C-Peptide 1 (rat)

The podocyte is one of the main components of the glomerular filtration barrier in the kidney, and its injury may contribute to proteinuria, glomerulosclerosis and eventually kidney failure. C-peptide, a cleavage product of proinsulin, shows therapeutic potential for treating diabetic nephropathy (DN). The aim of this study was to investigate the effect of C-peptide on high glucose-induced podocyte dysfunction. In the present study, we found that the protective effects of islet transplantation were superior to simple insulin therapy for the treatment of DN in streptozotocin (STZ)-treated rats. And such superiority may due to the function of C-peptide secreted at the implanted site. Based on this background, we determined that the application of C-peptide significantly prevented high glucose-induced podocyte injury by increasing the expression of nephrin and synaptopodin. Meanwhile, C-peptide suppressed high glucose-induced epithelial-mesenchymal transition (EMT) and renal fibrosis via decreasing the expression of snail, vimentin, α-smooth muscle actin (α-SMA) and connective tissue growth factor (CTGF). Moreover, the Notch and transforming growth factor-β (TGF-β) signaling pathways were activated by high glucose, and treatment with C-peptide down-regulated the expression of the Notch signaling molecules Notch 1 and Jagged 1 and the TGF-β signaling molecule TGF-β1. These findings suggested that C-peptide might serve as a novel treatment method for DN and podocyte dysfunction.

The repair capacity of progenitor skeletal muscle satellite cells (SC) in Type 1 diabetes mellitus (T1DM) is decreased. This is associated with the loss of skeletal muscle function. In T1DM, the deficiency of C-peptide along with insulin is associated with an impairment of skeletal muscle functions such as growth, and repair, and is thought to be an important contributor to increased morbidity and mortality. Recently, cholesterol-lowering drugs (statins) have also been reported to increase the risk of skeletal muscle dysfunction. We hypothesised that C-peptide activates key signaling pathways in myoblasts, thus promoting cell survival and protecting against simvastatin-induced myotoxicity. This was tested by investigating the effects of C-peptide on the L6 rat myoblast cell line under serum-starved conditions. Results: C-peptide at concentrations as low as 0.03 nM exerted stimulatory effects on intracellular signaling pathways-MAP kinase (ERK1/2) and Akt. When apoptosis was induced by simvastatin, 3 nM C-peptide potently suppressed the apoptotic effect through a pertussis toxin-sensitive pathway. Simvastatin strongly impaired Akt signaling and stimulated the reactive oxygen species (ROS) production; suggesting that Akt signaling and oxidative stress are important factors in statin-induced apoptosis in L6 myoblasts. The findings indicate that C-peptide exerts an important protective effect against death signaling in myoblasts. Therefore, in T1DM, the deficiency of C-peptide may contribute to myopathy by rendering myoblast-like progenitor cells (involved in muscle regeneration) more susceptible to the toxic effects of insults such as simvastatin.

Diabetic polyneuropathy (DPN) occurs more frequently in type 1 diabetes resulting in a more severe DPN. The differences in DPN between the two types of diabetes are due to differences in the availability of insulin and C-peptide. Insulin and C-peptide provide gene regulatory effects on neurotrophic factors with effects on axonal cytoskeletal proteins and nerve fiber integrity. A significant abnormality in type 1 DPN is nodal degeneration. In the type 1 BB/Wor-rat, C-peptide replacement corrects metabolic abnormalities ameliorating the acute nerve conduction defect. It corrects abnormalities of neurotrophic factors and the expression of neuroskeletal proteins with improvements of axonal size and function. C-peptide corrects the expression of nodal adhesive molecules with prevention and repair of the functionally significant nodal degeneration. Cognitive dysfunction is a recognized complication of type 1 diabetes, and is associated with impaired neurotrophic support and apoptotic neuronal loss. C-peptide prevents hippocampal apoptosis and cognitive deficits. It is therefore clear that substitution of C-peptide in type 1 diabetes has a multitude of effects on DPN and cognitive dysfunction. Here the effects of C-peptide replenishment will be extensively described as they pertain to DPN and diabetic encephalopathy, underpinning its beneficial effects on neurological complications in type 1 diabetes.