma-jor link between obesity, beta cell dysfunction, and type 2 diabetes. Cell 2001; 105: 745-755
102. Wild S, Roglic G, Green A, Sicree R, King H. Global preva-lence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047-1053
103. Tschöp M, Weyer C, Tataranni PA, Devanarayan V, Ravus-sin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707-709
104. Holdstock C, Ludvigsson J, Karlsson FA. Abnormal ghrelin secretion in new onset childhood Type 1 diabetes. Diabetolo-gia 2004; 47: 150-151
105. Martos-Moreno GA, Barrios V, Soriano-Guillén L, Argente J. Relationship between adiponectin levels, acylated ghrelin levels, and short-term body mass index changes in children with diabetes mellitus type 1 at diagnosis and after insulin therapy. Eur J Endocrinol 2006; 155: 757-761
106. Ashraf A, Mick G, Meleth S, Wang X, McCormick K. Insulin treatment reduces pre-prandial plasma ghrelin concentra-tions in children with type 1 diabetes. Med Sci Monit 2007; 13: CR533-CR537
107. Murdolo G, Lucidi P, Di Loreto C, Parlanti N, De Cicco A, Fatone C, Fanelli CG, Bolli GB, Santeusanio F, De Feo P. In-sulin is required for prandial ghrelin suppression in humans. Diabetes 2003; 52: 2923-2927
108. Ishii S, Kamegai J, Tamura H, Shimizu T, Sugihara H, Oikawa S. Role of ghrelin in streptozotocin-induced diabetic hyperphagia. Endocrinology 2002; 143: 4934-4937
109. Gelling RW, Overduin J, Morrison CD, Morton GJ, Frayo RS, Cummings DE, Schwartz MW. Effect of uncontrolled diabetes on plasma ghrelin concentrations and ghrelin-induced feeding. Endocrinology 2004; 145: 4575-4582
110. Masaoka T, Suzuki H, Hosoda H, Ota T, Minegishi Y, Na-gata H, Kangawa K, Ishii H. Enhanced plasma ghrelin levels in rats with streptozotocin-induced diabetes. FEBS Lett 2003; 541: 64-68
111. Dong J, Peeters TL, De Smet B, Moechars D, Delporte C, Vanden Berghe P, Coulie B, Tang M, Depoortere I. Role of endogenous ghrelin in the hyperphagia of mice with strepto-zotocin-induced diabetes. Endocrinology 2006; 147: 2634-2642
112. Verhulst PJ, De Smet B, Saels I, Thijs T, Ver Donck L, Moechars D, Peeters TL, Depoortere I. Role of ghrelin in the relationship between hyperphagia and accelerated gas-tric emptying in diabetic mice. Gastroenterology 2008; 135: 1267-1276
113. Irako T, Akamizu T, Hosoda H, Iwakura H, Ariyasu H, Tojo K, Tajima N, Kangawa K. Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats. Diabetologia 2006; 49: 1264-1273
114. Granata R, Volante M, Settanni F, Gauna C, Ghé C, An-nunziata M, Deidda B, Gesmundo I, Abribat T, van der Lely AJ, Muccioli G, Ghigo E, Papotti M. Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newborn rats. J Mol Endocrinol 2010; 45: 9-17
115. Kerem M, Salman B, Ozsoy S, Pasaoglu H, Bedirli A, Haz-iroglu R, Yilmaz TU. Exogenous ghrelin enhances endocrine and exocrine regeneration in pancreatectomized rats. J Gas-trointest Surg 2009; 13: 775-783
116. Kyoraku I, Shiomi K, Kangawa K, Nakazato M. Ghrelin reverses experimental diabetic neuropathy in mice. Biochem Biophys Res Commun 2009; 389: 405-408
117. Granata R, Settanni F, Trovato L, Destefanis S, Gallo D, Martinetti M, Ghigo E, Muccioli G. Unacylated as well as acylated ghrelin promotes cell survival and inhibit apoptosis in HIT-T15 pancreatic beta-cells. J Endocrinol Invest 2006; 29: RC19-RC22
118. Wang W, Zhang D, Zhao H, Chen Y, Liu Y, Cao C, Han L, Liu G. Ghrelin inhibits cell apoptosis induced by lipotoxicity in pancreatic beta-cell line. Regul Pept 2010; 161: 43-50
119. Ikezaki A, Hosoda H, Ito K, Iwama S, Miura N, Matsuoka H, Kondo C, Kojima M, Kangawa K, Sugihara S. Fasting plasma ghrelin levels are negatively correlated with insulin resis-tance and PAI-1, but not with leptin, in obese children and adolescents. Diabetes 2002; 51: 3408-3411
120. McLaughlin T, Abbasi F, Lamendola C, Frayo RS, Cum-mings DE. Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls. J Clin Endocrinol Metab 2004; 89: 1630-1635
121. Iwakura H, Ariyasu H, Li Y, Kanamoto N, Bando M, Yama-da G, Hosoda H, Hosoda K, Shimatsu A, Nakao K, Kangawa K, Akamizu T. A mouse model of ghrelinoma exhibited acti-vated growth hormone-insulin-like growth factor I axis and glucose intolerance. Am J Physiol Endocrinol Metab 2009; 297: E802-E811
122. Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE, Clasey JL, Heymsfield SB, Bach MA, Vance ML, Thorner MO. Ef-fects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med 2008; 149: 601-611
123. Qi Y, Longo KA, Giuliana DJ, Gagne S, McDonagh T, Govek E, Nolan A, Zou C, Morgan K, Hixon J, Saunders JO, Diste-fano PS, Geddes BJ. Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps. BMC Physiol 2011; 11: 1
124. Garner AL, Janda KD. A small molecule antagonist of ghre-lin O-acyltransferase (GOAT). Chem Commun (Camb) 2011; 47: 7512-7514
125. Halem HA, Taylor JE, Dong JZ, Shen Y, Datta R, Abizaid A, Diano S, Horvath T, Zizzari P, Bluet-Pajot MT, Epelbaum J, Culler MD. Novel analogs of ghrelin: physiological and clinical implications. Eur J Endocrinol 2004; 151 Suppl 1: S71-S75