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Proinsulin C-peptide: Friend or foe in the development of diabetes-associated complications?

By Lina Nordquist and M Johansson


The proinsulin connecting peptide, C-peptide, is a cleavage product of insulin synthesis that is co-secreted with insulin by pancreatic β-cells following glucose stimulation. Recombinant insulin, used in the treatment of diabetes, lacks C-peptide and preclinical and clinical studies suggest that lack of C-peptide may exacerbate diabetes-associated complications. In accordance with this, several studies suggest that C-peptide has beneficial effects in a number of diabetes-associated complications. C-peptide has been shown to prevent diabetic neuropathy by improving endoneural blood flow, preventing neuronal apoptosis and by preventing axonal swelling. In the vascular system, C-peptide has been shown to prevent vascular dysfunction in diabetic rats, and to possess anti-proliferative effects on vascular smooth muscle cells, which may prevent atherosclerosis. However, C-peptide depositions have been found in arteriosclerotic lesions of patients with hyperinsulinemic diabetes and C-peptide has been shown to induce pro-inflammatory mediators, such as nuclear factor kappa B, inducible nitric oxide synthase, and cyclooxygenase-2, indicating that C-peptide treatment could be associated with side-effects that may accelerate the development of diabetes-associated complications. This review provides a brief summary of recent research in the field and discusses potential beneficial and detrimental effects of C-peptide supplementation

Topics: Review
Publisher: Dove Medical Press
OAI identifier:
Provided by: PubMed Central

