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.
Highlights
Diabetes mellitus (DM), a chronic metabolic disease affecting the homeostasis of blood glucose levels, remains an increasing health problem both in developing and developed countries [1,2,3]
Additional factors that play an important role in the setting up of type 2 diabetes mellitus (T2DM) include the chronic hyperglycemia itself and obesity which is recognised as a risk factor for the insulin resistance development and T2DM
It is known that nitric oxide (NO) production dependent of eNOS stimulates vasodilation, but the overproduction of O2− withdraw the accessible NO, enhancing the development of intracellular ONOO− as well as nitrotyrosine in diabetic vasculopathy [95,96]. with the correlation between hyperglycemic memory (HGM) and cardiovascular complications in DM is very well known; in order to prevent long-term cardiovascular complications associated with diabetes, it is recommended the premature aggressive treatment of glycemic control as well as the supplementation with agents which defend against the generation of intracellular reactive oxygen and nitrogen species [84,97,98]
Summary
Diabetes mellitus (DM), a chronic metabolic disease affecting the homeostasis of blood glucose levels, remains an increasing health problem both in developing and developed countries [1,2,3]. Hormone involved in tissue growth and in recovery after injury, affect angiogenesis through some mechanisms: (i) control of the interaction between endothelium and pericytes; (ii) endothelial cell migration and proliferation ( in microcirculation); (iii) synthesis of pro-angiogenic. Sci. 2020, 21, 645 factors such as VEGF and angiotensin (Ang) and (iv) regulation of tissue metabolism, which affects endothelial cell survival These effects are well explained in the literature, but the underling signalling pathways have not yet been fully described. In endothelial cells and pericytes functional expression of IR-A and IR-B was described, triggering intracellular signalling (PI3K and MAPK pathways) and activation of phosphorylation cascades, producing pro-angiogenic factors (VEGF and Ang) which results in modulation of cell migration and proliferation, in vitro angiogenesis, endothelial differentiation and survival. In T2DM patients under glycemic control (in particular, when using insulin analogues), the epidemiological analyses have shown enhanced risk of developing cancer in breast, kidney, colon, prostate and pancreas [34]
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