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

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.