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Current Diabetes Reports

, Volume 1, Issue 3, pp 261–266 | Cite as

C-peptide: A new potential in the treatment of diabetic nephropathy

  • John Wahren
  • Karin Ekberg
  • Björn Samnegård
  • Bo-Lennart Johansson
Article

Abstract

C-peptide is formed in the biosynthesis of insulin and the two peptides are subsequently released in equimolar amounts to the circulation. C-peptide has long been considered to be without physiologic effects. Recent data now demonstrate that C-peptide in the nanomolar concentration range binds specifically to cell surfaces, probably to G protein-coupled receptors, with subsequent activation of Ca2+-dependent intracellular signaling pathways and stimulation of Na+,K+-ATPase activities. C-peptide replacement in animal models of type 1 diabetes results in diminished hyperfiltration, improved functional reserve, reduction of urinary albumin excretion, and prevention of glomerular and renal hypertrophy. Administration of C-peptide to physiologic concentrations in patients with type 1 diabetes and incipient nephropathy for periods of 3 hours to 3 months is accompanied by reduced glomerular hyperfiltration and filtration fraction, and diminished urinary albumin excretion. C-peptide replacement together with insulin therapy may be beneficial in type 1 diabetes patients with nephropathy.

Keywords

Glomerular Filtration Rate Diabetic Nephropathy ATPase Activity Proinsulin Urinary Albumin Excretion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References and Recommended Reading

