Human C-peptide is a ligand of the elastin-receptor-complex and therewith central to human vascular remodelling and disease in metabolic syndrome

Abstract

This hypothesis ties together various causal risk factors from our “Western-lifestyle” (elevated blood-glucose, smoking, processed red-meat-products, obesity, and inflammation) in a unifying perspective on the cause of human vascular disease in metabolic syndrome.When, in response to enhanced blood-glucose levels, insulin is excreted, it is always excreted together with C-peptide. I identified an elastin-receptor-complex (ERC) binding amino-acid motif xGxxPG in C-peptide and pose that C-peptide’s earlier unknown receptor is this ERC. This receptor is involved in vascular remodelling, commonly activated by vascular-lesion-derived elastin-peptides with said motif xGxxPG. Systemic elastin-peptides may arise from smoking or from consuming elastin-rich processed red-meat-products, therewith interfering with vascular remodelling. Both excess elastin-peptides as well as excess C-peptide associate with core-manifestations of metabolic syndrome: insulin resistance, angiogenesis, and vascular remodelling. C-peptide fragments as well as elastin peptide-fragments with motif xGxxPG are angiogenic and blocked by antagonists of ERC. Many other bioactive peptides with an xGxxPG motif exist, a third example discussed here is galectin-3, elevated in obesity and inflammation, and again associated with insulin resistance, angiogenesis, and vascular remodelling in metabolic syndrome.On the one side of this hypothesis, a lack of ERC-mediated vascular remodelling through a lack of C-peptide is central to microvascular disease in T1D. On the other side, excess ERC-activity through excess activation (by systemic C-peptide, elastin-peptide, galectin-3, or others), is centrally involved in metabolic syndrome and T2D, inducing insulin resistance with excess and maladaptive macrovascular remodelling. Systemic C-peptide is increased in a “Western-diet” lifestyle, systemic elastin peptides are increased after smoking and possibly after elastin-consumption, and systemic galectin-3 increases in chronic inflammation and obesity. As all these risk-factors associate with life-style mediated metabolic syndrome, this hypothesis poses one up-stream cause: excess activation of ERC stands central in causing metabolic syndrome.