Skip to main content
SpringerLink
Log in

Role of C-Peptide in the Regulation of Microvascular Blood Flow

  • Chapter
  • First Online:
Diabetes & C-Peptide

Part of the book series: Contemporary Diabetes ((CDI))

Abstract

Patients with type 1 diabetes mellitus present with an excessive risk for microvascular complications such as retinopathy, nephropathy, and peripheral neuropathy. Endothelial dysfunction is an early ­feature of vascular disease in patients with type 1 diabetes mellitus. Although elevated blood glucose levels were shown to predict the risk of microvascular complications in type 1 diabetic patients [1], even in patients with good metabolic control, microvascular complications cannot be prevented. Therefore, additional ­factors beyond glucose ­control are thought to contribute to the ­pathogenesis of microvascular complications. Endothelial dysfunction and low-grade inflammation are early ­features of vascular disease in patients with type 1 diabetes mellitus [2, 3] and precede the development of microvascular complications like retinopathy, nephropathy, and neuropathy. Endothelial dysfunction is characterized by an impaired flow mediated dilatation (FMD) [2], low grade inflammation [4], increased expression of endothelial cell adhesion molecules [4, 5], and the generation of reactive oxygen species (ROS) [6].

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Tripathi K. EUCLID study. Lancet. 1997;350(9084):1102–3.

    Article  PubMed  CAS  Google Scholar 

  2. Jarvisalo MJ, Raitakari M, Toikka JO, et al. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation. 2004;109(14):1750–5.

    Article  PubMed  Google Scholar 

  3. Hu H, Li N, Yngen M, et al. Enhanced leukocyte-platelet cross-talk in Type 1 diabetes mellitus: relationship to microangiopathy. J Thromb Haemost. 2004;2(1):58–64.

    Article  PubMed  CAS  Google Scholar 

  4. Yngen M, Ostenson CG, Hu H, et al. Enhanced P-selectin expression and increased soluble CD40 ligand in patients with type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation. Int J Obes Relat Metab Disord. 2004;47(3):537–40.

    CAS  Google Scholar 

  5. Clausen P, Jacobsen P, Rossing K, et al. Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with type 1 diabetes mellitus with microalbuminuria and overt nephropathy. Diabet Med. 2000;17(9):644–9.

    Article  PubMed  CAS  Google Scholar 

  6. Devaraj S, Cheung AT, Jialal I, et al. Evidence of increased inflammation and microcirculatory abnormalities in patients with type 1 diabetes and their role in microvascular complications. Diabetes. 2007;56(11):2790–6.

    Article  PubMed  CAS  Google Scholar 

  7. Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol. 1986;250(5 Pt 2):H822–7.

    PubMed  CAS  Google Scholar 

  8. Janssen-Heininger YM, Poynter ME, Baeuerle PA. Recent advances towards understanding redox mechanisms in the activation of nuclear factor kappaB. Free Radic Biol Med. 2000;28(9):1317–27.

    Article  PubMed  CAS  Google Scholar 

  9. Forst T, Kunt T. Effects of C-peptide on microvascular blood flow and blood hemorheology. Exp Diabesity Res. 2004;5(1):51–64.

    Article  PubMed  CAS  Google Scholar 

  10. Forst T, Kunt T, Wilhelm B, et al. Role of C-peptide in the regulation of microvascular blood flow. Exp Diabetes Res. 2008;2008:176245.

    PubMed  CAS  Google Scholar 

  11. Delaney C, Shaw J, Day T. Acute, local effects of iontophoresed insulin and C-peptide on cutaneous microvascular function in type 1 diabetes mellitus. Diabet Med. 2004;21(5):428–33.

    Article  PubMed  CAS  Google Scholar 

  12. Kitamura T, Kimura K, Jung BD, 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. Biochem J. 2002;366(Pt 3):737–44.

    PubMed  CAS  Google Scholar 

  13. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–86.

    Article  Google Scholar 

  14. Steffes MW, Sibley S, Jackson M, et al. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care. 2003;26(3):832–6.

    Article  PubMed  Google Scholar 

  15. Panero F, Novelli G, Zucco C, et al. Fasting plasma C-peptide and micro- and macrovascular complications in a large clinic-based cohort of type 1 diabetic patients. Diabetes Care. 2009;32(2):301–5.