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  1. (1996). Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion.
  2. (1997). Activation of nuclear factor-kappaB in cultured endothelial cells by increased glucose concentration: prevention by calphostin C.
  3. (1999). Advanced glycation end products-cytokine-nitric oxide sequence pathway in the development of diabetic nephropathy: aminoguanidine ameliorates the overexpression of tumour necrosis factor-alpha and inducible nitric oxide synthase in diabetic rat glomeruli.
  4. (2000). Benefi cial effects of C-peptide on incipient nephropathy and neuropathy in patients with Type 1 diabetes mellitus. Diabet Med,
  5. (2003). Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care,
  6. (2001). Biochemistry and molecular cell biology of diabetic complications.
  7. (1998). Biological activity of C-peptide on the skin microcirculation in patients with insulin-dependent diabetes mellitus.
  8. (2004). C-peptide and captopril are equally effective in lowering glomerular hyperfi ltration in diabetic rats. Nephrol Dial Transplant,
  9. (2004). C-peptide and central nervous system complications in diabetes. Exp Diabesity Res,
  10. (2004). C-peptide and retinal microangiopathy in diabetes. Exp Diabesity Res,
  11. (2004). C-peptide colocalizes with macrophages in early arteriosclerotic lesions of diabetic subjects and induces monocyte chemotaxis in vitro. Arterioscler Thromb Vasc Biol,
  12. (2003). C-peptide enhances insulin-mediated cell growth and protection against high glucose-induced apoptosis in SH-SY5Y cells. Diabetes Metab Res Rev,
  13. (2002). C-peptide exerts benefi cial effects on myocardial blood fl ow and function in patients with type 1 diabetes.
  14. (2000). C-peptide exerts cardioprotective effects in myocardial ischemia-reperfusion.
  15. (2003). C-peptide increases forearm blood fl ow in patients with type 1 diabetes via a nitric oxide-dependent mechanism.
  16. (2004). C-peptide induces chemotaxis of human CD4-positive cells: involvement of pertussis toxin-sensitive G-proteins and phosphoinositide 3-kinase. Diabetes,
  17. (2006). C-Peptide induces vascular smooth muscle cell proliferation: involvement of SRC-kinase, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinase 1/2. Circ Res,
  18. (2000). C-peptide inhibits leukocyteendothelium interaction in the microcirculation during acute endothelial dysfunction.
  19. (2008). C-peptide normalizes glomerular fi ltration rate in hyperfi ltrating streptozotocin-induced diabetic rats. In vivo measurements in conscious rats. Adv Exp Med Biol, In press.
  20. (2006). C-peptide signals via Galpha i to protect against TNF-alpha-mediated apoptosis of opossum kidney proximal tubular cells.
  21. (2005). C-peptide stimulates ERK1/2 and JNK MAP kinases via activation of protein kinase C in human renal tubular cells.
  22. (2004). C-peptide stimulates Na+, K+–ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells. Cell Mol Life Sci,
  23. (2003). C-peptide stimulates Na+,K+-ATPase activity via PKC alpha in rat medullary thick ascending limb.
  24. (1993). Diabetes Control and Complications Trial Research Group.
  25. (2002). Effect of C-peptide on wound healing and microcirculation in diabetic mice.
  26. (1992). Effects of C-peptide on blood fl ow, capillary diffusion capacity and glucose utilization in the exercising forearm of type 1 (insulin-dependent) diabetic patients.
  27. (2001). Effects of C-peptide on glomerular and renal size and renal function in diabetic rats.
  28. (1998). Effects of C-peptide on renal function at the early stage of experimental diabetes.
  29. (1998). Erythrocyte Na/K ATPase activity and diabetes: relationship with C-peptide level.
  30. (1989). Features of endothelial dysfunction in early diabetic nephropathy.
  31. (2002). Human C-peptide acutely lowers glomerular hyperfi ltration and proteinuria in diabetic rats: a dose-response study. Naunyn Schmiedebergs Arch Pharmacol,
  32. (2005). Human proinsulin C-peptide prevents proliferation of rat aortic smooth muscle cells cultured in high-glucose conditions.
  33. (1999). Hyperglycemia-induced activation of nuclear transcription factor kappaB in vascular smooth muscle cells.
  34. (2003). Infl ammatory parameters are independently associated with urinary albumin in type 2 diabetes mellitus.
  35. (2006). Infl uence of C-peptide on early glomerular changes in diabetic mice. Diabetes Metab Res Rev,
  36. (2006). International trial of the Edmonton protocol for islet transplantation.
  37. (1998). Interstitial collagenase and the ED-B oncofetal domain of fi bronectin are markers of angiogenesis in human skin tumors. Cancer Detect Prev,
  38. (2003). Islet transplantation is associated with improvement of renal function among uremic patients with type I diabetes mellitus and kidney transplants.
  39. (1999). Mechanisms of TNF-alpha-induced insulin resistance. Exp Clin Endocrinol Diabetes,
  40. (2001). Molecular basis for the insulinomimetic effects of C-peptide.
  41. (1993). mRNA expression of growth factors in glomeruli from diabetic rats.
  42. (1998). New aspects on biological activity of C-peptide in IDDM patients. Exp Clin Endocrinol Diabetes,
  43. (1997). NF-kappa B: a crucial transcription factor for glial and neuronal cell function. Trends Neurosci,
  44. (2000). NF-kappaB transcription factors: critical regulators of hematopoiesis and neuronal survival. Cytokine Growth Factor Rev,
  45. (2004). Oncofetal fi bronectin in diabetic retinopathy.
  46. (2004). Pentoxifylline ameliorates renal tumor necrosis factor expression, sodium retention, and renal hypertrophy in diabetic rats.
  47. (2005). Plasma IL-6 concentration is inversely related to insulin sensitivity, and acute-phase proteins associate with glucose and lipid metabolism in healthy subjects. Diabetes Obes Metab.
  48. (1991). Possible role of tumor necrosis factor and interleukin-1 in the development of diabetic nephropathy.
  49. (1997). Prevention of vascular and neural dysfunction in diabetic rats by C-peptide.
  50. (2001). Proinsulin C-peptide rapidly stimulates mitogen-activated protein kinases in Swiss 3T3 fi broblasts: requirement of protein kinase C, phosphoinositide 3-kinase and pertussis toxin-sensitive G-protein.
  51. (2006). Proinsulin C-peptide stimulates a PKC/IkappaB/NF-kappaB signaling pathway to activate COX-2 gene transcription in Swiss 3T3 fibroblasts.
  52. (2007). Regulation of renal sodium transporters during severe infl ammation.
  53. (2005). Relationship between C peptide and chronic complications in type-2 diabetes mellitus.
  54. (2003). Residual C-peptide secretion and endothelial function in patients with Type II diabetes. Clin Sci (Lond ),
  55. (1998). Reversal of lesions of diabetic nephropathy after pancreas transplantation.
  56. (1991). Role of oxidized low density lipoprotein in atherogenesis.
  57. (2007). The C-peptide fragment EVARQ reduces glomerular hyperfi ltration in streptozotocin-induced diabetic rats. Diabetes Metab Res Rev,
  58. (1999). The effect of human proinsulin C-peptide on erythrocyte deformability in patients with Type I diabetes mellitus.
  59. (2006). The effect of whole organ pancreas transplantation and PIT on diabetic complications. Curr Diab Rep,
  60. (1994). The fi bronectin isoform containing the ED-B oncofetal domain: a marker of angiogenesis.
  61. (1999). The role of TNFalpha and TNF receptors in obesity and insulin resistance.
  62. (1994). Tumor necrosis factor alpha inhibits signaling from the insulin receptor.
  63. (2004). Type 1 diabetic neuropathy and C-peptide. Exp Diabesity Res,
  64. (2003). Urinary and renal interstitial concentrations of TNF-alpha increase prior to the rise in albuminuria in diabetic rats.

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