Table of Contents Author Guidelines Submit a Manuscript
International Journal of Endocrinology
Volume 2015, Article ID 235727, 11 pages
http://dx.doi.org/10.1155/2015/235727
Research Article

Ghrelin’s Effects on Proinflammatory Cytokine Mediated Apoptosis and Their Impact on β-Cell Functionality

1Research Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain
2Department of Endocrinology and Nutrition, Jerez de la Frontera General Hospital, 11407 Jerez de la Frontera, Spain
3Andalusian Cellular Reprogramming Laboratory, 41092 Sevilla, Spain
4Genetics and Molecular Biology Research Institute, University of Valladolid-CSIC, 47003 Valladolid, Spain
5Salus Infirmorum Faculty of Nursing, Cadiz University, 11001 Cadiz, Spain
6Department of Maternal and Pediatric Medicine and Radiology, Pediatrics Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain

Received 25 March 2015; Revised 5 June 2015; Accepted 18 June 2015

Academic Editor: Sabrina Corbetta

Copyright © 2015 Antonia Diaz-Ganete et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. M. Kojima, H. Hosoda, Y. Date, M. Nakazato, H. Matsuo, and K. Kangawa, “Ghrelin is a growth-hormone-releasing acylated peptide from stomach,” Nature, vol. 402, no. 6762, pp. 656–660, 1999. View at Publisher · View at Google Scholar · View at Scopus
  2. A. Inui, A. Asakawa, C. Y. Bowers et al., “Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ,” The FASEB Journal, vol. 18, no. 3, pp. 439–456, 2004. View at Publisher · View at Google Scholar · View at Scopus
  3. T. Sato, Y. Nakamura, Y. Shiimura, H. Ohgusu, K. Kangawa, and M. Kojima, “Structure, regulation and function of ghrelin,” Journal of Biochemistry, vol. 151, no. 2, pp. 119–128, 2012. View at Publisher · View at Google Scholar · View at Scopus
  4. G. Bottazzo, A. Florin-Christensen, and D. Doniach, “Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies,” The Lancet, vol. 304, no. 7892, pp. 1279–1283, 1974. View at Publisher · View at Google Scholar · View at Scopus
  5. A. C. Maccuish, W. J. Irvine, E. W. Barnes, and L. J. P. Duncan, “Antibodies to pancreatic islet cells in insulin-dependent diabetics with coexistent autoimmune disease,” The Lancet, vol. 304, no. 7896, pp. 1529–1531, 1974. View at Publisher · View at Google Scholar · View at Scopus
  6. D. L. Eizirik, M. L. Colli, and F. Ortis, “The role of inflammation in insulitis and beta-cell loss in type 1 diabetes,” Nature Reviews Endocrinology, vol. 5, no. 4, pp. 219–226, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. S. Cottet, P. Dupraz, F. Hamburger, W. Dolci, M. Jaquet, and B. Thorens, “cFLIP protein prevents tumor necrosis factor-α-mediated induction of caspase-8-dependent apoptosis in insulin-secreting βTc-Tet cells,” Diabetes, vol. 51, no. 6, pp. 1805–1814, 2002. View at Publisher · View at Google Scholar · View at Scopus
  8. L. G. Grunnet, R. Aikin, M. F. Tonnesen et al., “Proinflammatory cytokines activate the intrinsic apoptotic pathway in β-cells,” Diabetes, vol. 58, no. 8, pp. 1807–1815, 2009. View at Publisher · View at Google Scholar · View at Scopus
  9. C. Kantari and H. Walczak, “Caspase-8 and bid: caught in the act between death receptors and mitochondria,” Biochimica et Biophysica Acta, vol. 1813, no. 4, pp. 558–563, 2011. View at Publisher · View at Google Scholar · View at Scopus
  10. M. C. Åkerfeldt, J. Howes, J. Y. Chan et al., “Cytokine-induced β-cell death is independent of endoplasmic reticulum stress signaling,” Diabetes, vol. 57, no. 11, pp. 3034–3044, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. S. Vasu, N. H. McClenaghan, J. T. McCluskey, and P. R. Flatt, “Mechanisms of toxicity by proinflammatory cytokines in a novel human pancreatic beta cell line, 1.1B4,” Biochimica et Biophysica Acta—General Subjects, vol. 1840, no. 1, pp. 136–145, 2014. View at Publisher · View at Google Scholar · View at Scopus
  12. M. Cnop, N. Welsh, J.-C. Jonas, A. Jörns, S. Lenzen, and D. L. Eizirik, “Mechanisms of pancreatic β-cell death in type 1 and type 2 diabetes: many differences, few similarities,” Diabetes, vol. 54, supplement 2, pp. S97–S107, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. I. Kharroubi, L. Ladrière, A. K. Cardozo, Z. Dogusan, M. Cnop, and D. L. Eizirik, “Free fatty acids and cytokines induce pancreatic β-cell apoptosis by different mechanisms: role of nuclear factor-κB and endoplasmic reticulum stress,” Endocrinology, vol. 145, no. 11, pp. 5087–5096, 2004. View at Publisher · View at Google Scholar · View at Scopus
  14. A. K. Cardozo, F. Ortis, J. Storling et al., “Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic β-cells,” Diabetes, vol. 54, no. 2, pp. 452–461, 2005. View at Publisher · View at Google Scholar · View at Scopus
  15. I. Mehmeti, S. Lenzen, and S. Lortz, “Modulation of Bcl-2-related protein expression in pancreatic beta cells by pro-inflammatory cytokines and its dependence on the antioxidative defense status,” Molecular and Cellular Endocrinology, vol. 332, no. 1-2, pp. 88–96, 2011. View at Publisher · View at Google Scholar · View at Scopus
  16. B. Kutlu, A. K. Cardozo, M. I. Darville et al., “Discovery of gene networks regulating cytokine-induced dysfunction and apoptosis in insulin-producing INS-1 cells,” Diabetes, vol. 52, no. 11, pp. 2701–2719, 2003. View at Publisher · View at Google Scholar · View at Scopus
  17. R. Granata, F. Settanni, L. Biancone et al., “Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic β-cells and human islets: involvement of 3′,5′-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-kinase/Akt signaling,” Endocrinology, vol. 148, no. 2, pp. 512–529, 2007. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Kerem, B. Salman, S. Ozsoy et al., “Exogenous ghrelin enhances endocrine and exocrine regeneration in pancreatectomized rats,” Journal of Gastrointestinal Surgery, vol. 13, no. 4, pp. 775–783, 2009. View at Publisher · View at Google Scholar · View at Scopus
  19. T. Irako, T. Akamizu, H. Hosoda et al., “Ghrelin prevents development of diabetes at adult age in streptozotocin-treated newborn rats,” Diabetologia, vol. 49, no. 6, pp. 1264–1273, 2006. View at Publisher · View at Google Scholar · View at Scopus
  20. R. Granata, M. Volante, F. Settanni et al., “Unacylated ghrelin and obestatin increase islet cell mass and prevent diabetes in streptozotocin-treated newborn rats,” Journal of Molecular Endocrinology, vol. 45, no. 1, pp. 9–17, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. R. Granata, F. Settanni, M. Julien et al., “Des-acyl ghrelin fragments and analogues promote survival of pancreatic β-cells and human pancreatic islets and prevent diabetes in streptozotocin-treated rats,” Journal of Medicinal Chemistry, vol. 55, no. 6, pp. 2585–2596, 2012. View at Publisher · View at Google Scholar · View at Scopus
  22. J. A. Corbett and M. L. McDaniel, “Intraislet release of interleukin 1 inhibits β cell function by inducing β cell expression of inducible nitric oxide synthase,” Journal of Experimental Medicine, vol. 181, no. 2, pp. 559–568, 1995. View at Publisher · View at Google Scholar · View at Scopus
  23. A. Merglen, S. Theander, B. Rubi, G. Chaffard, C. B. Wollheim, and P. Maechler, “Glucose sensitivity and metabolism-secretion coupling studied during two-year continuous culture in INS-1E insulinoma cells,” Endocrinology, vol. 145, no. 2, pp. 667–678, 2004. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Blandino-Rosano, G. Perez-Arana, J. M. Mellado-Gil, C. Segundo, and M. Aguilar-Diosdado, “Anti-proliferative effect of pro-inflammatory cytokines in cultured β cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide-1,” Journal of Molecular Endocrinology, vol. 41, no. 1-2, pp. 35–44, 2008. View at Publisher · View at Google Scholar · View at Scopus
  25. J. M. Mellado-Gil and M. Aguilar-Diosdado, “High glucose potentiates cytokine- and streptozotocin-induced apoptosis of rat islet cells: effect on apoptosis-related genes,” Journal of Endocrinology, vol. 183, no. 1, pp. 155–162, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. M. L. McDaniel, J. R. Colca, N. Kotagal, and P. E. Lacy, “A subcellular fractionation approach for studying insulin release mechanisms and calcium metabolism in islets of Langerhans,” Methods in Enzymology, vol. 98, pp. 182–200, 1983. View at Google Scholar · View at Scopus
  27. C. W. Lindsley, “The Akt/PKB family of protein kinases: a review of small molecule inhibitors and progress towards target validation: a 2009 update,” Current Topics in Medicinal Chemistry, vol. 10, no. 4, pp. 458–477, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. A. K. Cardozo, M. Kruhøffer, R. Leeman, T. Ørntoft, and D. L. Eizirik, “Identification of novel cytokine-induced genes in pancreatic β-cells by high-density oligonucleotide arrays,” Diabetes, vol. 50, no. 5, pp. 909–920, 2001. View at Publisher · View at Google Scholar · View at Scopus
  29. W. D'Hertog, L. Overbergh, K. Lage et al., “Proteomics analysis of cytokine-induced dysfunction and death in insulin-producing INS-1E cells: new insights into the pathways involved,” Molecular and Cellular Proteomics, vol. 6, no. 12, pp. 2180–2199, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Lopes, B. Kutlu, M. Miani et al., “Temporal profiling of cytokine-induced genes in pancreatic β-cells by meta-analysis and network inference,” Genomics, vol. 103, no. 4, pp. 264–275, 2014. View at Publisher · View at Google Scholar · View at Scopus
  31. L. Li, W. El-Kholy, C. J. Rhodes, and P. L. Brubaker, “Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B,” Diabetologia, vol. 48, no. 7, pp. 1339–1349, 2005. View at Publisher · View at Google Scholar · View at Scopus
  32. Y. Zhang, B. Ying, L. Shi et al., “Ghrelin inhibit cell apoptosis in pancreatic β cell line HIT-T15 via mitogen-activated protein kinase/phosphoinositide 3-kinase pathways,” Toxicology, vol. 237, no. 1–3, pp. 194–202, 2007. View at Publisher · View at Google Scholar · View at Scopus
  33. F. Ortis, A. K. Cardozo, D. Crispim, J. Störling, T. Mandrup-Poulsen, and D. L. Eizirik, “Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-κB activation,” Molecular Endocrinology, vol. 20, no. 8, pp. 1867–1879, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. J. Størling, J. Binzer, A. K. Andersson et al., “Nitric oxide contributes to cytokine-induced apoptosis in pancreatic beta cells via potentiation of JNK activity and inhibition of Akt,” Diabetologia, vol. 48, no. 10, pp. 2039–2050, 2005. View at Publisher · View at Google Scholar · View at Scopus
  35. I. Santin, F. Moore, M. L. Colli et al., “PTPN2, a candidate gene for type 1 diabetes, modulates pancreatic β-cell apoptosis via regulation of the BH3-only protein bim,” Diabetes, vol. 60, no. 12, pp. 3279–3288, 2011. View at Publisher · View at Google Scholar · View at Scopus
  36. F. Moore, I. Santin, T. C. Nogueira et al., “The transcription factor C/EBP delta has anti-apoptotic and anti-inflammatory roles in pancreatic beta cells,” PLoS ONE, vol. 7, no. 2, Article ID e31062, 2012. View at Publisher · View at Google Scholar · View at Scopus
  37. W. Wang, D. Zhang, H. Zhao et al., “Ghrelin inhibits cell apoptosis induced by lipotoxicity in pancreatic β-cell line,” Regulatory Peptides, vol. 161, no. 1–3, pp. 43–50, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. X. Zhou and C. Xue, “Ghrelin inhibits the development of acute pancreatitis and nuclear factor kappaB activation in pancreas and liver,” Pancreas, vol. 38, no. 7, pp. 752–757, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. G. D. Pavitt and D. Ron, “New insights into translational regulation in the endoplasmic reticulum unfolded protein response,” Cold Spring Harbor Perspectives in Biology, vol. 4, no. 6, 2012. View at Publisher · View at Google Scholar · View at Scopus
  40. M. Bando, H. Iwakura, H. Ariyasu et al., “Transgenic overexpression of intraislet ghrelin does not affect insulin secretion or glucose metabolism in vivo,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 302, no. 4, pp. E403–E408, 2012. View at Publisher · View at Google Scholar · View at Scopus
  41. A. M. Wren, C. J. Small, C. R. Abbott et al., “Ghrelin causes hyperphagia and obesity in rats,” Diabetes, vol. 50, no. 11, pp. 2540–2547, 2001. View at Publisher · View at Google Scholar · View at Scopus
  42. K. Dezaki, H. Sone, and T. Yada, “Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis,” Pharmacology and Therapeutics, vol. 118, no. 2, pp. 239–249, 2008. View at Publisher · View at Google Scholar · View at Scopus
  43. S. Sangiao-Alvarellos and F. Cordido, “Effect of ghrelin on glucose-insulin homeostasis: therapeutic implications,” International Journal of Peptides, vol. 2010, Article ID 234709, 25 pages, 2010. View at Publisher · View at Google Scholar · View at Scopus
  44. F. Cordido, “Insulin regimens in type 2 diabetes,” The New England Journal of Medicine, vol. 362, no. 10, p. 960, 2010. View at Google Scholar · View at Scopus
  45. M. Bando, H. Iwakura, H. Ariyasu et al., “Overexpression of intraislet ghrelin enhances β-cell proliferation after streptozotocin-induced β-cell injury in mice,” The American Journal of Physiology—Endocrinology and Metabolism, vol. 305, no. 1, pp. E140–E148, 2013. View at Publisher · View at Google Scholar · View at Scopus