Physiological effects and therapeutic potential of proinsulin C-peptide

American Journal of Physiology - Endocrinology and Metabolism

Volumn 307, Issue 11, 2014, Pages 955-968

  Yosten, Gina L C ^a   Maric Bilkan, Christine ^b,c   Luppi, Patrizia ^d   Wahren, John ^e  

^a SAINT LOUIS UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b NATIONAL HEART LUNG AND BLOOD INSTITUTE   (United States)

^c UNIVERSITY OF MISSISSIPPI SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^e KAROLINSKA INSTITUTE   (Sweden)

Author keywords

C peptide; Diabetes; Diabetes associated complications

Indexed keywords

C PEPTIDE; GLUCOSE; PERTUSSIS TOXIN; PROINSULIN; ANTIDIABETIC AGENT; INSULIN RECEPTOR;

ADRENAL FUNCTION; ANTIINFLAMMATORY ACTIVITY; CELL MEMBRANE; DIABETIC ANGIOPATHY; DIABETIC NEPHROPATHY; DIABETIC NEUROPATHY; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; INTRACELLULAR SIGNALING; KIDNEY DISEASE; KIDNEY FUNCTION; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PERIPHERAL NERVE; RENAL PROTECTION; REVIEW; SENSORY NERVE; ANIMAL; DIABETES COMPLICATIONS; DIABETES MELLITUS; DRUG EFFECTS;

ANIMALS; C-PEPTIDE; DIABETES COMPLICATIONS; DIABETES MELLITUS; HUMANS; HYPOGLYCEMIC AGENTS; RECEPTOR, INSULIN;

EID: 84913580156     PISSN: 01931849     EISSN: 15221555     Source Type: Journal    
DOI: 10.1152/ajpendo.00130.2014     Document Type: Review

References (119)

