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Plasma Ghrelin Levels in Lean and Obese Humans and the Effect of Glucose on Ghrelin Secretion

Department of Internal Medicine, Miyazaki Medical College (T.S., M.N., M.M., Y.D., M.S.M., S.M.), Miyazaki 889-1692, Japan; National Cardiovascular Center Research Institute (H.H., K.K.), Osaka 565-8565, Japan; and Department of Psychosomatic Medicine, Kagoshima University School of Medicine (M.T., S.N.), Kagoshima 890-8520, Japan

Address all correspondence and requests for reprints to: Masamitsu Nakazato, M.D., Ph.D., Third Department of Internal Medicine, Miyazaki Medical College, Kiyotake, Miyazaki 889-1692, Japan. E-mail: nakazato{at}post.miyazaki-med.ac.jp

Ghrelin, a novel GH-releasing peptide isolated from human and rat stomach, stimulates food intake and GH secretion. We determined plasma ghrelin concentrations in patients with simple obesity, anorexia nervosa, and type 2 diabetes mellitus by RIA. We also studied plasma ghrelin responses to glucose load and meal intake and obtained a 24-h profile of circulating ghrelin in humans.

Plasma ghrelin concentrations in patients with simple obesity and anorexia nervosa were lower and higher, respectively, than those of healthy subjects with normal body weight. Among those with type 2 diabetes mellitus, obese patients had lower and lean patients higher fasting plasma ghrelin concentrations than normal-weight patients. Fasting plasma ghrelin concentration was negatively correlated with body mass index in both nondiabetic and diabetic patients. Plasma ghrelin concentrations of normal subjects decreased significantly after oral and iv glucose administration; a similar response was also observed in diabetic patients after a meal tolerance test, reaching a nadir of 69% of the basal level after the meal. Circulating plasma ghrelin showed a diurnal pattern with preprandial increases, postprandial decreases, and a maximum peak at 0200 h. This study demonstrates that nutritional state is a determinant of plasma ghrelin in humans. Ghrelin secretion is up-regulated under conditions of negative energy balance and down-regulated in the setting of positive energy balance. These findings suggest the involvement of ghrelin in the regulation of feeding behavior and energy homeostasis.

This study was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan; the Ministry of Health, Labor and Welfare, Japan; the NOVARTIS Foundation (Japan) for the Promotion of Science; the Society of Molecular Mechanism of the Digestive Tract; Mitsui Life Foundation; and The Foundation for Growth Science (to M.N.).

Abbreviations: BMI, Body mass index; DM, diabetes mellitus; GPCR, G protein-coupled cell surface receptor.

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				C. Langenberg, J. Bergstrom, G. A. Laughlin, and E. Barrett-Connor Ghrelin and the Metabolic Syndrome in Older Adults J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6448 - 6453. [Abstract] [Full Text] [PDF]

				C. Feinle-Bisset, M. Patterson, M. A. Ghatei, S. R. Bloom, and M. Horowitz Fat digestion is required for suppression of ghrelin and stimulation of peptide YY and pancreatic polypeptide secretion by intraduodenal lipid Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E948 - E953. [Abstract] [Full Text] [PDF]

				M. Tesauro, F. Schinzari, M. Iantorno, S. Rizza, D. Melina, D. Lauro, and C. Cardillo Ghrelin Improves Endothelial Function in Patients With Metabolic Syndrome Circulation, November 8, 2005; 112(19): 2986 - 2992. [Abstract] [Full Text] [PDF]

				P. Koutkia, S. Schurgin, J. Berry, J. Breu, B. S. H. Lee, A. Klibanski, and S. Grinspoon Reciprocal changes in endogenous ghrelin and growth hormone during fasting in healthy women Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E814 - E822. [Abstract] [Full Text] [PDF]

				R. Giordano, A. Picu, U. Pagotto, R. De Iasio, L. Bonelli, F. Prodam, F. Broglio, L. Marafetti, R. Pasquali, M. Maccario, et al. The negative association between total ghrelin levels, body mass and insulin secretion is lost in hypercortisolemic patients with Cushing's disease Eur. J. Endocrinol., October 1, 2005; 153(4): 535 - 543. [Abstract] [Full Text] [PDF]

				E T Vestergaard, T K Hansen, S Nielsen, N Moller, J S Christiansen, and J O L Jorgensen Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis Eur. J. Endocrinol., October 1, 2005; 153(4): 545 - 549. [Abstract] [Full Text] [PDF]

				M A Arafat, B Otto, H Rochlitz, M Tschop, V Bahr, M Mohlig, S Diederich, J Spranger, and A F H Pfeiffer Glucagon inhibits ghrelin secretion in humans Eur. J. Endocrinol., September 1, 2005; 153(3): 397 - 402. [Abstract] [Full Text] [PDF]

				Y. H. Choe, S. Y. Song, K.-H. Paik, Y. J. Oh, S.-H. Chu, S. H. Yeo, E. K. Kwon, E. M. Kim, M. Y. Rha, and D.-K. Jin Increased Density of Ghrelin-Expressing Cells in the Gastric Fundus and Body in Prader-Willi Syndrome J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5441 - 5445. [Abstract] [Full Text] [PDF]

				C. Daousi, I. A. MacFarlane, P. J. English, J. P. H. Wilding, M. Patterson, T. M. Dovey, J. C. G. Halford, M. A. Ghatei, and J. H. Pinkney Is There a Role for Ghrelin and Peptide-YY in the Pathogenesis of Obesity in Adults with Acquired Structural Hypothalamic Damage? J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5025 - 5030. [Abstract] [Full Text] [PDF]