    Article  PubMed  CAS  Google Scholar 

  16. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524–6.

    Article  PubMed  CAS  Google Scholar 

  17. Calles-Escandon J, Cipolla M. Diabetes and endothelial dysfunction: a clinical perspective. Endocr Rev. 2001;22(1):36–52.

    Article  PubMed  CAS  Google Scholar 

  18. Morris SJ, Shore AC, Tooke JE. Responses of the skin microcirculation to acetylcholine and sodium nitroprusside in patients with NIDDM. Diabetologia. 1995;38(11):1337–44.

    Article  PubMed  CAS  Google Scholar 

  19. Pieper GM, Siebeneich W, Moore-Hilton G, et al. Reversal by L-arginine of a dysfunctional arginine/nitric oxide pathway in the endothelium of the genetic diabetic BB rat. Diabetologia. 1997;40:910–5.

    Article  PubMed  CAS  Google Scholar 

  20. McNally PG, Watt PAC, Rimmer T, et al. Impaired contraction and endothelium-dependent relaxation in isolated resistance vessels from patients with insulin-dependent diabetes mellitus. Clin Sci. 1994;87:31–6.

    PubMed  CAS  Google Scholar 

  21. Kamata K, Miyata N, Abiru T, et al. Functional changes in vascular smooth muscle and endothelium of arteries during diabetes mellitus. Life Sci. 1992;50(19):1379–87.

    Article  PubMed  CAS  Google Scholar 

  22. Johnstone MT, Craeger SJ, Scales KM, et al. Impaired endothelium-dependent vasodilatation in patients with insulin-dependent diabetes mellitus. Circulation. 1993;88:2510–6.

    PubMed  CAS  Google Scholar 

  23. Hach T, Forst T, Kunt T, et al. C-peptide and its C-terminal fragments improve erythrocyte deformability in type 1 diabetes patients. Exp Diabetes Res. 2008;2008:730594.

    PubMed  Google Scholar 

  24. Forst T, Hohberg C, Pfutzner A. Cardiovascular effects of disturbed insulin activity in metabolic syndrome and in type 2 diabetic patients. Horm Metab Res. 2009;41(2):123–31.

    Article  PubMed  CAS  Google Scholar 

  25. Forstermann U, Closs EI, Pollock JS, et al. Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension. 1994;23(6 Pt 2):1121–31.

    PubMed  CAS  Google Scholar 

  26. Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993;329(27):2002–12.

    Article  PubMed  CAS  Google Scholar 

  27. Wallerath T, Kunt T, Forst T, et al. Stimulation of endothelial nitric oxide synthase by proinsulin C-peptide. Nitric Oxide. 2003;9(2):95–102.

    Article  PubMed  CAS  Google Scholar 

  28. Kunt T, Schneider S, Pfutzner A, et al. The effect of human proinsulin C-peptide on erythrocyte deformability in patients with type 1 diabetes mellitus. Diabetologia. 1999;42:465–71.

    Article  PubMed  CAS  Google Scholar 

  29. Jensen ME, Messina EJ. C-peptide induces a concentration-dependent dilation of skeletal muscle arterioles only in presence of insulin. Am J Physiol. 1999;276(4 Pt 2):H1223–8.

    PubMed  CAS  Google Scholar 

  30. Danthuluri NR, Cybulsky MI, Brock TA. ACh-induced calcium transients in primary cultures of rabbit aortic endothelial cells. Am J Physiol. 1988;255(6 Pt 2):H1549–53.

    PubMed  CAS  Google Scholar 

  31. Elliott TG, Cockcroft JR, Groop PH, et al. Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria. Clin Sci (Lond). 1993;85(6):687–93.

    CAS  Google Scholar 

  32. Clarkson P, Celermajer DS, Donald AE, et al. Impaired vascular reactivity in insulin-dependent diabetes mellitus is related to disease duration and low density lipoprotein cholesterol levels. J Am Coll Cardiol. 1996;28(3):573–9.