1. Al-Rasheed NM, Meakin F, Royal EL, Lewington AJ, Brown J, Willars GB, Brunskill NJ. Potent activation of multiple signaling pathways by C-peptide in opossum kidney proximal tubular cells. Dia-betologia 47: 987-997, 2004.
2. Al-Rasheed NM, Willars GB, Brunskill NJ. C-peptide signals via Galpha i to protect against TNF-alpha-mediated apoptosis of opossum kidney proximal tubular cells. J Am Soc Nephrol 17: 986-995, 2006.
3. Alpers CE, Hudkins KL. Mouse models of diabetic nephropathy. Curr Opin Nephrol Hypertens 20: 278-284, 2011.
4. Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ. Relaxin family peptides and their receptors. Physiol Rev 93: 405-480, 2013.
5. Bhatt MP, Lim YC, Hwang J, Na S, Kim YM, Ha KS. C-peptide prevents hyperglycemia-induced endothelial apoptosis through inhibition of reactive oxygen species-mediated transglutaminase 2 activation. Diabetes 62: 243-253, 2013.
6. Bhatt MP, Lim YC, Kim YM, Ha KS. C-peptide activates AMPKa and prevents ROS-mediated mitochondrial fission and endothelial apoptosis in diabetes. Diabetes 62: 3851-3862, 2013.
7. Bindokas VP, Kuznetsov A, Sreenan S, Polonsky KS, Roe MW, Philipson LH. Visualizing superoxide production in normal and diabetic rat islets of Langerhans. J Biol Chem 278: 9796-9801, 2003.
8. Bo S, Gentile L, Castiglione A, Prandi V, Canil S, Ghigo E, Ciccone G. C-peptide and the risk for incident complications and mortality in type 2 diabetic patients: a retrospective cohort study after a 14-year follow-up. Eur J Endocrinol 167: 173-180, 2012.
9. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 414: 813-820, 2001.
10. Bugliani M, Torri S, Lupi R, Del Guerra S, Grupillo M, Del Chiaro M, Mosca F, Boggi U, Del Prato S, Marchetti P. Effects of C-peptide on isolated human pancreatic islet cells. Diabetes Metab Res Rev 23: 215-219, 2007.
11. Chima RS, Maltese G, Lamontagne T, Piraino G, Denenberg A, O’Connor M, Zingarelli B. C-peptide ameliorates kidney injury following hemorrhagic shock. Shock 35: 524-529, 2011.
12. Chou DH, Bodycombe NE, Carrinski HA, Lewis TA, Clemons PA, Schreiber SL, Wagner BK. Small-molecule suppressors of cytokine-induced beta-cell apoptosis. ACS Chem Biol 5: 729-734, 2010.
13. Cifarelli V, Geng X, Styche A, Lakomy M, Trucco M, Luppi P. C-peptide reduces high glucose-induced apoptosis of endothelial cells and decreases NAD(P)H-oxidase reactive oxygen species generation. Diabetologia 54: 2702-2712, 2011.
14. Cifarelli V, Luppi P, Tse HM, He J, Piganelli J, Trucco M. Human proinsulin C-peptide reduces high glucose-induced proliferation and NF-kappaB activation in vascular smooth muscle cells. Atherosclerosis 201: 248-257, 2008.
15. Cotter MA, Ekberg K, Wahren J, Cameron NE. Effects of proinsulin C-peptide in experimental diabetic neuropathy: vascular actions and modulation by nitric oxide synthase inhibition. Diabetes 52: 1812-1817, 2003.
16. Dugan LL, You YH, Ali SS, Diamond-Stanic M, Miyamoto S, DeCleves AE, Andreyev A, Quach T, Ly S, Shekhtman G, Nguyen W, Chepetan A, Le TP, Wang L, Xu M, Paik KP, Fogo A, Viollet B, Murphy A, Brosius F, Naviaux RK, Sharma K. AMPK dysregulation promotes diabetes-related reduction of superoxide and mitochondrial function. J Clin Invest 123: 4888-4899, 2013.
17. Dyck PJ, Lambert EH, O’Brien PC. Pain in peripheral neuropathy related to rate and kind of fiber degeneration. Neurology 26: 466-471, 1976.
18. Eizirik DL, Mandrup-Poulsen T. A choice of death—the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44: 2115-2133, 2001.
19. Ekberg K, Brismar T, Johansson BL, Jonsson B, Lindstrom P, Wahren J. Amelioration of sensory nerve dysfunction by C-Peptide in patients with type 1 diabetes. Diabetes 52: 536-541, 2003.
20. Ekberg K, Brismar T, Johansson BL, Lindstrom P, Juntti-Berggren L, Norrby A, Berne C, Arnqvist HJ, Bolinder J, Wahren J. C-Peptide replacement therapy and sensory nerve function in type 1 diabetic neuropathy. Diabetes Care 30: 71-76, 2007.
21. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. Are oxidative stress-activated signaling pathways mediators of insulin resistance and beta-cell dysfunction? Diabetes 52: 1-8, 2003.
22. Faber OK, Hagen C, Binder C, et al. Kinetics of human connecting peptide in normal and diabetic subjects. J Clin Invest 62: 197-203, 1978.
23. Fiorina P, Folli F, Zerbini G, et al. Islet transplantation is associated with improvement of renal function among uremic patients with type I diabetes mellitus and kidney transplants. J Am Soc Nephrol 14: 2150-2158, 2003.
24. Flynn ER, Lee J, Hutchens ZM, Jr., Chade AR, Maric-Bilkan C. C-peptide preserves the renal microvascular architecture in the strepto-zotocin-induced diabetic rat. J Diabetes Complications 27: 538-547, 2013.
25. Forst T, De La Tour DD, Kunt T, Pfutzner A, Goitom K, Pohlmann T, Schneider S, Johansson BL, Wahren J, Lobig M, Engelbach M, Beyer J, Vague P. Effects of proinsulin C-peptide on nitric oxide, microvascular blood flow and erythrocyte Na+,K+-ATPase activity in diabetes mellitus type 1. Clin Sci (London) 98: 283-290, 2000.
26. Freeman H, Shimomura K, Cox RD, Ashcroft FM. Nicotinamide nucleotide transhydrogenase: a link between insulin secretion, glucose metabolism and oxidative stress. Biochem Soc Trans 34: 806-810, 2006.
27. Fujimoto S, Mukai E, Inagaki N. Role of endogenous ROS production in impaired metabolism-secretion coupling of diabetic pancreatic fj cells. Prog Biophys Mol Biol 107: 304-31, 2011.
28. Furuya DT, Ishii T, Kamikawa A, Shimada K, Machado UF, Saito M, Kimura K. Proinsulin C-peptide induces c-Jun N-terminal kinase 1 expression in LEII mouse lung capillary endothelial cells. Jpn J Vet Res 57: 163-167, 2009.
29. Gier B, Krippeit-Drews P, Sheiko T, Aguilar-Bryan L, Bryan J, Düfer M, Drews G. Suppression of KATP channel activity protects murine pancreatic fj-cells against oxidative stress. J Clin Invest 119: 3246-3256, 2009.
30. Gregg D, Rauscher FM, Goldschmidt-Clermont PJ. Rac regulates cardiovascular superoxide through diverse molecular interactions: more than a binary GTP switch. Am J Physiol Cell Physiol 285: C723-C734, 2003.
31. Grunberger G, Qiang X, Li Z, Mathews ST, Sbrissa D, Shisheva A, Sima AA. Molecular basis for the insulinomimetic effects of C-peptide. Diabetologia 44: 1247-1257, 2001.
32. Hach T, Forst T, Kunt T, Ekberg K, Pfutzner A, Wahren J. C-peptide and its C-terminal fragments improve erythrocyte deformability in type 1 diabets patients. Exp Diabetes Res 2008: 730594, 2008.
33. Hagen C, Faber OK, Binder C, Alberti K. Lack of metabolic effect of C-peptide in normal subjects and juvenile diabetic patients. Acta Endocrinol 85: 29, 1977.
34. Haidet J, Cifarelli V, Trucco M, Luppi P. C-peptide reduces proinflammatory cytokine secretion in LPS-stimulated U937 monocytes in condition of hyperglycemia. Inflamm Res 61: 27-35, 2012.
35. Henriksen JH, Tronier B, Bulow JB. Kinetics of circulating endogenous insulin, C-peptide, and proinsulin in fasting nondiabetic man. Metabolism 36: 463-468, 1987.
36. Henriksson M, Pramanik A, Shafqat J, Zhong Z, Tally M, Ekberg K, Wahren J, Rigler R, Jahansson J, Jornvall H. Specific binding of proinsulin C-peptide to intact and to detergent-solubilized human skin fibroblasts. Biochem Biophys Res Commun 280: 423–427, 2001.
37. Henriksson M, Shafqat J, Liepinsh E, et al. Unordered structured of proinsulin C-peptide in aqueous solution and in the presence of lipid vesicles. Cell Mol Life Sci 57: 337-342, 2000.
38. Hills CE, Al-Rasheed N, Willars GB, Brunskill NJ. C-peptide reverses TGF-fj1-induced changes in renal proximal tubular cells: implications for treatment of diabetic nephropathy. Am J Physiol Renal Physiol 296: F614-F621, 2009.