  1. 1.
    Steiner D, Cunningham D, Spigelman L, Aten B: Insulin biosynthesis: evidence for a precursor. Science 1967, 157:697–700.PubMedCrossRefGoogle Scholar
  2. 2.
    Rigler R, Pramanik A, Jonasson P, et al.: Specific binding of proinsulin C-peptide to human cell membranes. Proc Natl Acad Sci U S A 1999, 96:13318–13323. Demonstrates specific binding of fluorescently labeled C-peptide in the nanomolar concentration range to cell membranes using a new technique, FCS.PubMedCrossRefGoogle Scholar
  3. 3.
    Ido Y, Vindigni A, Chang K, et al.: Prevention of vascular and neural dysfunction in diabetic rats by C-peptide. Science 1997, 277:563–566.PubMedCrossRefGoogle Scholar
  4. 4.
    Henriksson M, Shafqat J, Liepinsh E, et al.: Unordered structure of proinsulin C-peptide in aqueous solution and in the presence of lipid vesicles. Cell Mol Life Sci 2000, 57:337–342.PubMedCrossRefGoogle Scholar
  5. 5.
    Ohtomo Y, Aperia A, Sahlgren B, et al.: C-peptide stimulates rat renal tubular Na+, K+-ATPase activity in synergism with neuropeptide Y. Diabetologia 1996, 39:199–205.PubMedCrossRefGoogle Scholar
  6. 6.
    Sima A, Zhang W, Sugimoto K, et al.: C-peptide prevents and improves chronic type 1 diabetic neuropathy in the BB/Wor-rat. Diabetologia 2001, 44:889–897.PubMedCrossRefGoogle Scholar
  7. 7.
    Forst T, De La Tour D, Kunt T, et al.: Effects of proinsulin C-peptide on nitric oxide, microvascular blood flow and erythrocyte Na+, K+-ATPase activity in diabetes mellitus type 1. Clin Sci 2000, 98:283–290.PubMedCrossRefGoogle Scholar
  8. 8.
    Kunt T, Schneider S, Pfützner, A, et al.: The effect of human proinsulin C-peptide on erythrocyte deformability in patients with type 1 diabetes mellitus. Diabetologia 1999, 42:465–471.PubMedCrossRefGoogle Scholar
  9. 9.
    Wahren J, Owada S, Johansson B-L, et al.: C-peptide stimulates beta-cell Na+, K+-ATPase activity: a negative feedback mechanism on insulin secretion? Diabetologia 1996, 39(suppl 1):A71.Google Scholar
  10. 10.
    Kunt T, Forst T, Closs E, et al.: Activation of endothelial nitric oxide synthase (eNOS) by C-peptide. Diabetologia 1998, 41:A176.Google Scholar
  11. 11.
    Johansson B-L, Linde B, Wahren J: Effects of C-peptide on blood flow, capillary diffusion capacity and glucose utilization in the exercising forearm of type I (insulindependent) diabetic patients. Diabetologia 1992, 35:1151–1158.PubMedCrossRefGoogle Scholar
  12. 12.
    Johansson B-L, Pernow J: C-peptide potentiates the vasoconstrictor effect of neuropeptide Y in insulin dependent diabetic patients. Acta Physiol Scand 1999, 165:39–44.PubMedCrossRefGoogle Scholar
  13. 13.
    Johansson B-L, Pernow J, Wahren J: Muscle vasodilatation by C-peptide is NO-mediated. Diabetologia 1999, 42(suppl 1):A324.Google Scholar
  14. 14.
    Forst T, Kunt T, Pohlmann T, et al.: Biological activity of C-peptide on the skin microcirculation in patients with insulin dependent diabetes mellitus. J Clin Invest 1998, 101:2036–2041.PubMedCrossRefGoogle Scholar
  15. 15.
    Wahren J, Ekberg K, Johansson J, et al.: Role of C-peptide in human physiology. Am J Physiol Endocrinol Metab 2000, 278:E759-E768. Provides a survey of recent new findings in the field of C-peptide biochemistry and physiology.PubMedGoogle Scholar
  16. 16.
    Andersen AR, Christiansen JS, Andersen JK, et al.: Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 1983, 25:496–501.PubMedCrossRefGoogle Scholar
  17. 17.
    Krolewski AS, Warram JH, Christlieb AR, et al.: The changing natural history of nephropathy in type I diabetes. Am J Med 1985, 78:785–794.PubMedCrossRefGoogle Scholar
  18. 18.
    Bosch JP, Saccaggi A, Lauer A, et al.: Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate. Am J Med 1983, 75:943–950.PubMedCrossRefGoogle Scholar
  19. 19.
    Mogensen CE: Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives to microalbuminuria? Diabetes 1990, 39:761–767.PubMedCrossRefGoogle Scholar
  20. 20.
    Fioretto P, Steffes MW, Brown DM, Mauer SM: An overview of renal pathology in insulin-dependent diabetes mellitus in relationship to altered glomerular hemodynamics. Am J Kidney Dis 1992, 20:549–558.PubMedGoogle Scholar
  21. 21.
    DCCT Group: Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney Int 1995, 47:1703–1720.CrossRefGoogle Scholar
  22. 22.
    Bojestig M, Arnqvist HJ, Hermansson G, et al.: Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med 1994, 330:15–18.PubMedCrossRefGoogle Scholar
  23. 23.
    Kofoed-Enevoldsen A, Borch-Johnsen K, Kreiner S, et al.: Declining incidence of persistent proteinuria in type I (insulin- dependent) diabetic patients in Denmark. Diabetes 1987, 36:205–209.PubMedCrossRefGoogle Scholar
  24. 24.
    Parving HH, Andersen AR, Hommel E, Smidt U: Effects of long-term antihypertensive treatment on kidney function in diabetic nephropathy. Hypertension 1985, 7:II114-II117.PubMedGoogle Scholar
  25. 25.
    Viberti G, Mogensen CE, Groop LC, Pauls JF: Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. European Microalbuminuria Captopril Study Group. JAMA 1994, 271:275–279.PubMedCrossRefGoogle Scholar
  26. 26.
    EUCLID study group: Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 1997, 349:1787–1792.CrossRefGoogle Scholar
  27. 27.
    Fabre J, Balant LP, Dayer PG, et al.: The kidney in maturity onset diabetes mellitus: a clinical study of 510 patients. Kidney Int 1982, 21:730–738.PubMedCrossRefGoogle Scholar
  28. 28.
    Olivarius N, Andreasen AH, Keiding N, Mogensen CE: Epidemiology of renal involvement in newly-diagnosed middle-aged and elderly diabetic patients. Cross-sectional data from the population-based study “Diabetes Care in General Practice”, Denmark. Diabetologia 1993, 36:1007–1016.CrossRefGoogle Scholar
  29. 29.
    Mogensen CE: Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. Diabetologia 1999, 42:263–285.PubMedCrossRefGoogle Scholar
  30. 30.
    Dalla Vestra M, Saller A, Bortoloso E, et al.: Structural involvement in type 1 and type 2 diabetic nephropathy. Diabetes Metab 2000, 26(suppl 4):8–14.PubMedGoogle Scholar
  31. 31.
    Schmitz A, Gundersen H, Österby R: Glomerular morphology by light microscopy in non-insulin-dependent diabetes mellitus. Lack of glomerular hypertrophy. Diabetes 1988, 37:38–43.PubMedCrossRefGoogle Scholar
  32. 32.
    Fioretto P, Steffes M, Sutherland D, et al.: Reversal of lesions of diabetic nephropathy after pancreas transplantation. New Engl J Med 1998, 339:69–75.PubMedCrossRefGoogle Scholar
  33. 33.
    Luzi L: Pancreas transplantation and diabetic complications. New Engl J Med 1998, 339:115–117.PubMedCrossRefGoogle Scholar
  34. 34.
    Sjöquist M, Huang W, Johansson B-L: Effects of C-peptide on renal function at the early stage of experimental diabetes. Kindey Int 1998, 54:758–764.CrossRefGoogle Scholar
  35. 35.
    Samnegård B, Jacobson S, Jaremko G, et al.: Effects of C-peptide on glomerular and renal size and renal function in diabetic rats. Kidney Int 2001, 60:1258–1265.PubMedCrossRefGoogle Scholar
  36. 36.
    Johansson B-L, Sjöberg S, Wahren J: The influence of human C-peptide on renal function and glucose utilization in type I (insulin-dependent) diabetic patients. Diabetologia 1992, 35:121–128.PubMedCrossRefGoogle Scholar
  37. 37.
    Johansson B-L, 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 1993, 77:976–981.PubMedCrossRefGoogle Scholar
  38. 38.
    Johansson B-L, Borg K, Fernqvist-Forbes E, et al.: Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with type I diabetes—a three-month study. Diabet Med 2000, 17:181–189.PubMedCrossRefGoogle Scholar
  39. 39.
    Körner A, Wahren J, Johansson B-L, Aperia A: Effect of C-peptide on glomerular Na+, K+-ATPase activity in streptozotocin diabetic rats. Diabetologia 2000, 43(suppl 1):A258.Google Scholar
  40. 40.
    Patrakka J, Ruotslainen V, Ketola I, et al.: Expression of nephrin in pediatric kidney diseases. J Am Soc Nephrol 2001, 12:289–296.PubMedCrossRefGoogle Scholar
  41. 41.
    Flyvbjerg A, Hill C, Logan A: Pathophysiological role of growth factors in diabetic kidney disease: focus on innovative therapy. Trends Endocrinol Metabol 1999, 10:267–272.CrossRefGoogle Scholar

Copyright information

© Current Science Inc 2001

Authors and Affiliations

  • John Wahren
    • 1
  • Karin Ekberg
    • 1
  • Björn Samnegård
    • 1
  • Bo-Lennart Johansson
    • 1
  1. 1.Clinical Physiology A2:01, Department of Surgical SciencesKarolinska HospitalStockholmSweden

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