The link between metabolic abnormalities and endothelial dysfunction in type 2 diabetes: an update

Abstract

Despite abundant clinical evidence linking metabolic abnormalities to diabetic vasculopathy, the molecular basis of individual susceptibility to diabetic vascular complications is still largely undetermined. Endothelial dysfunction in diabetes-associated vascular complications is considered an early stage of vasculopathy and has attracted considerable research interests. Type 2 diabetes is characterized by metabolic abnormalities, such as hyperglycemia, excess liberation of free fatty acids (FFA), insulin resistance and hyperinsulinemia. These abnormalities exert pathological impact on endothelial function by attenuating endothelium-mediated vasomotor function, enhancing endothelial apoptosis, stimulating endothelium activation/endothelium-monocyte adhesion, promoting an atherogenic response and suppressing barrier function. There are multiple signaling pathways contributing to the adverse effects of glucotoxicity on endothelial function. Insulin maintains the normal balance for release of several factors with vasoactive properties. Abnormal insulin signaling in the endothelium does not affect the whole-body glucose metabolism, but impairs endothelial response to insulin and accelerates atherosclerosis. Excessive level of FFA is implicated in the pathogenesis of insulin resistance. FFA induces endothelial oxidative stress, apoptosis and inflammatory response, and inhibits insulin signaling. Although hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia independently contribute to endothelial dysfunction via various distinct mechanisms, the mutual interactions may synergistically accelerate their adverse effects. Oxidative stress and inflammation are predicted to be among the first alterations which may trigger other downstream mediators in diabetes associated with endothelial dysfunction. These mechanisms may provide insights into potential therapeutic targets that can delay or reverse diabetic vasculopathy.

Fig. 1

The impact of hyperglycemia on endothelial dysfunction. Hyperglycemia causes an increase in toxic metabolites resulting in increased production of ROS, advanced glycation end products (AGE), production of sorbitol and stimulation of protein kinase C (PKC). Activation of these pathways promotes increased vascular oxidative stress, inflammation, apoptosis, atherogenesis and impaired endothelial function. See text for details. AGE advanced glycation end products, COX-2 cyclooxygenase-2, ECE endothelin converting enzyme, ET-1 endothelin-1, LOX-1 lectin-like oxLDL receptor-1, MMP matrix metalloproteinase, NO nitric oxide, Nrf2 transcription factor NF-E2-related factor-2, PKC protein kinase C, RAGE receptor of AGE, ROS reactive oxygen species, SHP-1 Src homology-2 domain-containing phosphatase-1, TLR4 toll-like receptor 4, TXA₂ thromboxane A₂, TXNIP thioredoxin-interacting protein

Fig. 2

Role of insulin resistance in endothelial dysfunction. Insulin regulates endothelial function through both Ras-MAPK and PI3K-Akt-eNOS signaling pathways to maintain the balance between production of vasodilator mechanisms and vasoconstrictor mechanisms. Akt protein kinase B, eNOS endothelial nitric oxide synthase, GSK3β glycogen synthase kinase-3beta, IRS-1 insulin receptor substrate-1, MAPK mitogen-activated protein kinase, PDK-1 phophoinositide-dependent protein kinase-1, PTEN phosphatase and tensin homolog, Ras rat sarcoma

Fig. 3

Role of free fatty acids in endothelial dysfunction. Free fatty acids (FFA) stimulate endothelial apoptosis, augment vascular oxidative stress, reduce NO availability, enhance endothelial and monocyte activation and increase inflammatory responses. CRP C-reactive protein, ICAM-1 intercellular adhesion molecule-1, IκBα inhibitory subunit of NFκB, IKKβ IκB kinase-β, NFκB nuclear factor-kappa B, sE-selectin soluble E-selectin, VCAM-1 vascular cell adhesion molecule-1