39. Hills CE, Brunskill NJ. C-peptide and its intracellular signaling. Rev Diabet Stud 6: 138-147, 2009.
40. Hoogwerf BJ, Bantle JP, Gaenslen HE, et al. Infusion of synthetic human C-peptide does not affect plasma glucose, serum insulin, or plasma glucagon in healthy subjects. Metabolism 35: 122-125, 1986.
41. Hordij KPL. Regulation of NADPH oxidases. The role of Racc proteins. Circ Res 98: 453–462, 2006.
42. Horwitz DL, Starr JI, Mako ME, Blackard WG, Rubenstein AH. Proinsulin, insulin, and C-Peptide concentrations in human portal and peripheral blood. J Clin Invest 55: 1278-1283, 1975.
43. Huang DY, Richter K, Breidenbach A, Vallon V. Human C-peptide acutely lowers glomerular hyperfiltration and proteinuria in diabetic rats: a dose-response study. Naunyn Schmiedebergs Arch Pharmacol 365: 67-73, 2002.
44. Ido Y, Vindigni A, Chang K, Stramm L, Chance R, Heath WF, DiMarchi RD, Di Cera E, Williamson JR. Prevention of vascular and neural dysfunction in diabetic rats by C-peptide. Science 277: 563-566, 1997.
45. Ishii T, Fukano K, Shimada K, Kamikawa A, Okamatsu-Ogura Y, Terao A, Yoshida T, Saito M, Kimura K. Proinsulin C-peptide activates alpha-enolase: implications for C-peptide-cell membrane interaction. J Biochem 152: 53-62, 2012.
46. Jagerbrink T, Lindahl E, Shafqat J, Jornvall H. Proinsulin C-peptide interaction with protein tyrosine phosphatase 1B demonstrated with a labeling reaction. Biochem Biophys Res Comm 387: 31-35, 2009.
47. Johansson BL, Borg K, Fernqvist-Forbes E, Kernell A, Odergren T, Wahren J. Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus. Diabet Med 17: 181-189, 2000.
48. Johansson BL, Borg K, Fernqvist-Forbes E, Odergren T, Remahl S, Wahren J. C-peptide improves autonomic nerve function in IDDM patients. Diabetologia 39: 687-695, 1996.
49. Johansson BL, Kernell A, Sjöberg S, Wahren J. Influence of combined C-peptide and insulin administration on renal function and metabolic control in diabetes type 1. J Clin Endocrinol Metab 77: 976-981, 1993.
50. Johansson BL, Sjöberg S, Wahren J. The influence of human C-peptide on renal function and glucose utilization in type 1 (insulin-dependent) diabetic patients. Diabetologia 35: 121-128, 1992.
51. Kadmiel M, Fritz-Six KL, Caron KM. Understanding RAMPs through genetically engineered mouse models. Adv Exp Med Biol 744: 49-60, 2012.
52. Kaminitz A, Stein J, Yaniv I, Askenasy N. The vicious cycle of apoptotic beta-cell death in type 1 diabetes. Immunol Cell Biol 85: 582-589, 2007.
53. Kamiya H, Zhang W, Sima AA. C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol 56: 827-835, 2004.
54. Kimoto K, Suzuki K, Kizaki T, Hitomi Y, Ishida H, Katsuta H, Itoh E, Ookawara T, Suzuki K, Honke K, Ohno H. Gliclazide protects pancreatic beta-cells from damage by hydrogen peroxide. Biochem Biophys Res Commun 303: 112-119, 2003.
55. Kobayashi Y, Naruse K, Hamada Y, Nakashima E, Kato K, Akiyama N, Kamiya H, Watarai A, Nakae M, Oiso Y, Nakamura J. Human proinsulin C-peptide prevents proliferation of rat aortic smooth muscle cells cultured in high-glucose conditions. Diabetologia 48: 2396-401, 2005.
56. Kunt T, Schneider S, Pfutzner A, Goitum K, Engelbach M, Schauf B, Beyer J, Forst T. The effect of human proinsulin C-peptide on erythrocyte deformability in patients with Type 1 diabetes mellitus. Diabetologia 42: 465–471, 1999.
57. Laybutt DR, Kaneto H, Hasenkamp W, Grey S, Jonas JC, Sgroi DC, Groff A, Ferran C, Bonner-Weir S, Sharma A, Weir GC. Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to beta-cell survival during chronic hyperglycemia. Diabetes 51: 413-423, 2002.
58. Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20: 463-466, 1996.
59. Li L, Oshida Y, Kusunoki M, Yamanouchi K, Johansson BL, Wahren J, Sato Y. Rat C peptide I and II stimulate glucose utilization in STZ-induced diabetic rats. Diabetologia 42: 958-964, 1999.
