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Diabetologia

Erschienen in:

01.03.2007 | For debate

C-peptide is a bioactive peptide

verfasst von: J. Wahren, K. Ekberg, H. Jörnvall

Erschienen in: Diabetologia | Ausgabe 3/2007

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During the past decade, reports from several laboratories have focused on the physiological effects of C-peptide. Experimental data and clinical studies suggest that that C-peptide is a biologically active peptide. Clinical studies show that C-peptide administration in type 1 diabetes patients, who lack the peptide, results in amelioration of diabetes-induced renal and nerve dysfunction. Molecular studies demonstrate binding to cell membranes, activation of intracellular signalling pathways, and specific end effects of importance for vascular endothelial function. These findings have prompted the hypothesis that C-peptide deficiency in type 1 diabetes may contribute to the development of microvascular complications, and that C-peptide replacement, together with regular insulin therapy, may be beneficial in the treatment or prevention of these complications. In the present article we argue the case in favour of C-peptide as a biologically active peptide based on in vivo data and in vitro findings, as summarised in Table 1.

Table 1

Summary of clinical, in vivo animal and in vitro cellular effects of C-peptide

Effect	Reference
In vivo effects
Renal
Functional reserve ↑	[7]
Glomerular hyperfiltration ↓	[5, 7]
Urinary albumin excretion ↓	[6]
Structural abnormalities ↓	[8]
Nerve
Conduction velocity ↑	[9, 10, 12, 13, 37]
Vibration perception ↑	[10]
Blood flow ↑	[13, 20]
Na⁺/K⁺-ATPase activity ↑	[12, 37]
Hyperalgesia ↓	[14]
Structural abnormalities ↓	[12, 15]
Circulation
Muscle blood flow ↑	[16]
Skin blood flow ↑	[19]
Myocardial blood flow and contraction rate ↑	[17, 18]
Myocardial ejection fraction ↑	[17, 18]
QT interval ↓
In vitro effects
Membrane interaction
Specific binding in nanomolar range	[22, 23]
Intracellular signalling
G-protein involvement	[25‐29]
Intracellular Ca²⁺ ↑	[27, 30]
PKC, MAPK and PI-3Kγ ↑	[26, 28, 31]
NFκB, PPARγ, Bcl2, c-Fos, ZEB ↑	[29, 36, 46]
End effects
eNOS activity and protein levels ↑	[30, 33, 34]
Na⁺/K⁺-ATPase activity and protein levels ↑	[25, 31, 36]
Cell growth ↑	[40]
Apoptosis ↓	[29, 40]
Insulinomimetic effects	[32]
Anti-thrombotic effects	[21]
Other
Disaggregation of insulin hexamers	[41]

PI-3Kγ, phosphatidylinositol 3-kinase γ; PKC, protein kinase C; ZEB, zinc finger homeodomain enhancer-binding protein

…

Sjöberg S, Gunnarsson R, Gjötterberg M, Lefvert A, Persson A, Östman J (1987) Residual insulin production, glycemic control and prevalence of microvascular lesions and polyneuropathy in long-term type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30:208–213PubMedCrossRef

Zerbini G, Mangili R, Luzi L (1999) Higher post-absorptive C-peptide levels in type 1 diabetic patients without renal complications. Diabet Med 16:1048–1049PubMedCrossRef

Navarro X, Sutherland D, Kennedy W (1997) Long-term effects of pancreatic transplantation on diabetic neuropathy. Ann Neurol 42:727–736PubMedCrossRef

Fiorina P, Folli F, Zerbini G et al (2003) Islet transplantation is associated with improvement of renal function among uremic patients with type I diabetes mellitus and kidney transplants. J Am Soc Nephrol 14:2150–2158PubMedCrossRef

Johansson B-L, Sjöberg S, Wahren J (1992) The influence of human C-peptide on renal function and glucose utilization in Type I (insulin-dependent) diabetic patients. Diabetologia 35:121–128PubMedCrossRef

Johansson B-L, Borg K, Fernqvist-Forbes E, Kernell A, Odergren T, Wahren J (2000) Beneficial effects of C-peptide on incipient nephropathy and neuropathy in patients with type I diabetes. Diabet Med 17:181–189PubMedCrossRef

Sjöquist M, Huang W, Johansson B-L (1998) Effects of C-peptide on renal function at the early stage of experimental diabetes. Kidney Int 54:758–764PubMedCrossRef

Samnegård B, Jacobson S, Johansson B-L et al (2005) C-peptide prevents glomerular hypertrophy and mesangial matrix expansion in diabetic rats. Nephrol Dial Transplant 20:532–538PubMedCrossRef

Ekberg K, Brismar T, Johansson B-L, Jonsson B, Lindström P, Wahren J (2003) Amelioration of sensory nerve dysfunction by C-peptide in patients with type 1 diabetes. Diabetes 52:536–541PubMed

10.