    Article  PubMed  CAS  Google Scholar 

  33. Fernqvist-Forbes E, Johansson BL, Eriksson MJ. Effects of C-peptide on forearm blood flow and brachial artery dilatation in patients with type 1 diabetes mellitus. Acta Physiol Scand. 2001;172(3):159–65.

    Article  PubMed  CAS  Google Scholar 

  34. Cotter MA, Ekberg K, Wahren J, et al. Effects of proinsulin C-peptide in experimental diabetic neuropathy: vascular actions and modulation by nitric oxide synthase inhibition. Diabetes. 2003;52(7):1812–7.

    Article  PubMed  CAS  Google Scholar 

  35. Kamiya H, Zhang W, Ekberg K, et al. C-Peptide reverses nociceptive neuropathy in type 1 diabetes. Diabetes. 2006;55(12):3581–7.

    Article  PubMed  CAS  Google Scholar 

  36. Johansson BL, Borg K, Fernqvist-Forbes E, et al. Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with type 1 diabetes mellitus. Diabet Med. 2000;17(3):181–9.

    Article  PubMed  CAS  Google Scholar 

  37. Ekberg K, Juntti-Berggren L, Norrby A, et al. C-peptide improves sensory nerve function in type 1 diabetes and neuropathy. Int J Obes Relat Metab Disord. 2005;48 Suppl 1:A81.

    Google Scholar 

  38. Lindstrom K, Johansson C, Johnsson E, et al. Acute effects of C-peptide on the microvasculature of isolated perfused skeletal muscles and kidneys in rat. Acta Physiol Scand. 1996;156(1):19–25.

    Article  PubMed  CAS  Google Scholar 

  39. Ido Y, Vindigni A, Chang K, et al. Prevention of vascular and neural dysfunction in diabetic rats by C- peptide. Science. 1997;277(5325):563–6.

    Article  PubMed  CAS  Google Scholar 

  40. Johansson BL, Sjoberg S, Wahren J. The influence of human C-peptide on renal function and glucose utilization in type 1 (insulin-dependent) diabetic patients. Diabetologia. 1992;35(2):121–8.

    Article  PubMed  CAS  Google Scholar 

  41. Jorneskog G, Brismar K, Fagrell B. Skin capillary circulation is more impaired in the toes of diabetic than non-diabetic patients with peripheral vascular disease. Diabet Med. 1995;12(1):36–41.

    Article  PubMed  CAS  Google Scholar 

  42. Jorneskog G, Brismar K, Fagrell B. Skin capillary circulation severely impaired in toes of patients with IDDM, with and without late diabetic complications. Diabetologia. 1995;38:474–80.

    Article  PubMed  CAS  Google Scholar 

  43. Boulton AJ, Scarpello JHB, Ward JD. Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous shunting. Diabetologia. 1982;22:6–8.

    Article  PubMed  CAS  Google Scholar 

  44. Jorneskog G, Ostergren J, Tyden G, et al. Does combined kidney and pancreas transplantation reverse functional diabetic microangiopathy? Transpl Int. 1990;3(3):167–70.

    Article  PubMed  CAS  Google Scholar 

  45. Flynn MD, Tooke JE. Aetilogy of diabetic foot ulceration. Diabet Med. 1992;8:320–9.

    Article  Google Scholar 

  46. 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(10):2036–41.

    Article  PubMed  CAS  Google Scholar 

  47. Polska E, Kolodjaschna J, Berisha F, et al. C-peptide does not affect ocular blood flow in patients with type 1 diabetes. Diabetes Care. 2006;29(9):2034–8.

    Article  PubMed  CAS  Google Scholar 

  48. Tibirica E, Rodrigues E, Cobas RA, et al. Endothelial function in patients with type 1 diabetes evaluated by skin capillary recruitment. Microvasc Res. 2007;73(2):107–12.

    Article  PubMed  CAS  Google Scholar 

  49. Forst T, Pfutzner A, Kunt T, et al. Skin microcirculation in patients with type I diabetes with and without neuropathy after neurovascular stimulation. Clin Sci. 1998;94(3):255–61.

