Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection

Abstract

A major hallmark of diabetes is a constant high blood glucose level (hyperglycaemia), resulting in endothelial dysfunction. Transient or prolonged hyperglycemia can cause diabetic vasculopathy, a secondary systemic damage. C-Peptide is a product of cleavage of proinsulin by a serine protease that occurs within the pancreatic β-cells, being secreted in similar amounts as insulin. The biological activity of human C-peptide is instrumental in the prevention of diabetic neuropathy, nephropathy and other vascular complications. The main feature of type 1 diabetes mellitus is the lack of insulin and of C-peptide, but the progressive β-cell loss is also observed in later stage of type 2 diabetes mellitus. C-peptide has multifaceted effects in animals and diabetic patients due to the activation of multiple cell signalling pathways, highlighting p38 mitogen-activated protein kinase and extracellular signal–regulated kinase ½, Akt, as well as endothelial nitric oxide production. Recent works highlight the role of C-peptide in the prevention and amelioration of diabetes and also in organ-specific complications. Benefits of C-peptide in microangiopathy and vasculopathy have been shown through conservation of vascular function, and also in the prevention of endothelial cell death, microvascular permeability, neointima formation, and in vascular inflammation. Improvement of microvascular blood flow by replacing a physiological amount of C-peptide, in several tissues of diabetic animals and humans, mainly in nerve tissue, myocardium, skeletal muscle, and kidney has been described. A review of the multiple cell signalling pathways of human proinsulin C-peptide in vasculopathy protection is proposed, where the approaches to move beyond the state of the art in the development of innovative and effective therapeutic options of diabetic neuropathy and nephropathy are discussed.

Correlation between Glucose/C-Peptide Ratio and the Risk of Disease Progression in Diabetic Nephropathy Patients: A Clinical Retrospective Analysis

“…Serum cystatin C is a small molecule protein, and its production rate is not affected by age, inflammation, or medicines. Serum cystatin C is relatively constant, can almost be filtered from the glomerulus, is completely reabsorbed, and degraded by renal tubular epithelial cells, but cannot return to the blood [ 15 , 16 ]. Renal tubular epithelial cells do not secrete serum cystatin C into the lumen [ 17 , 18 ].…”

Hot Spots for the Use of Intranasal Insulin: Cerebral Ischemia, Brain Injury, Diabetes Mellitus, Endocrine Disorders and Postoperative Delirium

“…One of the promising approaches for the correction of brain functions in DM and MS is the combined use of INI with intranasally administered proinsulin C-peptide (ICP). C-peptide, synthesized in pancreatic beta cells from proinsulin, is the most important regulator of the nervous, cardiovascular, endocrine, and other systems [ 303 , 304 , 305 ]. The main mechanism of C-peptide action is considered to be its ability to form hetero-oligomeric complexes with insulin, which increases insulin bioavailability and potentiates its stimulatory effects on the insulin signaling system [ 306 , 307 , 308 ].…”

Molecular Mechanisms of the Vicious Cycle between Insulin Resistance and the Inflammatory Response in Obesity

“…Although it does not participate in the regulation of glucose levels, C-peptide might play a role in preventing and potentially reversing some of the chronic complications of diabetes, including vascular and nervous damage [30,31]. It remains an open question whether these activities related to the therapeutic potential of C-peptide are mediated by the receptor, the existence of which is still uncertain, or whether an alternative nonreceptor-mediated mechanism is involved [32,33].…”