Ekberg K, Brismar T, Johansson B-L et al (2007) C-peptide replacement therapy and sensory nerve function in type 1 diabetes neuropathy. Diabetes Care 30:71–76

11.

Johansson B-L, Borg K, Fernqvist-Forbes E, Odergren T, Remahl S, Wahren J (1996) C-peptide improves autonomic nerve function IDDM patients. Diabetologia 39:687–695PubMed

12.

Sima AA, Zhang W, Sugimoto K et al (2001) C-peptide prevents and improves chronic type 1 diabetic polyneuropathy in the BB/Wor rat. Diabetologia 44:889–897PubMedCrossRef

13.

Cotter M, Ekberg K, Wahren J, Cameron N (2003) Effects of proinsulin C-peptide in experimental diabetic neuropathy: vascular actions and modulation by nitric oxide synthase inhibition. Diabetes 52:1812–1817PubMed

14.

Kamiya H, Zhang W, Sima AA (2004) C-peptide prevents nociceptive sensory neuropathy in type 1 diabetes. Ann Neurol 56:827–835PubMedCrossRef

15.

Pierson C, Zhang W, Sima A (2003) Proinsulin C-peptide replacement in type 1 diabetic BB/Wor-rats prevents deficits in nerve fiber regeneration. J Neuropathol Exp Neurol 62:765–779PubMed

16.

Johansson B-L, Linde B, Wahren J (1992) Effects of C-peptide on blood flow, capillary diffusion capacity and glucose utilization in the exercising forearm of Type I (insulin-dependent) diabetic patients. Diabetologia 35:1151–1158PubMedCrossRef

17.

Johansson B-L, Sundell J, Ekberg K et al (2004) C-peptide improves adenosine-induced myocardial vasodilation in type 1 diabetes patients. Am J Physiol Endocrinol Metab 286:E14–E19PubMedCrossRef

18.

Hansen A, Johansson B-L, Wahren J, von Bibra H (2002) C-peptide exerts beneficial effects on myocardial blood flow and function in patients with type 1 diabetes. Diabetes 51:3077–3082PubMed

19.

Forst T, Kunt T, Pohlmann T et al (1998) Biological activity of C-peptide on the skin microcirculation in patients with insulin dependent diabetes mellitus. J Clin Invest 101:2036–2041PubMed

20.

Stevens M, Zhang W, Li F, Sima A (2004) C-peptide corrects endoneurial blood flow but not oxidative stress in type 1 BB/Wor rats. Am J Physiol Endocrinol Metab 287:E497–E505PubMedCrossRef

21.

Lindenblatt N, Braun B, Menger M, Klar E, Vollmar B (2006) C-peptide exerts antithrombotic effects that are repressed by insulin in normal and diabetic mice. Diabetologia 49:792–800PubMedCrossRef

22.

Rigler R, Pramanik A, Jonasson P et al (1999) Specific binding of proinsulin C-peptide to human cell membranes. Proc Natl Acad Sci USA 96:13318–13323PubMedCrossRef

23.

Henriksson M, Pramanik A, Shafqat J et al (2001) Specific binding of proinsulin C-peptide to detergent-solubilised human skin fibroblasts. Biochem Biophys Res Commun 280:423–427PubMedCrossRef

24.

Henriksson M, Shafqat J, Liepinsh E et al (2000) Unordered structure of proinsulin C-peptide in aqueous solution and in the presence of lipid vesicles. Cell Mol Life Sci 57:337–342PubMedCrossRef

25.

Zhong Z, Kotova O, Davidescu A et al (2004) C-peptide stimulates Na⁺,K⁺-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells. Cell Mol Life Sci 61:2782–2790PubMedCrossRef

26.

Zhong Z, Davidescu A, Ehrén I et al (2005) C-peptide stimulates ERK1/2 and JNK MAP-kinases via activation of PKC in human renal tubular cells. Diabetologia 48:187–197PubMedCrossRef

27.

Shafqat J, Juntti-Berggren L, Zhong Z et al (2002) Proinsulin C-peptide and its analogues induce intracellular Ca²⁺ increases in human renal tubular cells. Cell Mol Life Sci 59:1185–1189PubMedCrossRef

28.