    PubMed  CAS  Google Scholar 

  50. Kunt T, Forst T, Harzer O, et al. The influence of advanced glycation endproducts (AGE) on the expression of human endothelial adhesion molecules. Exp Clin Endocrinol Diabetes. 1998;106(3):183–8.

    Article  PubMed  CAS  Google Scholar 

  51. Ernst E, Matrai A. Altered red and white blood cell rheology in type II diabetes. Diabetes. 1986;35(12):1412–5.

    Article  PubMed  CAS  Google Scholar 

  52. Barnes AJ, Locke O, Scudder PR, et al. Is hyperviscosity a treatable component of diabetic microcirculatory disease. Lancet. 1977;2.2:789–91.

    Article  Google Scholar 

  53. Finotti P, Palatini P. Reduction of erythrocyte (Na+K+)ATPase activity in type 1 (insulin-dependent) diabetic subjects. Diabetologia. 1986;29:623–8.

    Article  PubMed  CAS  Google Scholar 

  54. McMillan DE, Utterback NG, LaPuma J. Reduced erythrocyte deformability in diabetes. Diabetes. 1998;27:895–901.

    Google Scholar 

  55. Bareford D, Jennings PE, Stone PC, et al. Effects of hyperglycaemia and sorbitol accumulation on erythrocyte deformability in diabetes mellitus. J Clin Pathol. 1986;39(7):722–7.

    Article  PubMed  CAS  Google Scholar 

  56. Chimori K, Miyazaki S, Kosaka J, et al. Increased sodium influx into erythrocytes in diabetes mellitus and hypertension. Clin Exp Hypertens A. 1986;8(2):185–99.

    Article  PubMed  CAS  Google Scholar 

  57. Cohen NS, Ekholm JE, Luthra MG, et al. Biochemical characterization of density-separated human erythrocytes. Biochim Biophys Acta. 1976;419(2):229–42.

    Article  PubMed  CAS  Google Scholar 

  58. Baba Y, Kai M, Kamada T, et al. Higher levels of erythrocyte membrane microviscosity in diabetes. Diabetes. 1979;28(12):1138–40.

    Article  PubMed  CAS  Google Scholar 

  59. Schmid-Schonbein H, Volger E. Red-cell aggregation and red-cell deformability in diabetes. Diabetes. 1976;25(2 Suppl):897–902.

    PubMed  CAS  Google Scholar 

  60. 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(23):13318–23.

    Article  PubMed  CAS  Google Scholar 

  61. Zhong Z, Davidescu A, Ehren I, et al. C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells. Int J Obes Relat Metab Disord. 2005;48(1):187–97.

    CAS  Google Scholar 

  62. Zhang W, Yorek M, Pierson CR, et al. Human C-peptide dose dependently prevents early neuropathy in the BB/Wor-rat. Int J Exp Diabetes Res. 2001;2(3):187–93.

    Article  PubMed  CAS  Google Scholar 

  63. Meyer JA, Froelich JM, Reid GE, et al. Metal-activated C-peptide facilitates glucose clearance and the release of a nitric oxide stimulus via the GLUT1 transporter. Int J Obes Relat Metab Disord. 2008;51(1):175–82.

    CAS  Google Scholar 

  64. 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(2):199–205.

    Article  PubMed  CAS  Google Scholar 

  65. Ohtomo Y, Bergman T, Johansson BL, et al. Differential effects of proinsulin C-peptide fragments on Na+, K+-ATPase activity of renal tubule segments. Diabetologia. 1998;41(3):287–91.

    Article  PubMed  CAS  Google Scholar 

  66. Mazzanti L, Rabini RA, Faloia E, et al. Altered cellular Ca2+ and Na+ transport in diabetes mellitus. Diabetes. 1990;39:850–4.

    Article  PubMed  CAS  Google Scholar 

  67. Takakuwa Y, Mohandes N. Modulation of erythrocyte membrane material properties by Ca2+ and calmodulin. J Clin Invest. 1988;82:394–400.

    Article  PubMed  CAS  Google Scholar 

  68. Schischmanoff PO, Winardi R, Discher DE, et al. Defining of the minimal domain of protein 4.1 involved in spectrin-actin binding. J Biol Chem. 1995;270(36):21243–50.