60. Li N, Brun T, Cnop M, Cunha DA, Eizirik DL, Maechler P. Transient oxidative stress damages mitochondrial machinery inducing persistent beta-cell dysfunction. J Biol Chem 284: 23602-23612, 2009.
61. Li ZG, Zhang W, Sima AA. C-peptide enhances insulin-mediated cell growth and protection against high glucose-induced apoptosis in SH-SY5Y cells. Diabetes Metab Res Rev 19: 375-385, 2003.
62. Li Y, Zhao M, Li B, Qi J. Dynamic localization and functional implications of C-peptide might for suppression of iNOS in high glucose-simtulated rat mesangial cells. Mol Cell Endocrinol 381: 255-260, 2013.
63. Lindahl E, Nyman U, Melles E, Sigmundsson K, Stahlberg M, Wahren J, Obrink B, Safqat J, Joseph B, Jornvall H. Cellular internatilzation of proinsulin C-peptide. Cell Mol Life Sci 64: 479-486, 2007.
64. Luppi P, Cifarelli V, Tse H, Piganelli J, Trucco M. Human C-peptide antagonises high glucose-induced 27 endothelial dysfunction through the nuclear factor-kappaB pathway. Diabetologia 51: 1534-1543, 2008.
65. Luppi P, Drain P. Autocrine C-peptide mechanism underlying INS1 pj-cell adaptation to oxidative stress. Diabetes Metab Res Rev In Press, 2014.
66. Luppi P, Geng X, Cifarelli V, Drain P, Trucco M. 1 C-peptide is internalised in human endothelial and 2 vascular smooth muscle cells via early endosomes. Diabetologia 252: 2218-2228, 2009.
67. Luppi P, Kallas Å, Wahren J. Can C-peptide mediated anti-inflammatory effects retard the development of microvascular complications of type 1 diabetes? Diabetes Metab Res Rev 29: 357-362, 2013.
68. Melles E, Jornvall H, Tryggvason S, et al. Degradation of proinsulin C-peptide in kidney and placenta extracts by a specific endoprotease activity. Cell Mol Life Sci 61: 2979-2982, 2004.
69. Melloul D. Role of NF-kB in beta-cell death. Biochem Soc Trans 36: 334-339, 2008.
70. Mughal RS, Scragg JL, Lister P, Warburton P, Riches K, O’Regan DJ, Ball SG, Turner NA, Porter KE. Cellular mechanisms by which proinsulin C-peptide prevents insulin-induced neointima formation in human saphenous vein. Diabetologia 53: 1761-1771, 2010.
71. Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M. Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404: 787-790, 2000.
72. Nordquist L, Brown R, Fasching A, Persson P, Palm F. Proinsulin C-peptide reduces diabetes-induced glomerular hyperfiltration via efferent arteriole dilation and inhibition of tubular sodium reabsorption. Am J Physiol Renal Physiol 297: F1265-F1272, 2009.
73. Nordquist L, Lai EY, Sjoquist M, Patzak A, Persson AE. Proinsulin C-peptide constricts glomerular afferent arterioles in diabetic mice. A potential renoprotective mechanism. Am J Physiol Regul Integr Comp Physiol 294: R836-R841, 2008.
74. Nordquist L, Moe E, Sjoquist M. The C-peptide fragment EVARQ reduces glomerular hyperfiltration in streptozotocin-induced diabetic rats. Diabetes Metab Res Rev 23: 400–405, 2007.
75. Norlin S, Ahlgren U, Edlund H. Nuclear factor-(kappa)B activity in (beta)-cells is required for glucose-stimulated insulin secretion. Diabetes 54: 125-132, 2005.
76. Panero F, Novelli G, Zucco C, Fornengo P, Perotto M, Segre O, Grassi G, Cavallo-Perin P, Bruno G. Fasting plasma C-peptide and micro- and macrovascular complications in a large clinic-based cohort of type 1 diabetic patients. Diabetes Care 32: 301-305, 2009.
77. Pi J, Bai Y, Zhang Q, Wong V, Floering LM, Daniel K, Reece JM, Deeney JT, Andersen ME, Corkey BE, Collins S. Reactive oxygen species as a signal in glucose-stimulated insulin secretion. Diabetes 56: 1783-1791, 2007.
78. Polonsky KS, Given BD, Van Cauter E. Twenty-four-hour profiles and pulsatile patterns of insulin secretion in normal and obese subjects. J Clin Invest 81: 442–448, 1988.
79. Polonsky K, O’Meara N. Secretion and metabolism of insulin, proinsulin and C-peptide. In: Endocrinology. DeGroot L, Jameson J, eds. Philadelphia, PA: WB Saunders, 2001, p. 697-711.