				L. J. Moran, N. D. Luscombe-Marsh, M. Noakes, G. A. Wittert, J. B. Keogh, and P. M. Clifton The Satiating Effect of Dietary Protein Is Unrelated to Postprandial Ghrelin Secretion J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5205 - 5211. [Abstract] [Full Text] [PDF]

				Y. Date, K. Toshinai, S. Koda, M. Miyazato, T. Shimbara, T. Tsuruta, A. Niijima, K. Kangawa, and M. Nakazato Peripheral Interaction of Ghrelin with Cholecystokinin on Feeding Regulation Endocrinology, August 1, 2005; 146(8): 3518 - 3525. [Abstract] [Full Text] [PDF]

				D. Panidis, D. Farmakiotis, G. Koliakos, D. Rousso, A. Kourtis, I. Katsikis, C. Asteriadis, V. Karayannis, and E. Diamanti-Kandarakis Comparative study of plasma ghrelin levels in women with polycystic ovary syndrome, in hyperandrogenic women and in normal controls Hum. Reprod., August 1, 2005; 20(8): 2127 - 2132. [Abstract] [Full Text] [PDF]

				A. Masuda, M. Nakazato, T. Kihara, S. Minagoe, and C. Tei Repeated Thermal Therapy Diminishes Appetite Loss and Subjective Complaints in Mildly Depressed Patients Psychosom Med, July 1, 2005; 67(4): 643 - 647. [Abstract] [Full Text] [PDF]

				D. Yasuhara, T. Naruo, N. Nagai, T. Muranaga, T. Nakahara, M. Tanaka, S. Kojima, K.-i. Sagiyama, A. Masuda, and A. Inui Glucose Tolerance Predicts Short-term Refeeding Outcome in Females With Anorexia Nervosa Psychosom Med, July 1, 2005; 67(4): 669 - 676. [Abstract] [Full Text] [PDF]

				L. F. Canosa, S. Unniappan, and R. E. Peter Periprandial changes in growth hormone release in goldfish: role of somatostatin, ghrelin, and gastrin-releasing peptide Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2005; 289(1): R125 - R133. [Abstract] [Full Text] [PDF]

				G Natalucci, S Riedl, A Gleiss, T Zidek, and H Frisch Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern Eur. J. Endocrinol., June 1, 2005; 152(6): 845 - 850. [Abstract] [Full Text] [PDF]

				Y. Nishi, H. Hiejima, H. Mifune, T. Sato, K. Kangawa, and M. Kojima Developmental Changes in the Pattern of Ghrelin's Acyl Modification and the Levels of Acyl-Modified Ghrelins in Murine Stomach Endocrinology, June 1, 2005; 146(6): 2709 - 2715. [Abstract] [Full Text] [PDF]

				T. Sato, Y. Fukue, H. Teranishi, Y. Yoshida, and M. Kojima Molecular Forms of Hypothalamic Ghrelin and Its Regulation by Fasting and 2-Deoxy-D-Glucose Administration Endocrinology, June 1, 2005; 146(6): 2510 - 2516. [Abstract] [Full Text] [PDF]

				M. Groschl, H. G. Topf, J. Bohlender, J. Zenk, S. Klussmann, J. Dotsch, W. Rascher, and M. Rauh Identification of Ghrelin in Human Saliva: Production by the Salivary Glands and Potential Role in Proliferation of Oral Keratinocytes Clin. Chem., June 1, 2005; 51(6): 997 - 1006. [Abstract] [Full Text] [PDF]

				J. M. Garcia, M. Garcia-Touza, R. A. Hijazi, G. Taffet, D. Epner, D. Mann, R. G. Smith, G. R. Cunningham, and M. Marcelli Active Ghrelin Levels and Active to Total Ghrelin Ratio in Cancer-Induced Cachexia J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2920 - 2926. [Abstract] [Full Text] [PDF]

				E. Kellokoski, S. M. Poykko, A. H. Karjalainen, O. Ukkola, J. Heikkinen, Y. A. Kesaniemi, and S. Horkko Estrogen Replacement Therapy Increases Plasma Ghrelin Levels J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2954 - 2963. [Abstract] [Full Text] [PDF]

				F. Bacha and S. A. Arslanian Ghrelin Suppression in Overweight Children: A Manifestation of Insulin Resistance? J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2725 - 2730. [Abstract] [Full Text] [PDF]

				S. Kanumakala, R. Greaves, C. C. Pedreira, S. Donath, G. L. Warne, M. R. Zacharin, and M. Harris Fasting Ghrelin Levels Are Not Elevated in Children with Hypothalamic Obesity J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2691 - 2695. [Abstract] [Full Text] [PDF]

				J. Erdmann, F. Lippl, S. Wagenpfeil, and V. Schusdziarra Differential Association of Basal and Postprandial Plasma Ghrelin With Leptin, Insulin, and Type 2 Diabetes Diabetes, May 1, 2005; 54(5): 1371 - 1378. [Abstract] [Full Text] [PDF]

				D. L. Williams and D. E. Cummings Regulation of Ghrelin in Physiologic and Pathophysiologic States J. Nutr., May 1, 2005; 135(5): 1320 - 1325. [Abstract] [Full Text] [PDF]

				A. Geliebter, M. E. Gluck, and S. A. Hashim Plasma Ghrelin Concentrations Are Lower in Binge-Eating Disorder J. Nutr., May 1, 2005; 135(5): 1326 - 1330. [Abstract] [Full Text] [PDF]