Invited reviewC-peptide: New findings and therapeutic possibilities
Section snippets
Background
In the course of insulin biosynthesis, discovered in 1967 [1], proinsulin is cleaved into insulin and C-peptide. The two are stored in the secretory granules of the pancreatic beta cells and eventually released to the circulation in equimolar amounts. C-peptide has an important role in facilitating the correct folding of insulin and formation of its disulfide bridges. Following its discovery several attempts were made to detect insulin-like effects of C-peptide. The results were negative and,
Binding of C-peptide to cell membranes
Specific binding of C-peptide to cell membranes has been demonstrated for several different cell types and the binding curve indicates that saturation of binding occurs already at 0.9 nM, which is well within the physiological concentration range [3]. No cross-reactivity has been observed with insulin, proinsulin, NPY, IGF-I or IGF-II. The C-terminal pentapeptide of the native human C-peptide (EGSLQ) has been shown to competitively displace binding of the full-length peptide [3], indicating
Intracellular signaling by C-peptide
Fig. 1 presents a schematic overview of C-peptide signaling. When cells are exposed to C-peptide in physiological concentrations there is a prompt elevation of intra-cellular Ca2+ concentrations [16], [20]. C-peptide also elicits phosphorylation of phospholipase C and several PKC isoforms, notably alpha, delta and epsilon, observed in renal tubular cells and fibroblasts [21], [22], [23]. PI3-K activation has been observed in fibroblasts, myoblasts, renal tubular cells and lymphocytes [23], [24]
Anti-inflammatory effects of C-peptide
Several anti-inflammatory, cytoprotective and anti-apoptotic effects of C-peptide are reported to be activated by C-peptide, as presented in Fig. 2. Thus, C-peptide at physiological concentrations mediates a reduction in the formation of reactive oxygen species (ROS) in endothelial cells of streptozotocin (STZ)-diabetic mice following exposure to stressful conditions. This effect is elicited via RAC-1 mediated inhibition of NAD(P)H oxidase [30], [31], the principal source of ROS generation in
Animal studies
Positive effects of C-peptide on peripheral nerve function have been demonstrated in animal models of type 1 diabetes. In BB/Wor rats, with spontaneous development of type 1-like diabetes, C-peptide administration (homologous C-peptide in replacement dose by continuous subcutaneous infusion) prevented the development of nerve conduction velocity (NCV) deficits when the peptide was given from one week after the onset of diabetes [41]. In addition, C-peptide elicited a marked increase in NCV and
C-peptide and renal dysfunction in type 1 diabetes
Early signs of diabetic nephropathy include glomerular hyperfiltration and onset of glomerular enlargement due to mesangial matrix expansion [52]. Within a few years the structural changes may develop further; glomerular expansion continues and thickening of the basement membrane occurs [53]. Microalbuminuria (30–300 mg/day) is an early sign, frequently in combination with hypertension. Subsequently, the albumin excretion may accelerate and the condition develops into overt diabetic nephropathy
Blood flow and rheology
C-peptide has been found under in vivo conditions to consistently increase blood flow in a number of tissues, in agreement with the in vitro findings that C-peptide activates and induces the expression of eNOS [20], [26]. In type 1 diabetes patients, forearm blood flow, measured by venous occlusion plethysmography, showed a concentration-dependent increase in response to C-peptide infusion in the range 0–1 nM [58]. Forearm vascular dynamics and C-peptide effects have also been studied during
C-peptide and retinopathy in type 1 diabetes
An effect of C-peptide on retinal vascular dysfunction in STZ diabetic rats has been reported following five weeks of C-peptide administration. Extravascular permeation of 125I-labeled albumin in the retina was increased in the diabetic animals and C-peptide administration was found to markedly attenuate the albumin permeation to levels comparable to those in the healthy control animals [45], indicating that C-peptide mediated a reduction of retinal vascular leakage. This finding has been
Role of C-peptide in normal physiology and diabetes—A hypothesis
Considering the anti-oxidant, anti-inflammatory and anti-apoptotic effects that have been documented for C-peptide, it can be speculated that its physiological role may be to prevent or diminish the formation of ROS and other oxidant species that accompany also the modest elevations of blood glucose that result from ingestion of a carbohydrate-rich meal in healthy subjects. In short, C-peptide may be viewed as an endogenous antioxidant, counteracting any ROS generation secondary to the rise in
Conclusion and perspectives
The findings for C-peptide described above presents, contrary to previous views, the picture of an endogenous peptide with biological activity of its own. It is now clear that C-peptide initiates intracellular signaling cascades via interaction with a specific membrane-bound receptor or receptor complex, and that its intracellular effects may result in protection or amelioration of the microvascular complications that result from the chronic hyperglycemia of diabetes, particularly type 1
Conflicts of interest statement
J.W and C.L are employed by Cebix AB, Stockholm. The authors declare no other conflict of interest relevant to this article.
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2023, Journal of Translational AutoimmunityCitation Excerpt :Insulin, and its precursor proinsulin, are important targets of autoimmune responses in T1D [10]. C-peptide is a 31-amino acid peptide that is excised from proinsulin during the biosynthesis of insulin [11]. Our analysis of CD4+ T cells that infiltrated the residual pancreatic islets of deceased organ donors who suffered from T1D revealed that many islet-infiltrating CD4+ T cells were specific for epitopes derived from the C-peptide of proinsulin [7].
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2022, PeptidesCitation Excerpt :The body’s only hypoglycaemic hormone, insulin is derived from a precursor proinsulin, via an enzymatic cleavage, yielding equimolar amounts of insulin and C-peptide. Whereas the primary function of insulin in humans is to regulate the sequestering of the elevated plasma glucose into liver, muscle and adipose tissue, the function of C-peptide within the body is still a matter of speculation [33]. Beyond debate is the utilitarian role of this mysterious post-translational proinsulin product, which has been successfully used as a surrogate to report the portal levels of its ‘non-identical twin’ insulin, - an otherwise very challenging task, given high rates of clearance for insulin by peripheral tissues, such as liver [34,35].
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2021, Current Opinion in Colloid and Interface ScienceCitation Excerpt :Also, all oral formulations have failed to lower the pronounced metabolic effects, and its faster removal from circulation than subcutaneous injections are greater concerns. The insulin currently used in insulin therapy does not contain C-peptide that can result in highly biologically active, monomeric insulin [88]. Also, insulin is 51 amino acids short-lived polypeptide that also require a cold chain for its storage and transport that hamper its access to medication, especially in the development world.