C-peptide in diabetes: A player in a dual hormone disorder?

Dakroub, Ali; Dbouk, Ali; Asfour, Aref; Nasser, Suzanne A.; El‐Yazbi, Ahmed F.; Sahebkar, Amirhossein; Eid, Assaad A.; Iratni, Rabah; Eid, Ali H; Nasser, Suzanne A; El-Yazbi, Ahmed F; Eid, Assaad A

Abstract

C-peptide, a byproduct of insulin synthesis believed to be biologically inert, is emerging as a multifunctional molecule. C-peptide serves an anti-inflammatory and anti-atherogenic role in type 1 diabetes mellitus (T1DM) and early T2DM. C-peptide protects endothelial cells by activating AMP-activated protein kinase α, thus suppressing the activity of NAD(P)H oxidase activity and reducing reactive oxygen species (ROS) generation. It also prevents apoptosis by regulating hyperglycemia-induced p53 upregulation and mitochondrial adaptor p66shc overactivation, as well as reducing caspase-3 activity and promoting expression of B-cell lymphoma-2. Additionally, C-peptide suppresses platelet-derived growth factor (PDGF)-beta receptor and p44/p42 mitogen-activated protein (MAP) kinase phosphorylation to inhibit vascular smooth muscle cells (VSMC) proliferation. It also diminishes leukocyte adhesion by virtue of its capacity to abolish nuclear factor kappa B (NF-kB) signaling, a major pro-inflammatory cascade. Consequently, it is envisaged that supplementation of C-peptide in T1DM might ameliorate or even prevent end-organ damage. In marked contrast, C-peptide increases monocyte recruitment and migration through phosphoinositide 3-kinase (PI-3 kinase)-mediated pathways, induces lipid accumulation via peroxisome proliferator-activated receptor γ upregulation, and stimulates VSMC proliferation and CD4 lymphocyte migration through Src-kinase and PI-3K dependent pathways. Thus, it promotes atherosclerosis and microvascular damage in late T2DM. Indeed, C-peptide is now contemplated as a potential biomarker for insulin resistance in T2DM and linked to increased coronary artery disease risk. This shift in the understanding of the pathophysiology of diabetes from being a single hormone deficiency to a dual hormone disorder warrants a careful consideration of the role of C-peptide as a unique molecule with promising diagnostic, prognostic, and therapeutic applications. [Abstract copyright: © 2024 Wiley Periodicals LLC.]

Citation

Dakroub, A., Dbouk, A., Asfour, A., Nasser, S. A., El‐Yazbi, A. F., Sahebkar, A., …Eid, A. A. (in press). C-peptide in diabetes: A player in a dual hormone disorder?. Journal of Cellular Physiology, 10.1002/jcp.31212. https://doi.org/10.1002/jcp.31212

• Journal Article Type: Review
• Acceptance Date: Jan 22, 2024
• Online Publication Date: Feb 3, 2024
• Deposit Date: Feb 20, 2024
• Journal: Journal of cellular physiology
• Print ISSN: 0021-9541
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Pages: 10.1002/jcp.31212
• DOI: https://doi.org/10.1002/jcp.31212
• Keywords: cardiovascular disease, insulin resistance, metabolic disease, atherosclerosis, vascular smooth muscle, cardiovascular disease
• Publisher URL: https://onlinelibrary.wiley.com/doi/10.1002/jcp.31212