Al-Rasheed N, Meakin F, Royal E et al (2004) Potent activation of multiple signalling pathways by C-peptide in oppossum kidney proximal tubular cells. Diabetologia 47:987–997PubMedCrossRef

29.

Al-Rasheed N, Willars G, Brunskill N (2006) C-peptide signals via G_αi to protect against TNF-α-mediated apoptosis of opossum kidney proximal tubular cells. J Am Soc Nephrol 17:986–995PubMedCrossRef

30.

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

31.

Tsimaratos M, Roger F, Chabardès D et al (2003) C-peptide stimulates Na,K-ATPase activity via PKC alpha in rat medullary thick ascending limb. Diabetologia 46:124–131PubMed

32.

Grunberger G, Qiang X, Li Z et al (2001) Molecular basis for the insulinomimetic effects of C-peptide. Diabetologia 44:1247–1257PubMedCrossRef

33.

Kitamura T, Kimura K, Makondo K et al (2003) 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 46:1698–1705PubMedCrossRef

34.

Scalia R, Coyle K, Levine B, Booth G, Lefer A (2000) C-peptide inhibits leukocyte–endothelium interaction in the microcirculation during endothelial dysfunction. FASEB J 14:2357–2364PubMedCrossRef

35.

Joshua I, Zhang Q, Falcone J, Bratcher A, Rodriguez W, Tyagi S (2005) Mechanisms of endothelial dysfunction with development of type 1 diabetes mellitus: role of insulin and C-peptide. J Cell Biochem 96:1149–1156PubMedCrossRef

36.

Chibalin A, Zhong Z, Kotova O, Ehrén I, Ekberg K, Wahren J (2006) Physiological concentrations of C-peptide increase Na,K-ATPase expression via PKC- and MAP kinase dependent activation of transcription factor ZEB in human renal tubular cells. Diabetologia 49(Suppl 1):A348

37.

Ido Y, Vindigni A, Chang K et al (1997) Prevention of vascular and neural dysfunction in diabetic rats by C-peptide. Science 277:563–566PubMedCrossRef

38.

Forst T, Dufayet De La Tour D, Kunt T et al (2000) Effects of proinsulin C-peptide on nitric oxide, microvascular blood flow and erythrocyte Na⁺,K⁺ATPase activity in diabetes mellitus type 1. Clin Sci (Lond) 98:283–290CrossRef

39.

Kunt T, Schneider S, Pfützner A et al (1999) The effect of human proinsulin C-peptide on erythrocyte deformability in patients with type 1 diabetes mellitus. Diabetologia 42:465–471PubMedCrossRef

40.

Li Z, Zhang W, Sima A (2003) C-peptide enhances insulin-mediated cell growth and protection against high glucose-induced apoptosis in SH-SY5Y cells. Diabetes/Metab Res Rev 19:375–385CrossRef

41.

Shafqat J, Melles E, Sigmundson K et al (2006) Proinsulin C-peptide elicits disaggregation of insulin resulting in enhanced physiological insulin effects. Cell Mol Life Sci 63:1805–1811PubMedCrossRef

42.

Henriksson M, Nordling E, Melles E et al (2005) Separate functional features of proinsulin C-peptide. Cell Mol Life Sci 62:1772–1778PubMedCrossRef

43.

DCCT Group (1995) Effect of intensive diabetes treatment on nerve conduction in the diabetes control and complications trial. Ann Neurol 38:869–880CrossRef

44.

Sima AA, Nathaniel V, Bril V, McEwen T, Green D (1988) Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy. J Clin Invest 81:349–364PubMedCrossRef

45.

Sima AA (2004) Diabetic neuropathy in type 1 and 2 diabetes and the effect of C-peptide. J Neurol Sci 220:133–136PubMedCrossRef

46.

Sima A, Zhang W, Li Z, Murakawa Y, Pierson C (2004) Molecular alterations underlie nodal and paranodal degeneration in type 1 diabetic neuropathy and are prevented by C-peptide. Diabetes 53:1556–1563PubMed

47.

Luzi L, Zerbini G, Caumo A (2007) C-peptide: a redundant relative of insulin? Diabetologia. doi: 10.1007/s00125-006-0576-x

Titel: C-peptide is a bioactive peptide
verfasst von: J. Wahren
K. Ekberg
H. Jörnvall
Publikationsdatum: 01.03.2007
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 3/2007
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0559-y

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