C-peptide in diabetes: A player in a dual hormone disorder?
Ali DakroubAli DboukAref AsfourSuzanne A NasserAhmed F El-YazbiAmir Hossein SahebkarAssaad A EidRabah IratniAli Hussein EidPublished in: Journal of cellular physiology (2024)
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.
Keyphrases
- protein kinase
- signaling pathway
- nuclear factor
- glycemic control
- growth factor
- type diabetes
- oxidative stress
- coronary artery disease
- endothelial cells
- vascular smooth muscle cells
- cardiovascular disease
- reactive oxygen species
- poor prognosis
- tyrosine kinase
- insulin resistance
- anti inflammatory
- magnetic resonance
- toll like receptor
- adipose tissue
- heart failure
- magnetic resonance imaging
- cell proliferation
- high glucose
- escherichia coli
- atrial fibrillation
- staphylococcus aureus
- skeletal muscle
- biofilm formation
- cardiovascular events
- computed tomography
- mouse model
- angiotensin ii
- candida albicans