Table of Contents Author Guidelines Submit a Manuscript
Mediators of Inflammation
Volume 2012 (2012), Article ID 858692, 8 pages
http://dx.doi.org/10.1155/2012/858692
Review Article

C-Peptide: A New Mediator of Atherosclerosis in Diabetes

Department of Internal Medicine II-Cardiology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany

Received 30 November 2011; Revised 11 January 2012; Accepted 11 January 2012

Academic Editor: Fabrizio Montecucco

Copyright © 2012 Dusica Vasic and Daniel Walcher. 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. D. Steiner, G. Bell, and H. Tager, “Chemistry and biosynthesis of pancreatic protein hormones,” in Endocrinology, L. DeGroot, Ed., pp. 1296–1328, Saunders, Philadelphia, Pa, USA, 1995. View at Google Scholar
  2. A. H. Rubenstein, J. L. Clark, F. Melani, and D. F. Steiner, “Secretion of proinsulin C-Peptide by pancreatic β cells and its circulation in blood,” Nature, vol. 224, no. 5220, pp. 697–699, 1969. View at Publisher · View at Google Scholar · View at Scopus
  3. C. E. Munte, L. Vilela, H. R. Kalbitzer, and R. C. Garratt, “Solution structure of human proinsulin C-peptide,” The FEBS Journal, vol. 272, no. 16, pp. 4284–4293, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. P. R. Flatt, S. K. Swanston-Flatt, S. M. Hampton, C. J. Bailey, and V. Marks, “Specific binding of the C-peptide of proinsulin to cultured B-cells from a transplantable rat islet cell tumor,” Bioscience Reports, vol. 6, no. 2, pp. 193–199, 1986. View at Publisher · View at Google Scholar · View at Scopus
  5. Y. Ohtomo, T. Bergman, B. L. Johansson, H. Jörnvall, and J. Wahren, “Differential effects of proinsulin C-peptide fragments on Na+, K+- ATPase activity of renal tubule segments,” Diabetologia, vol. 41, no. 3, pp. 287–291, 1998. View at Publisher · View at Google Scholar · View at Scopus
  6. V. Mutt and J. E. Jorpes, “Structure of porcine cholecystokinin-pancreozymin. 1. Cleavage with thrombin and with trypsin,” European Journal of Biochemistry, vol. 6, no. 1, pp. 156–162, 1968. View at Google Scholar · View at Scopus
  7. J. Wahren, K. Ekberg, J. Johansson et al., “Role of C-peptide in human physiology,” American Journal of Physiology, vol. 278, no. 5, pp. E759–E768, 2000. View at Google Scholar
  8. T. Kitamura, K. Kimura, B. D. Jung et al., “Proinsulin C-peptide rapidly stimulates mitogen-activated protein kinases in swiss 3T3 fibroblasts: requirement of protein kinase C, phosphoinositide 3-kinase and pertussis toxin-sensitive G-protein,” Biochemical Journal, vol. 355, no. 1, pp. 123–129, 2001. View at Publisher · View at Google Scholar · View at Scopus
  9. T. Kitamura, K. Kimura, B. D. Jung et al., “Proinsulin C-peptide activates cAMP response element-binding proteins through the p38 mitogen-activated protein kinase pathway in mouse lung capillary endothelial cells,” Biochemical Journal, vol. 366, no. 3, pp. 737–744, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  10. P. Luppi, X. Geng, V. Cifarelli, P. Drain, and M. Trucco, “C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes,” Diabetologia, vol. 52, no. 10, pp. 2218–2228, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  11. Z. Zhong, O. Kotova, A. Davidescu et al., “C-peptide stimulates Na+,K+-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells,” Cellular and Molecular Life Sciences, vol. 61, no. 21, pp. 2782–2790, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  12. J. Wahren, J. Shafqat, J. Johansson, A. Chibalin, K. Ekberg, and H. Jörnvall, “Molecular and cellular effects of C-peptide—new perspectives on an old peptide,” Experimental Diabesity Research, vol. 5, no. 1, pp. 15–23, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  13. B. Samnegård, S. H. Jacobson, B. L. Johansson et al., “C-peptide and captopril are equally effective in lowering glomerular hyperfiltration in diabetic rats,” Nephrology Dialysis Transplantation, vol. 19, no. 6, pp. 1385–1391, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  14. L. Nordquist, E. Moe, and M. Sjöquist, “The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats,” Diabetes/Metabolism Research and Reviews, vol. 23, no. 5, pp. 400–405, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. N. Marx, D. Walcher, C. Raichle et al., “C-peptide colocalizes with macrophages in early atherosclerotic lesions of diabetic subjects and induces monocytes chemotaxis in vitro,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 24, no. 3, pp. 540–545, 2004. View at Publisher · View at Google Scholar · View at PubMed
  16. D. Vasic, N. Marx, G. Sukhova et al., “Walcher C-peptide promotes the inflammatory process in atherosclerotic lesions of ApoE-deficient mice,” Journal of Cellular and Molecular Medicine. In press.
  17. R. Ross, “Atherosclerosis—an inflammatory disease,” The New England Journal of Medicine, vol. 340, no. 2, pp. 115–126, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. G. M. Reaven, “Role of insulin resistance in human disease (syndrome X): an expanded definition,” Annual Review of Medicine, vol. 44, pp. 121–131, 1993. View at Google Scholar · View at Scopus
  19. M. I. Cybulsky, K. Iiyama, H. Li et al., “A major role for VCAM-1, but not ICAM-1, in early atherosclerosis,” The Journal of Clinical Investigation, vol. 107, no. 10, pp. 1255–1262, 2001. View at Google Scholar · View at Scopus
  20. A. Zernecke, E. Shagdarsuren, and C. Weber, “Chemokines in atherosclerosis an update,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 11, pp. 1897–1908, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  21. C. Murdoch and A. Finn, “Chemokine receptors and their role in inflammation and infectious diseases,” Blood, vol. 95, no. 10, pp. 3032–3043, 2000. View at Google Scholar · View at Scopus
  22. C. A. Janeway Jr. and R. Medzhitov, “Innate immune recognition,” Annual Review of Immunology, vol. 20, pp. 197–216, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. A. N. Seneviratne, B. Sivagurunathan, and C. Monaco, “Toll-like receptors and macrophage activation in atherosclerosis,” Clinica Chimica Acta, vol. 413, no. 1-2, pp. 3–14, 2012. View at Publisher · View at Google Scholar · View at PubMed
  24. G. K. Hansson, “Regulation of immune mechanisms in atherosclerosis,” Annals of the New York Academy of Sciences, vol. 947, pp. 157–166, 2001. View at Google Scholar · View at Scopus
  25. A. C. Doran, N. Meller, and C. A. McNamara, “Role of smooth muscle cells in the initiation and early progression of atherosclerosis,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 28, no. 5, pp. 812–819, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. P. Libby, “Current concepts of the pathogenesis of the acute coronary syndromes,” Circulation, vol. 104, no. 3, pp. 365–372, 2001. View at Google Scholar · View at Scopus
  27. P. Libby and M. Aikawa, “Stabilization of atherosclerotic plaques: new mechanisms and clinical targets,” Nature Medicine, vol. 8, no. 11, pp. 1257–1262, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. S. M. Haffner, S. Lehto, T. Rönnemaa, K. Pyörälä, and M. Laakso, “Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction,” The New England Journal of Medicine, vol. 339, no. 4, pp. 229–234, 1998. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. D. Walcher, M. Aleksic, V. Jerg et al., “C-peptide induces chemotaxis of human CD4-positive cells: involvement of pertussis toxin-sensitive G-proteins and phosphoinositide 3-kinase,” Diabetes, vol. 53, no. 7, pp. 1664–1670, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. M. Aleksic, D. Walcher, K. Giehl et al., “Signalling processes involved in C-peptide-induced chemotaxis of CD4-positive lymphocytes,” Cellular and Molecular life Sciences, vol. 66, no. 11-12, pp. 1974–1984, 2009. View at Google Scholar · View at Scopus
  31. C. E. Hills and N. J. Brunskill, “Intracellular signalling by C-peptide,” Experimental Diabetes Research, vol. 2008, Article ID 635158, 8 pages, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  32. Z. Zhong, A. Davidescu, I. Ehrén et al., “C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells,” Diabetologia, vol. 48, no. 1, pp. 187–197, 2005. View at Publisher · View at Google Scholar · View at PubMed
  33. D. Walcher, C. Babiak, P. Poletek et al., “C-peptide induces vascular smooth muscle cell proliferation: involvement of Src-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2,” Circulation Research, vol. 99, no. 11, pp. 1181–1187, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. T. Forst, T. Kunt, B. Wilhelm, M. M. Weber, and A. Pfützner, “Role of C-Peptide in the regulation of microvascular blood flow,” Experimental Diabetes Research, vol. 2008, Article ID 176245, 8 pages, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  35. G. J. Irving, Q. Zhang, J. C. Falcone, A. P. Bratcher, W. E. Rodriguez, and S. C. Tyagi, “Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: role of insulin and C-peptide,” Journal of Cellular Biochemistry, vol. 96, no. 6, pp. 1149–1156, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. T. Kitamura, K. Kimura, K. Makondo et al., “Proinsulin C-peptide increases nitric oxide production by enhancing mitogen-activated protein-kinase-dependent transcription of endothelial nitric oxide synthase in aortic endothelial cells of Wistar rats,” Diabetologia, vol. 46, no. 12, pp. 1698–1705, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. N. M. Al-Rasheed, R. S. Chana, R. J. Baines, G. B. Willars, and N. J. Brunskill, “Ligandindependent activation of peroxisome proliferator-activated receptor-gamma by insulin and C-peptide in kidney proximal tubular cells: dependent on phosphatidylinositol 3-kinase activity,” The Journal of Biological Chemistry, vol. 26, no. 48, pp. 49747–49754, 2004. View at Google Scholar
  38. V. Velarde, A. J. Jenkins, J. Christopher, T. J. Lyons, and A. A. Jaffa, “Activation of MAPK by modified low-density lipoproteins in vascular smooth muscle cells,” Journal of Applied Physiology, vol. 91, no. 3, pp. 1412–1420, 2001. View at Google Scholar · View at Scopus
  39. R. L. Beijersbergen and R. Bernards, “Cell cycle regulation by the retinoblastoma family of growth inhibitory proteins,” Biochimica et Biophysica Acta, vol. 1287, no. 2-3, pp. 103–120, 1996. View at Publisher · View at Google Scholar · View at Scopus
  40. J. W. Harbour and D. C. Dean, “Rb function in cell-cycle regulation and apoptosis,” Nature Cell Biology, vol. 2, no. 4, pp. E65–E67, 2000. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. R. S. Mughal, J. L. Scragg, P. Lister et al., “Cellular mechanisms by which proinsulin C-peptide prevents insulin-induced neointima formation in human saphenous vein,” Diabetologia, vol. 53, no. 8, pp. 1761–1771, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  42. E. Lindahl, U. Nyman, F. Zaman et al., “Proinsulin C-peptide regulates ribosomal RNA expression,” The Journal of Biological Chemistry, vol. 285, no. 5, pp. 3462–3469, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. N. Lindenblatt, B. Braun, M. D. Menger, E. Klar, and B. Vollmar, “C-peptide exerts antithrombotic effects that are repressed by insulin in normal and diabetic mice,” Diabetologia, vol. 49, no. 4, pp. 792–800, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. L. A. Suzuki, M. Poot, R. G. Gerrity, and K. E. Bornfeldt, “Diabetes accelerates smooth muscle accumulation in lesions of atherosclerosis: lack of direct growth-promoting effects of high glucose levels,” Diabetes, vol. 50, no. 4, pp. 851–860, 2001. View at Google Scholar · View at Scopus
  45. B. L. Johansson, K. Borg, E. Fernqvist-Forbes, A. Kernell, T. Odergren, and J. Wahren, “Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus,” Diabetic Medicine, vol. 17, no. 3, pp. 181–189, 2000. View at Publisher · View at Google Scholar · View at Scopus
  46. B. Samnegård, S. H. Jacobson, G. Jaremko et al., “C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats,” Nephrology Dialysis Transplantation, vol. 20, no. 3, pp. 532–538, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  47. K. Ekberg, T. Brismar, B. L. Johansson et al., “C-peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy,” Diabetes Care, vol. 30, no. 1, pp. 71–76, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  48. T. Hach, T. Forst, T. Kunt, K. Ekberg, A. Pfützner, and J. Wahren, “C-peptide improves adenosine-induced myocardial vasodilation in type 1 diabetes patients,” American Journal of Physiology, vol. 286, no. 1, pp. E14–E19, 2004. View at Google Scholar
  49. T. Wallerath, T. Kunt, T. Forst et al., “Stimulation of endothelial nitric oxide synthase by proinsulin C-peptide,” Nitric Oxide, vol. 9, no. 2, pp. 95–102, 2003. View at Publisher · View at Google Scholar · View at Scopus
  50. J. Johansson, K. Ekberg, J. Shafqat et al., “Molecular effects of proinsulin C-peptide,” Biochemical and Biophysical Research Communications, vol. 295, no. 5, pp. 1035–1040, 2002. View at Publisher · View at Google Scholar · View at Scopus
  51. A. A. F. Sima, W. Zhang, and G. Grunberger, “Type 1 diabetic neuropathy and C-peptide,” Experimental Diabesity Research, vol. 5, no. 1, pp. 65–77, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. S. Stridh, J. Sällström, M. Fridén, P. Hansell, L. Nordquist, and F. Palm, “C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats,” Advances in Experimental Medicine and Biology, vol. 645, pp. 219–225, 2009. View at Publisher · View at Google Scholar · View at Scopus
  53. M. K. Heliövaara, A. M. Teppo, S. L. Karonen, J. A. Tuominen, and P. Ebeling, “Plasma IL-6 concentration is inversely related to insulin sensitivity, and acute-phase proteins associate with glucose and lipid metabolism in healthy subjects,” Diabetes, Obesity and Metabolism, vol. 7, no. 6, pp. 729–736, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  54. A. M. McNeill, W. D. Rosamond, C. J. Girman et al., “Prevalence of coronary heart disease and carotid arterial thickening in patients with the metabolic syndrome (The ARIC Study),” American Journal of Cardiology, vol. 94, no. 10, pp. 1249–1254, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  55. R. Scalia, K. M. Coyle, B. J. Levine, G. Booth, and A. M. Lefer, “C-peptide inhibits leukocyte-endothelium interaction in the microcirculation during acute endothelial dysfunction,” The FASEB Journal, vol. 14, no. 14, pp. 2357–2364, 2000. View at Google Scholar · View at Scopus
  56. P. Luppi, V. Cifarelli, H. Tse, J. Piganelli, and M. Trucco, “Human C-peptide antagonises high glucose-induced endothelial dysfunction through the nuclear factor-κB pathway,” Diabetologia, vol. 51, no. 8, pp. 1534–1543, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  57. M. G. Vish, P. Mangeshkar, G. Piraino et al., “Proinsulin c-peptide exerts beneficial effects in endotoxic shock in mice,” Critical Care Medicine, vol. 35, no. 5, pp. 1348–1355, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  58. H. C. Stary, A. B. Chandler, R. E. Dinsmore et al., “A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the council on arteriosclerosis, American heart association,” Circulation, vol. 92, no. 5, pp. 1355–1374, 1995. View at Google Scholar · View at Scopus
  59. J. A. Bittl, “Advances in coronary angioplasty,” The New England Journal of Medicine, vol. 335, no. 17, pp. 1290–1302, 1996. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. B. Liu, M. Fisher, and P. Groves, “Down-regulation of the ERK1 and ERK2 mitogen-activated protein kinases using antisense oligonucleotides inhibits intimal hyperplasia in a porcine model of coronary balloon angioplasty,” Cardiovascular Research, vol. 54, no. 3, pp. 640–648, 2002. View at Publisher · View at Google Scholar · View at Scopus
  61. Y. Kobayashi, K. Naruse, Y. Hamada et al., “Human proinsulin C-peptide prevents proliferation of rat aortic smooth muscle cells cultured in high-glucose conditions,” Diabetologia, vol. 48, no. 11, pp. 2396–2401, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. V. Cifarelli, X. Geng, A. Styche, R. Lakomy, M. Trucco, and P. Luppi, “C-peptide reduces high-glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation in human aortic endothelial cells,” Diabetologia, vol. 54, no. 10, pp. 2702–2712, 2011. View at Publisher · View at Google Scholar · View at PubMed
  63. R. S. Chima, T. LaMontagne, G. Piraino, P. W. Hake, A. Denenberg, and B. Zingarelli, “C-peptide, a novel inhibitor of lung inflammation following hemorrhagic shock,” American Journal of Physiology, vol. 300, no. 5, pp. L730–L739, 2011. View at Publisher · View at Google Scholar · View at PubMed
  64. S. T. Kim, B. J. Kim, D. M. Lim et al., “Basal C-peptide level as a surrogate marker of subclinical atherosclerosis in type 2 diabetic patients,” Diabetes and Metabolism Journal, vol. 35, no. 1, pp. 41–49, 2011. View at Google Scholar