Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2015, vol. 24, nr 3, May-June, p. 401–407

doi: 10.17219/acem/43723

Publication type: original article

Language: English

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The Effects of Long-Term Diabetes on Ghrelin Expression in Rat Stomachs

Mehmet F. Sönmez1,A,B,C,D,E,F, Derya Karabulut1,B,C, Yusuf Gunduz1,B,C, Munis Dundar2,B,C

1 Department of Histology and Embryology, Faculty of Medicine, Erciyes University, Kayseri, Turkey

2 Department of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey

Abstract

Background. Ghrelin is a hormone which has effects on the secretion of growth hormone, the gastrointestinal system, the cardiovascular system, cell proliferation and the reproductive system.
Objectives. This study focused on relative ghrelin and GHS-R1a gene expression in the stomach of long-term diabetic rats.
Material and Methods. A total of 36 male Wistar albino rats were divided into four groups: a control group, one-month diabetic rats, two-month diabetic rats and three-month diabetic rats. Diabetes was induced by streptozotocin STZ (40 mg/kg i.p). The rats were decapitated under ketamine anesthesia and their stomach tissues were removed. Tissue ghrelin expression, ghrelin and GHS-R mRNA levels were then compared using immunohistochemistry and qRT-PCR.
Results. After one month of diabetes, the number of ghrelin-immunopositive cells decreased significantly compared to those of the control rats. However, the ghrelin-immunopositive cells increased numerically in the twoand three-month diabetic rats compared to those of the control rats. It was also observed that there were high levels of ghrelin mRNA in the oneand two-month diabetic rats, and a subsequent decrease of ghrelin mRNA levels in the three-month diabetic rats compared to the control rats. However, ghrelin receptor mRNA expression levels decreased in the one-month diabetic rats, and ghrelin levels subsequently increased in the twoand three-month diabetic rats compared to the control rats.
Conclusion. The twoand three-month diabetic rats became cachectic due to the large amount of weight lost. The authors therefore concluded that ghrelin-immunopositive cells increased in these rats due to their cachectic state.

Key words

diabetes mellitus, ghrelin, stomach, immunohistochemistry, RT-PCR.

References (33)

  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.
  2. 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.
  3. Hewson AK, Dickson SL: Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J Neuroendocrinol 2000, 12, 1047–1049.
  4. 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.
  5. Toshinai K, Mondal MS, Nakazato M, Date Y, Murakami N, Kojima M, Kangawa K, Matsukura S: Upregulation of Ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem Biophys Res Commun 2001, 281, 1220–1225.
  6. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML: Circulating ghrelin levels are decreased in human obesity. Diabetes 2001, 50, 707–709.
  7. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR: The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000, 141, 4325–4328.
  8. Inui A: Ghrelin, an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2001, 2, 551–560.
  9. Kojima M, Hosoda H, Matsuo H, Kangawa K: Ghrelin, discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab 2001, 12, 118–122.
  10. Muccioli G, Tschop M, Papotti M, Deghenghi R, Heiman M, Ghigo E: Neuroendocrine and peripheral activities of ghrelin, implications in metabolism and obesity. Eur J Pharmacol 2002, 440, 235–254.
  11. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M: 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.
  12. Sakata I, Tanaka T, Matsubara M, Yamazaki M, Tani S, Hayashi Y, Kangawa K, Sakai T: Postnatal changes in ghrelin mRNA expression and in ghrelin-producing cells in the rat stomach. J Endocrinol 2002, 174, 463–471.
  13. Zhao Z, Sakai T: Characteristic features of ghrelin cells in the gastrointestinal tract and the regulation of stomach ghrelin expression and production. World J Gastroenterol 2008, 14, 6306–6311.
  14. Masaoka T, Suzuki H, Hosoda H, Ota T, Minegishi Y, Nagata H, Kangawa K, Ishii H: Enhanced plasma ghrelin levels in rats with streptozotocin-induced diabetes. FEBS Lett 2003, 541, 64–68.
  15. Dietrich M, Grepl UH, Kramer B, Walch H: Real Time ready RT-qPCR Assay Development and Qualification. Roche Diagnostics GmbH. Nonnenwald 82377 Pnezberg Germany.
  16. Al Massadi O, Tschop MH, Tong J: Ghrelin acylation and metabolic control. Peptides 2011, 32, 2301–2308.
  17. Arvat E, Maccario M, Di Vito L, Broglio F, Benso A, Gottero C, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E: 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.
  18. Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL: The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003, 37, 649–661.
  19. Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, Castaneda TR, Muzzin P, Schürmann A, Szanto I, Tschöp MH, Rohner-Jeanrenaud F: Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest 2006, 116, 1983–1993.
  20. Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, Date Y, Mondal MS, Shimbara T, Kawagoe T, Murakami 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. Sun Y, Asnicar M, Smith RG: Central and peripheral roles of ghrelin on glucose homeostasis. Neuroendocrinology 2007, 86, 215–228.
  22. 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.
  23. McLaughlin T, Abbasi F, Lamendola C, Frayo RS, Cummings 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.
  24. Tong J, Prigeon RL, Davis HW, Bidlingmaier M, Kahn SE, Cummings DE, Tschöp MH, D’Alessio D: Ghrelin suppresses glucose-stimulated insulin secretion and deteriorates glucose tolerance in healthy humans. Diabetes 2010, 59, 2145–2151.
  25. Ukkola O: Ghrelin in Type 2 diabetes mellitus and metabolic syndrome. Mol Cell Endocrinol 2011, 340, 26–28.
  26. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K: Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 2001, 86, 4753–4758.
  27. Sonmez MF, Ozan E: Determination of ghrelin immunoreactivity in the rat stomach after fasting and refeeding. Acta Histochem 2007, 109, 193–199.
  28. 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.
  29. Rauma J, Spangeus A, El-Salhy M: Ghrelin cell density in the gastrointestinal tracts of animal models of human diabetes. Histol Histopathol 2006, 21, 1–5.
  30. 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.
  31. 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 streptozotocin-induced diabetes. Endocrinology 2006, 147, 2634–2642.
  32. Castaneda TR, Tong J, Datta R, Culler M, Tschop MH: Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol 2010, 31, 44–60.
  33. 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.