    Article  PubMed  CAS  Google Scholar 

  69. Gardner K, Bennett V. A new erythrocyte membrane-associated protein with calmodulin binding activity. Identification and purification. J Biol Chem. 1986;261(3):1339–48.

    PubMed  CAS  Google Scholar 

  70. Scalia R, Coyle KM, Levine BJ, et al. A novel role for C-peptide in the regulation of leukocyte endothelium interaction during acute inflammatory events of the microcirculation. FASEB J. 2000;14:A10.

    Article  Google Scholar 

  71. Young LH, Ikeda Y, Scalia R, et al. C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion. Am J Physiol Heart Circ Physiol. 2000;279(4):H1453–9.

    PubMed  CAS  Google Scholar 

  72. Mughal RS, Scragg JL, Lister P, et al. Cellular mechanisms by which proinsulin C-peptide prevents insulin-induced neointima formation in human saphenous vein. Int J Obes Relat Metab Disord. 2010;53(8):1761–71.

    CAS  Google Scholar 

  73. Cifarelli V, Luppi P, Tse HM, et al. Human proinsulin C-peptide reduces high glucose-induced proliferation and NF-kappaB activation in vascular smooth muscle cells. Atherosclerosis. 2008;201(2):248–57.

    Article  PubMed  CAS  Google Scholar 

  74. Luppi P, Geng X, Cifarelli V, et al. C-peptide is internalised in human endothelial and vascular smooth muscle cells via early endosomes. Int J Obes Relat Metab Disord. 2009;52(10):2218–28.

    CAS  Google Scholar 

  75. Marx N, Walcher D, Raichle C, et al. C-peptide colocalizes with macrophages in early arteriosclerotic lesions of diabetic subjects and induces monocyte chemotaxis in vitro. Arterioscler Thromb Vasc Biol. 2004;24(3):540–5.

    Article  PubMed  CAS  Google Scholar 

  76. Walcher D, Aleksic M, Jerg V, et al. C-peptide induces chemotaxis of human CD4-positive cells: involvement of pertussis toxin-sensitive G-proteins and phosphoinositide 3-kinase. Diabetes. 2004;53(7):1664–70.

    Article  PubMed  CAS  Google Scholar 

  77. Forst T, De La Tour DD, 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 I. Clin Sci. 2000;98(3):283–90.

    Article  PubMed  CAS  Google Scholar 

  78. Mesquita R, Picarra B, Saldanha C, et al. Nitric oxide effects on human erythrocytes structural and functional properties – an in vitro study. Clin Hemorheol Microcirc. 2002;27(2):137–47.

    PubMed  CAS  Google Scholar 

  79. Bateman RM, Jagger JE, Sharpe MD, et al. Erythrocyte deformability is a nitric oxide-mediated factor in decreased capillary density during sepsis. Am J Physiol Heart Circ Physiol. 2001;280(6):H2848–56.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Medical Department, Institute for Clinical Research and Development, Parcusstrasse 8, 55116, Mainz, Germany

    Thomas Forst & Andreas Pfützner

  2. Department of Endocrinology and Metabolism, Johannes Gutenberg University, Mainz, Germany

    Thomas Forst & Matthias M. Weber

  3. Diabetes Center, Berlin, Germany

    Thomas Kunt

Authors
  1. Thomas Forst
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthias M. Weber
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Kunt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Pfützner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas Forst .

Editor information

Editors and Affiliations

  1. Departments of Pathology and Neurology, Wayne State University, Detroit, 48201, Michigan, USA

    Anders A.F. Sima

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Forst, T., Weber, M.M., Kunt, T., Pfützner, A. (2012). Role of C-Peptide in the Regulation of Microvascular Blood Flow. In: Sima, A. (eds) Diabetes & C-Peptide. Contemporary Diabetes. Humana Press. https://doi.org/10.1007/978-1-61779-391-2_5

Download citation

  • DOI: https://doi.org/10.1007/978-1-61779-391-2_5

  • Published:

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-61779-390-5

  • Online ISBN: 978-1-61779-391-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation