{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T21:57:07Z","timestamp":1776376627432,"version":"3.51.2"},"reference-count":138,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,1,18]],"date-time":"2020-01-18T00:00:00Z","timestamp":1579305600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":":","award":["Nutraceutica come supporto nutrizionale nel paziente oncologico, CUP: B83D18000140007"],"award-info":[{"award-number":["Nutraceutica come supporto nutrizionale nel paziente oncologico, CUP: B83D18000140007"]}]},{"name":"Portuguese Science and Technology Foundation (FCT\/MCT) and European Funds (PRODER\/COMPETE)","award":["M-ERA-NET\/0004\/2015-PAIRED and UID\/QUI\/50006\/2013, co-financed by FEDER, under the Partnership Agreement PT2020"],"award-info":[{"award-number":["M-ERA-NET\/0004\/2015-PAIRED and UID\/QUI\/50006\/2013, co-financed by FEDER, under the Partnership Agreement PT2020"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u03b2-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 \u03b2-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\u2013regulated kinase \u00bd, 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.<\/jats:p>","DOI":"10.3390\/ijms21020645","type":"journal-article","created":{"date-parts":[[2020,1,20]],"date-time":"2020-01-20T04:27:09Z","timestamp":1579494429000},"page":"645","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Multiple Cell Signalling Pathways of Human Proinsulin C-Peptide in Vasculopathy Protection"],"prefix":"10.3390","volume":"21","author":[{"given":"Selma B.","family":"Souto","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Hospital de S\u00e3o Jo\u00e3o, Alameda Prof. Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9245-949X","authenticated-orcid":false,"given":"Joana R.","family":"Campos","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P\u00f3lo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra, Portugal"}]},{"given":"Joana F.","family":"Fangueiro","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P\u00f3lo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7524-9914","authenticated-orcid":false,"given":"Am\u00e9lia M.","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Biology and Environment, University of Tr\u00e1s-os-Montes e Alto Douro, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal"},{"name":"Centre for Research and Technology of Agro-Environmental and Biological Sciences, CITAB, UTAD, Quinta de Prados, P-5001-801 Vila Real, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8055-1915","authenticated-orcid":false,"given":"Nicola","family":"Cicero","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze biomediche, odontoiatriche e delle immagini morfologiche e funzionali, Universit\u00e0 degli Studi di Messina, Polo Universitario Annunziata, 98168 Messina, Italy"}]},{"given":"Massimo","family":"Lucarini","sequence":"additional","affiliation":[{"name":"CREA\u2014Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Rome, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7747-9107","authenticated-orcid":false,"given":"Alessandra","family":"Durazzo","sequence":"additional","affiliation":[{"name":"CREA\u2014Research Centre for Food and Nutrition, Via Ardeatina 546, 00178 Rome, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5505-3327","authenticated-orcid":false,"given":"Antonello","family":"Santini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9737-6017","authenticated-orcid":false,"given":"Eliana B.","family":"Souto","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra (FFUC), P\u00f3lo das Ci\u00eancias da Sa\u00fade, 3000-548 Coimbra, Portugal"},{"name":"CEB\u2014Centre of Biological Engineering, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Vieira, R., Souto, S.B., Sanchez-Lopez, E., Machado, A.L., Severino, P., Jose, S., Santini, A., Silva, A.M., Fortuna, A., and Garcia, M.L. (2019). Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome-Strategies for In Vivo Administration: Part-II. J. Clin. 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