80. Pramanik A, Ekberg K, Zhong Z,. C-peptide binding to human cell membranes: importance of Glu27. Biochem Biophys Res Commun 284: 94-98, 2001.
81. Rebsomen L, Pitel S, Boubred F, Buffat C, Feuerstein JM, Raccah D, Vague P, Tsimaratos M. C-peptide replacement improves weight gain and renal function in diabetic rats. Diabetes Metab 32: 223-228, 2006.
82. Remuzzi G, Macia M, Ruggenenti P. Prevention and treatment of diabetic renal disease in type 2 diabetes: the BENEDICT study. J Am Soc Nephrol 17: S90-S97, 2006.
83. Richards JP, Stephenson AH, Ellsworth ML, Sprague RS. Synergistic effects of C-peptide and insulin on low O2-induced ATP release from human erythrocytes. Am J Physiol Regul Integr Comp Physiol 305: R1331-R1336, 2013.
84. Rigler R, Pramanik A, Jonasson P, Kratz G, Jansson OT, Nygren PA, Stahl S, Ekberg K, Jahansson BL, Uhlen S, Uhlen M, Jornvall H, Wahren J. Specific binding of proinsulin C-peptide to human cell membranes. Proc Natl Acad Sci USA 96: 13318-13323, 1999.
85. Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic fj-cells in diabetes. J Biol Chem 279: 42351–42354, 2004.
86. Samnegard B, Jacobson SH, Jaremko G, Johansson BL, Ekberg K, Isaksson B, Eriksson L, Wahren J, Sjoquist M. C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats. Nephrol Dial Transplant 20: 532-538, 2005.
87. Samnegard B, Jacobson SH, Jaremko G, Johansson BL, Sjoquist M. Effects of C-peptide on glomerular and renal size and renal function in diabetic rats. Kidney Int 60: 1258-1265, 2001.
88. Samnegard B, Jacobson SH, Johansson BL, Ekberg K, Isaksson B, Wahren J, Sjoquist M. C-peptide and captopril are equally effective in lowering glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant 19: 1385–1391, 2004.
89. Sasaki M, Fujimoto S, Sato Y, Nishi Y, Mukai E, Yamano G, Sato H, Tahara Y, Ogura K, Nagashima K, Inagaki N. Reduction of reactive oxygen species ameliorates metabolism-secretion coupling in islets of diabetic GK rats by suppressing lactate overproduction. Diabetes 62: 1996–2003, 2013.
90. Sawyer RT, Flynn ER, Hutchens ZM, Jr., Williams JM, Garrett MR, Maric-Bilkan C. Renoprotective effects of C-peptide in the Dahl salt-sensitive rat. Am J Physiol Renal Physiol 303: F893–F899, 2012.
91. Scalia R, Coyle KM, Levine BJ, Booth G, Lefer AM. C-peptide inhibits leukocyte-endothelium interaction in the microcirculation during acute endothelial dysfunction. FASEB J 14: 2357–2364, 2000.
92. Shafqat J, Melles E, Sigmundsson K, Johansson BL, Ekbergy K, Alvelius G, Henriksson M, Johansson J, Wahren J, Jornvall H. Proinsulin C-peptide elicits disaggregation of insulin resulting in enhanced physiological insulin effects. Cell Mol Life Sci 63: 1805–1811, 2006.
93. Sharman JL, Benson HE, Pawson AJ, Lukito V, Pmamhanga CP, Bombail V, Davenport AP, Peters JA, Spedding M, Harmar AJ; NCIUPHAR. IUPHAR-DB: updated database content and new features. Nucleic Acids Res 41: D1083–D1088, 2013.
94. Short SM, Boyer JL, Juliano RL. Integrins regulate the linkage between upstream and downstream events in G protein-coupled receptor signaling to mitogen-activated protein kinase. J Biol Chem 275: 12970–12977, 2000.
95. Sima AA, Li ZG. The effect of C-peptide on cognitive dysfunction and hippocampal apoptosis in type 1 diabetic rats. Diabetes 54: 1497–1505, 2005.
96. Sima AA, Zhang W, Kreipke CW, Rafols JA, Hoffman WH. Inflammation in diabetic encephalopathy is prevented by C-peptide. Rev Diabet Stud 6: 37–42, 2009.
97. Sima AA, Zhang W, Sugimoto K, Henry D, Li Z, Wahren J, Grunberger G. C-peptide prevents and improves chronic Type I diabetic polyneuropathy in the BB/Wor rat. Diabetologia 44: 889–897, 2001.
