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Review

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

1
Department of Endocrinology, Hospital de São João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
2
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), Pólo das Ciências da Saúde, 3000-548 Coimbra, Portugal
3
Department of Biology and Environment, University of Trás-os-Montes e Alto Douro, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal
4
Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal
5
Dipartimento di Scienze biomediche, odontoiatriche e delle immagini morfologiche e funzionali, Università degli Studi di Messina, Polo Universitario Annunziata, 98168 Messina, Italy
6
CREA—Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Rome, Italy
7
Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy
8
CEB—Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(2), 645; https://doi.org/10.3390/ijms21020645
Submission received: 18 November 2019 / Revised: 15 January 2020 / Accepted: 16 January 2020 / Published: 18 January 2020

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.
Keywords: diabetes mellitus; C-peptide; vasculopathy; diabetic neuropathy; diabetic nephropathy diabetes mellitus; C-peptide; vasculopathy; diabetic neuropathy; diabetic nephropathy

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MDPI and ACS Style

Souto, S.B.; Campos, J.R.; Fangueiro, J.F.; Silva, A.M.; Cicero, N.; Lucarini, M.; Durazzo, A.; Santini, A.; Souto, E.B. Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection. Int. J. Mol. Sci. 2020, 21, 645. https://doi.org/10.3390/ijms21020645

AMA Style

Souto SB, Campos JR, Fangueiro JF, Silva AM, Cicero N, Lucarini M, Durazzo A, Santini A, Souto EB. Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection. International Journal of Molecular Sciences. 2020; 21(2):645. https://doi.org/10.3390/ijms21020645

Chicago/Turabian Style

Souto, Selma B., Joana R. Campos, Joana F. Fangueiro, Amélia M. Silva, Nicola Cicero, Massimo Lucarini, Alessandra Durazzo, Antonello Santini, and Eliana B. Souto. 2020. "Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection" International Journal of Molecular Sciences 21, no. 2: 645. https://doi.org/10.3390/ijms21020645

APA Style

Souto, S. B., Campos, J. R., Fangueiro, J. F., Silva, A. M., Cicero, N., Lucarini, M., Durazzo, A., Santini, A., & Souto, E. B. (2020). Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection. International Journal of Molecular Sciences, 21(2), 645. https://doi.org/10.3390/ijms21020645

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