Integrative Neuroendocrine Peptide in Health and Disease

Annals of Surgery

Volumn 239, Issue 4, 2004, Pages 464-474

  Wu, James T ^a   Kral, John G ^a  

^a SUNY Downstate Medical Center   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CORTICOTROPIN; GENE PRODUCT; GHRELIN; GROWTH HORMONE SECRETAGOGUE RECEPTOR; NEUROPEPTIDE; G PROTEIN COUPLED RECEPTOR; GROWTH HORMONE; PEPTIDE HORMONE;

ANTIINFLAMMATORY ACTIVITY; BIOSYNTHESIS; BODY WEIGHT; CACHEXIA; CATABOLISM; DIAGNOSTIC APPROACH ROUTE; DOWN REGULATION; EFFECTOR CELL; FEEDING; FEEDING DISORDER; FOOD INTAKE; FUNCTIONAL ASSESSMENT; GROWTH HORMONE RELEASE; GROWTH REGULATION; HOMEOSTASIS; HORMONE ACTION; HUMAN; HYPOPHYSIS; IMMUNE RESPONSE; LIGAND BINDING; METABOLIC REGULATION; NEUROSECRETORY CELL; OBESITY; OVERNUTRITION; PRIORITY JOURNAL; RECEPTOR BINDING; REVIEW; SENSORY NERVE; STOMACH; SURGICAL STRESS; VAGUS NERVE; BRAIN; CARDIOVASCULAR FUNCTION; CRITICAL ILLNESS; DIGESTIVE FUNCTION; ENERGY METABOLISM; FEEDING BEHAVIOR; IMMUNOLOGY; NEOPLASM; PATHOPHYSIOLOGY; PHYSIOLOGY; STOMACH BYPASS;

BRAIN; CACHEXIA; CARDIOVASCULAR PHYSIOLOGY; CRITICAL ILLNESS; DIGESTIVE PHYSIOLOGY; ENERGY METABOLISM; FEEDING BEHAVIOR; GASTRIC BYPASS; GROWTH HORMONE; HUMANS; NEOPLASMS; NEUROPEPTIDES; OBESITY; PEPTIDE HORMONES; RECEPTORS, G-PROTEIN-COUPLED;

EID: 1642354552     PISSN: 00034932     EISSN: None     Source Type: Journal    
DOI: 10.1097/01.sla.0000118561.54919.61     Document Type: Review

References (117)

1. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656-660.
2. Wajnrajch MP, Ten IS, Gertner JM, et al. Genomic organization of the Human GHRELIN Gene. J Endocr Genet. 2000;1:231-233.
3. Hosoda H, Kojima M, Matsuo H, et al. Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem. 2000;275:21995-22000.
4. Asakawa A, Inui A, Kaga T, et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology. 2001;120:337-345.
5. Kojima M, Hosoda H, Matusuo H, et al. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab. 2001;12:118-121.
6. Bednarek MA, Feighner SD, Pong SS, et al. Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem. 2000;43:4370-4376.
7. Casanueva FF, Dieguez C. Growth hormone secretagogues: physiological role and clinical utility. Trends Endocrinol Metab. 1999;10:30-38.
8. Smith RG, Van der Ploeg LH, Howard AD, et al. Peptidomimetic regulation of growth hormone secretion. Endocr Rev. 1997;18:621-645.
9. Bluet-Pajot MT, Tolle V, Zizzari P, et al. Growth hormone secretagogues and hypothalamic networks. Endocrine. 2001;14:1-8.
10. Tannenbaum GS, Bowers CY. Interactions of growth hormone secretagogues and growth hormone-releasing hormone/somatostatin. Endocrine. 2001;14:21-27.
11. McKee KK, Palyha OC, Feighner SD, et al. Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol. 1997;11:415-423.
12. Petersenn S, Rasch AC, Penshorn M, et al. Genomic structure and transcriptional regulation of the human growth hormone secretagogue receptor. Endocrinology. 2001;142:2649-2659.
13. Smith RG, Palyha OC, Feighner SD, et al. Growth hormone releasing substances: types and their receptors. Horm Res. 1999;51:1-8.
14. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273:974-977.
15. Feighner SD, Tan CP, McKee KK, et al. Receptor for motilin identified in the human gastrointestinal system. Science. 1999;284:2184-2188.
16. Hosoda H, Kojima M, Mizushima T, et al. Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem. 2003;278:64-70.
17. Date Y, Kojima M, Hosoda H, 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. 2000;141:4255-4261.
18. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002;87:2988-2991.
19. Papotti M, Ghe C, Cassoni P, et al. Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab. 2000;85:3803-3807.
20. Takaya K, Ariyasu H, Kanamoto N, et al. Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab. 2000; 85:4908-4911.
21. Hataya Y, Akamizu T, Takaya K, et al. A low dose of ghrelin stimulates growth hormone (gh) release synergistically with gh-releasing hormone in humans. J Clin Endocrinol Metab. 2001;86:4552-4555.
22. Date Y, Murakami N, Kojima M, et al. Central effects of a novel acylated peptide, ghrelin, on growth hormone release in rats. Biochem Biophys Res Commun. 2000;275:477-480.
23. Arvat E, Di Viteo L, Broglio F, et al. Preliminary evidence that ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest. 2000;23:493-495.
24. Muccioli G, Tschop M, Papotti M, et al. Neuroendocrine and peripheral activites of ghrelin: implications in metabolism and obesity. Eur J Pharmacol. 2002;440:235-254.
25. Arvat E, Maccario M, Di Vito L, et al. Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab. 2001;86:1169-1174.
26. Bowers CY. Unnatural growth hormone-releasing peptide begets natural ghrelin. J Clin Endocrinol Metab. 2001;86:1464-1469.
27. Asakawa A, Inui A, Kaga T, et al. A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology. 2001; 74:143-147.
28. Carlini VP, Monzon ME, Varas MM, et al. Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem Biophys Res Commun. 2002;299:739-743.
29. Muccioli G, Ghe C, Ghigo MC, et al. Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland. J Endocrinol. 1998;157:99-106.
30. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409:194-198.
31. Wren AM, Small CJ, Ward HL, et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology. 2000;141:4325-4328.
32. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407:908-913.
33. Wren AM, Small CJ, Abbott CR, et al. Ghrelin causes hyperphagia and obesity in rats. Diabetes. 2001;50:2540-2547.
34. Wren AM, Seal LJ, Cohen MA, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86: 5992-5995.
35. Cummings DE, Purnell JQ, Frayo RS, et al. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in human. Diabetes. 2001;50:1714-1719.
36. Broglio F, Arvat E, Benso A, et al. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab. 2001;86:5083-5086.
37. Schaller G, Schmidt A, Pleiner J, et al. Plasma ghrelin concentrations are not regulated by glucose or insulin: a double-blind, placebo-controlled crossover clamp study. Diabetes. 2003;52:16-20.
38. Kral JG. Surgical treatment of obesity. In: Bray GA, Bouchard C, James WPT, eds. Handbook of obesity. New York: Marcel Dekker; 1989:977-994.
39. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346:1623-1630.
40. Geloneze B, Tambascia MA, Pilla VF, et al. Ghrelin: a gut-brain hormone: effect of gastric bypass surgery. Obes Surg. 2003;13:17-22.
41. Tritos NA, Mun E, Bertkau A, et al. Serum ghrelin levels in response to glucose load in obese subjects post-gastric bypass surgery. Obes Res. 2003;11:919-924.
42. Faraj M, Havel PJ, Phelis S, et al. Plasma acylation-stimulating protein, adiponectin, leptin, and ghrelin before and after weight loss induced by gastric bypass surgery in morbidly obese subjects. J Clin Endocrinol Metab. 2003;88:1594-1602.
