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].
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Tripathi K. EUCLID study. Lancet. 1997;350(9084):1102–3.
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.
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.
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.
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.
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.
Rubanyi GM, Vanhoutte PM. Superoxide anions and hyperoxia inactivate endothelium-derived relaxing factor. Am J Physiol. 1986;250(5 Pt 2):H822–7.
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.
Forst T, Kunt T. Effects of C-peptide on microvascular blood flow and blood hemorheology. Exp Diabesity Res. 2004;5(1):51–64.
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.
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.
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.
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.
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.
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.
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.
Calles-Escandon J, Cipolla M. Diabetes and endothelial dysfunction: a clinical perspective. Endocr Rev. 2001;22(1):36–52.
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.
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.
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.
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.
Johnstone MT, Craeger SJ, Scales KM, et al. Impaired endothelium-dependent vasodilatation in patients with insulin-dependent diabetes mellitus. Circulation. 1993;88:2510–6.
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.
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.
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.
Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med. 1993;329(27):2002–12.
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.
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.
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.
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.
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.
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.
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.
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.
Kamiya H, Zhang W, Ekberg K, et al. C-Peptide reverses nociceptive neuropathy in type 1 diabetes. Diabetes. 2006;55(12):3581–7.
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.
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.
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.
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.
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.
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.
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.
Boulton AJ, Scarpello JHB, Ward JD. Venous oxygenation in the diabetic neuropathic foot: evidence of arteriovenous shunting. Diabetologia. 1982;22:6–8.
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.
Flynn MD, Tooke JE. Aetilogy of diabetic foot ulceration. Diabet Med. 1992;8:320–9.
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.
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.
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.
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.
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.
Ernst E, Matrai A. Altered red and white blood cell rheology in type II diabetes. Diabetes. 1986;35(12):1412–5.
Barnes AJ, Locke O, Scudder PR, et al. Is hyperviscosity a treatable component of diabetic microcirculatory disease. Lancet. 1977;2.2:789–91.
Finotti P, Palatini P. Reduction of erythrocyte (Na+K+)ATPase activity in type 1 (insulin-dependent) diabetic subjects. Diabetologia. 1986;29:623–8.
McMillan DE, Utterback NG, LaPuma J. Reduced erythrocyte deformability in diabetes. Diabetes. 1998;27:895–901.
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.
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.
Cohen NS, Ekholm JE, Luthra MG, et al. Biochemical characterization of density-separated human erythrocytes. Biochim Biophys Acta. 1976;419(2):229–42.
Baba Y, Kai M, Kamada T, et al. Higher levels of erythrocyte membrane microviscosity in diabetes. Diabetes. 1979;28(12):1138–40.
Schmid-Schonbein H, Volger E. Red-cell aggregation and red-cell deformability in diabetes. Diabetes. 1976;25(2 Suppl):897–902.
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.
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.
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.
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.
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.
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.
Mazzanti L, Rabini RA, Faloia E, et al. Altered cellular Ca2+ and Na+ transport in diabetes mellitus. Diabetes. 1990;39:850–4.
Takakuwa Y, Mohandes N. Modulation of erythrocyte membrane material properties by Ca2+ and calmodulin. J Clin Invest. 1988;82:394–400.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights 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)