98. Sjöberg S, Gunnarsson R, Gjötterberg M, Lefvert AK, Persson A, Ostman J. Residual insulin production, glycaemic control and prevalence of microvascular lesions and polyneuropathy in long-term type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30: 208–213, 1987.
99. Sjoquist M, Huang W, Johansson BL. Effects of C-peptide on renal function at the early stage of experimental diabetes. Kidney Int 54: 758–764, 1998.
100. Steiner DF, Cunningham D, Spigelman L, Aten B. Insulin biosynthesis: evidence for a precursor. Science 157: 697–700, 1967.
101. Stevens MJ, Zhang W, Li F, Sima AA. C-peptide corrects endoneurial blood flow but not oxidative stress in type 1 BB/Wor rats. Am J Physiol Endocrinol Metab 287: E497–E505, 2004.
102. Supale S, Li N, Brun T, Maechler P. Mitochondrial dysfunction in pancreatic b cells. Trends Endocr Metabol 23: 477–487, 2012.
103. Sutherland DE, Kendall DM, Moudry KC,. Pancreas transplantation in nonuremic, type I diabetic recipients. Surgery 104: 453–464, 1988.
104. Tanaka Y, Gleason CE, Tran PO, Harmon JS, Robertson RP. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc Natl Acad Sci USA 96: 10857–10862, 1999.
105. Tiedge M, Lortz S, Drinkgern J, Lenzen S. Relation between antiox-idant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes 46: 1733–1742, 1997.
106. Tiedge M, Lortz S, Munday R, Lenzen S. Complementary action of antioxidant enzymes in the protection of bioengineered insulin-producing RINm5F cells against the toxicity of reactive oxygen species. Diabetes 47: 1578–1585, 1998.
107. Vejandla H, Hollander JM, Kothur A, Brock RW. C-peptide reduces mitochondrial superoxide generation by restoring complex I activity in high glucose-exposed renal microvascular endothelial cells. ISRN Endo-crinol 2012: 162802, 2012.
108. Vish MG, Mangeshkar P, Piraino G, Denenberg A, Hake PW, O’Connor M, Zingarelli B. Proinsulin C-peptide exerts beneficial effects in endotoxic shock in mice. Crit Care Med 35: 1348–1355, 2007.
109. Wahren J, Kallas Å. Loss of pulsatile insulin secretion: a factor in the pathogenesis of type 2 diabetes? Diabetes 61: 2228–2229, 2012.
110. Wahren J, Kallas A, Sima AA. The clinical potential of C-peptide replacement in type 1 diabetes. Diabetes 61: 761–772, 2012.
111. Walcher D, Babiak C, Poletek P, Rosenkranz S, Bach H, Betz S, Durst R, Grub M, Hombach V, Strong J, Marx N. C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2. Circ Res 99: 1181–1187, 2006.
112. Wallerath T, Kunt T, Forst T, Closs EI, Lehmann R, Flohr T, Gabriel M, Schafer D, Gopfert A, Pfutzner A, Beyer J, Forstermann U. Stimulation of endothelial nitric oxide synthase by proinsulin C-pep-tide. Nitric Oxide 9: 95–102, 2003.
113. Yosten GL, Kolar GR, Redlinger LJ, Samson WK. Evidence for an interaction between proinsulin C- peptide and GPR146. J Endocrinol 218: B1–B8, 2013.
114. Yosten GL, Redlinger LJ, Samson WK. Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107. Am J Physiol Regul Integr Comp Physiol 303: R941–R949, 2012.
115. Young LH, Ikeda Y, Scalia R, Lefer AM. C-peptide exerts cardiopro-tective effects in myocardial ischemia-reperfusion. Am J Physiol Heart Circ Physiol 279: H1453–H1459, 2000.
116. Zerbini G, Mangili R, Luzi L. Higher post-absorptive C-peptide levels in Type 1 diabetic patients without renal complications. Diabet Med 16: 1048, 1999.
117. Zhang W, Kamiya H, Ekberg K, Wahren J, Sima AA. C-peptide improves neuropathy in type 1 diabetic BB/Wor-rats. Diabetes Metab Res Rev 23: 63-70, 2007.
118. Zhong Z, Davidescu A, Ehren I, Ekberg K, Jornvall H, Wahren J, Chibalin AV. C-peptide stimulates ERK1/2 and JNK MAP kinases via actvation of protein kinase C in human renal tubular cells. Diabetologia 48: 187-197, 2005.
119. Zhong Z, Kotova O, Davidescu A, Ehren I, Ekberg K, Jornvall H, Wahren J, Chibalin AV. C-peptide stimulates Na+,K+-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells. Cell Mol Life Sci 61: 2782-2790, 2004.