43. Holdstock C, Engstrom BE, Ohrvall M, et al. Ghrelin and adipose tissue regulatory peptides: effect of gastric bypass surgery in obese humans. J Clin Endocrinol Metab. 2003;88:3177-3183.
44. Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of food intake. Nature. 2000;404:661-671.
45. Kral JG. Vagotomy for treatment of severe obesity. Lancet. 1978;1: 307-308.
46. Kral JG. Behavioral effects of vagotomy in humans. J Auton Nerv Syst. 1983;9:273-281.
47. Elmquist JK, Maratos-Flier E, Saper CB, et al. Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci. 1998;1:445-450.
48. Licinio J, Mantzoros C, Negrao AB, et al. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med. 1997;3:575-579.
49. Bornstein SR, Uhlmann K, Haidan A, et al. Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes. 1997;46:1235-1238.
50. Heiman ML, Ahima RS, Craft LS, et al. Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress. Endocrinology. 1997;138:3859-3863.
51. Branson R, Potoczna N, Kral JG, et al. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med. 2003;348:1096-1103.
52. Ravussin E, Tschop M, Morales S, et al. Plasma ghrelin concentration and energy balance: overfeeding and negative energy balance studies in twins. J Clin Endocrinol Metab. 2001;86:4547-4551.
53. Tschop M, Wawarta R, Riepl RL, et al. Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest. 2001;24:RC19-21.
54. Tschop M, Weyer C, Tataranni PA, et al. Circulating ghrelin levels are decreased in human obesity. Diabetes. 2001;50:707-709.
55. Otto B, Cuntz U, Fruehauf E, et al. Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol. 2001;145:669-673.
56. Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med. 1995;1:1155-1161.
57. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292-295.
58. Ikezaki A, Hosoda H, Ito K, 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. 2002;51:3408-3411.
59. Barazzoni R, Zanetti M, Stebel M, et al. Hyperleptinemia prevents increased plasma ghrelin concentration during short-term moderate caloric restriction in rats. Gastroenterology. 2003;124:1188-1192.
60. Pinilla L, Barreiro ML, Tena-Sempere M, et al. Role of ghrelin in the control of growth hormone secretion in prepubertal rats: interactions with excitatory amino acids. Neuroendocrinology. 2003;77:83-90.
61. Asakawa A, Inui A, Kaga T, et al. Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut. 2003;52:947-952.
62. Palmiter RD, Erickson JC, Hollopeter G, et al. Life without neuropeptide Y. Recent Prog Horm Res. 1998;53:163-199.
63. Marsh DJ, Hollopeter G, Kafer KE, et al. Role of the Y5 neuropeptide Y receptor in feeding and obesity. Nat Med. 1998;6:718-721.
64. Holst B, Cygankiewicz A, Halkjar J, et al. High constitutive signaling of the ghrelin receptor-identification of a potent inverse agonist. Mol Endocrinol. 2003;Aug 7 epub.
65. Korbonits M, Gueorguiev M, O'Grady E, et al. A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. J Clin Endocrinol Metab. 2002;87:4005-4008.
66. Ukkola O, Ravussin E, Jacobson P, et al. Role of ghrelin polymorphisms in obesity based on three different studies. Obesity Res. 2002; 10:782-791.
67. Burman P, Ritzen EM, Lindgren AC. Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH. Endocr Rev. 2001;22:787-799.
68. DelParigi A, Tschop M, Heiman ML, et al. High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader-Willi syndrome. J Clin Endocrinol Metab. 2002;87:5461-5464.
69. Cummings DE, Clement K, Purnell JQ, et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med. 2002;8:643-644.
70. Haqq AM, Farooqi IS, O'Rahilly S, et al. Serum ghrelin levels are inversely correlated with body mass index, age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome. J Clin Endocrinol Metab. 2003;88:174-178.
71. Janssen JA, van der Toorn FM, Hofland LJ, et al. Systemic ghrelin levels in subjects with growth hormone deficiency are not modified by one year of growth hormone replacement therapy. Eur J Endocrinol. 2001;145:711-716.
72. Murdolo G, Lucidi P, Di Loreto C, et al. Circulating ghrelin levels of visceral obese men are not modified by a short-term treatment with very low doses of GH replacement. J Endocrinol Invest. 2003;26:244-249.
73. Haqq AM, Stadler DD, Jackson RH, et al. Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome. J Clin Endocrinol Metab. 2003;88:2206-2212.
74. Masuda Y, Tanaka T, Inomata N, et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophy Res Commun. 2000; 276:905-908.
75. Lee HM, Wang G, Englander EW, et al. Ghrelin: a new gastrointestinal endocrine peptide that stimulates insulin secretion-enteric distribution, ontogeny, influence of endocrine and dietary manipulations. Endocrinology. 2002;143:185-190.
76. Date Y, Nakazato M, Murakami N, et al. Ghrelin acts in the central nervous system to stimulate gastric acid secretion. Biochem Biophys Res Commun. 2001;280:904-907.
77. Date Y, Murakami N, Toshinai K, et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology. 2002;123:1120-1128.
78. Date Y, Nakazato M, Hashiguchi S, et al. Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes. 2002;51:124-129.
79. Zhang W, Chen M, Chen X, et al. Inhibition of pancreatic protein secretion by ghrelin in the rat. J Physiol. 2001;537:231-236.
80. Katugampola S, Davenport A. Emerging roles for orphan G-protein-coupled receptors in the cardiovascular system. Trends Pharmacol Sci. 2003;24:30-35.
81. Baldanzi G, Filigheddu N, Cutrupi S, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol. 2002;159:1029-1037.
82. Anker SD, Coats AJS. Cardiac cachexia: a syndrome with impaired survival and immune and neuroendocrine activation. Chest. 1999;115: 836-847.
83. Nagaya N, Uematsu M, Kojima M, et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation. 2001; 104:1430-1435.
84. Nagaya N, Kojima M, Uematsu M, et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol (Regul Integr Comp Physiol). 2001;280:R1483-R1487.
85. Nagaya N, Uematsu M, Kojima M, et al. Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic-catabolic factors. Circulation. 2001;104: 2034-2038.
86. Wiley KE, Davenport AP. Comparison of vasodilators in human mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol. 2002;136:1146-1152.
87. Fazio S, Sabatini D, Capaldo B, et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med. 1996;334:809-814.
88. Osterziel KJ, Strohm O, Schuler J, et al. Randomized, double-blind, placebo-controlled trial of human recombinant growth hormone in patients with chronic heart failure due to dilated cardiomyopathy. Lancet. 1998;351:1233-1237.
89. Hattori N, Saito T, Yagyu T, et al. GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils. J Clin Endocrinol Metab. 2001;86:4248-4291.
90. Koo GC, Huang C, Camacho R, et al. Immune enhancing effect of a growth hormone secretagogue. J Immunol. 2001;166:4195-4201.
91. Habib KE, Gold PW, Chrousos GP. Neuroendocrinology of stress. Endocrinol Metab Clin North Am. 2001;30:695-728.
92. Borovikova S, Ivanova M, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458-462.
93. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature. 2003;421: 384-388.
94. Wang X, Wang BR, Zhang XJ, et al. Evidence for vagus nerve in maintenance of immune balance and transmission of immune information from gut to brain in STM-infected rats. World J Gastroenterol. 2002;8:540-545.
95. Korbonits M, Jacobs RA, Aylwin SJ, et al. The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors. J Clin Endocrinol Metab. 2001;86:881-887.
96. Kim K, Arai K, Sanno N, et al. Ghrelin and growth hormone (GH) secretagogue receptor (GHSR) mRNA expression in human pituitary adenomas. Clin Endocrinol. 2001;54:759-768.
97. Cassoni P, Papotti M, Catapano F, et al. Specific binding sites for synthetic growth hormone secretagogues in non-tumoral and neoplastic human thyroid tissue. Endocrinol. 2000;165:139-146.
98. Ghe C, Cassoni P, Catapano F, et al. The antiproliferative effect of synthetic peptidyl GH secretagogues in human CALU-1 lung carcinoma cells. Endocrinology. 2002;143:484-491.
99. Jeffery PL, Herington AC, Chopin LK. Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines. J Endocrinol. 2002;172:R7-R11.
100. Murata M, Okimura Y, Iida K, et al. Ghrelin modulates the downstream of insulin signaling in hepatoma cells. J Biol Chem. 2002;277:5667-5674.
101. Kanamoto N, Akamizu T, Hosoda H, et al. Substantial production of ghrelin by a human medullary thyroid carcinoma cell line. J Clin Endocrinol Metab. 2001;86:4984-4990.
102. Papotti M, Cassoni P, Volante M, et al. Ghrelin-producing endocrine tumors of the stomach and intestine. J Clin Endocrinol Metab. 2001; 86:5052-5059.
103. Volante M, Allia E, Gugliotta P, et al. Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. J Clin Endocrinol Metab. 2002;87:1300-1308.
104. Cassoni P, Papotti M, Ghe C, 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. J Clin Endocrinol Metab. 2001;86:1738-1745.
105. Wisse BE, Frayo RS, Schwartz MW, et al. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology. 2001;142:3292-3301.
106. Schwartz GJ. The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition. 2000;16:866-873.
107. Schwartz MW, Dallman MF, Woods SC. Hypothalamic response to starvation: implications for the study of wasting disorders. Am J Physiol. 1995;269:R949-R957.
108. Inui A. Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res. 1999;59:4493-4501.
109. Plata-Salaman CR. Anorexia during acute and chronic disease. Nutrition. 1996;12:69-78.
110. Murphy MG, Plunkett LM, Gertz BJ, et al. MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J Clin Endocrinol Metab. 1998;83:320-325.
111. Van den Berghe G. Neuroendocrine pathobiology of chronic critical illness. Crit Care Clin. 2002;18:509-528.
112. Draghia-Akli R, Hahn KA, King GK, et al. Effects of plasmid-mediated growth hormone-releasing hormone in severely debilitated dogs with cancer. Mol Ther. 2002;6:830-836.
113. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986;233:305-312.
114. Karasik A, Rothenberg PL, Yamada K, et al. Increased protein kinase C activity is linked to reduced insulin receptor autophosphorylation in liver of starved rats. J Biol Chem. 1990;265:10226-10231.
115. Pillay TS, Whittaker J, Siddle K, et al. Phorbol ester-induced down-regulation of protein kinase C potentiates insulin receptor tyrosine autophosphorylation: evidence for a major constitutive role in insulin receptor regulation. Biochem Soc Trans. 1990;18:494-495.
116. Kral JG. Morbidity of severe obesity. Surg Clin North Am. 2001;81: 1039-1061.
117. Marceau P, Biron S, Hould FS, et al. Liver pathology and the metabolic syndrome X in severe obesity. J Clin Endocrinol Metab. 1999;84: 1513-1517.