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.

Glucose and palmitate uncouple AMPK from autophagy in human aortic endothelial cells

“…Apoptosis is the ultimate endothelial cell dysfunction and has been shown to predispose the vessel to the development of an atherosclerotic plaque (93). To better understand how nutrient-induced impairment of autophagy might contribute to apoptosis, we characterized an earlier indicator of endo- thelial dysfunction, inflammation, in HAECs exposed to excess nutrients.…”

A novel role for small molecule glycomimetics in the protection against lipid-induced endothelial dysfunction: Involvement of Akt/eNOS and Nrf2/ARE signaling

“…Palmitic acid stimulates the production of superoxide radicals through activating NADPH oxidases and downregulation of eNOS [12,13]. Superoxide reacts with NO, forming the potent and versatile oxidant peroxynitrite (ONOO•−) which may oxidize the eNOS cofactor tetrahydrobiopterin or destabilize the eNOS dimer, causing uncoupling of eNOS [29].…”

“…It has been reported that chronic elevations in plasma free fatty acids (FFAs) contribute to the development of endothelial damage, diminished endothelium-dependent vasodilation, and hypertension [9,10] by triggering overproduction of reactive oxygen species (ROS), leading to uncoupling of eNOS [11]. Palmitic acid, the most prominent FFA in the bloodstream, stimulates the production of ROS, at least in part, through activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and down-regulation of eNOS and associated protective pathways, including nuclear factor-erythroid 2-related factor 2 (Nrf2) [12,13]. Decreasing lipotoxicity and its associated oxidative stress, as well as promoting up-regulation of anti-oxidant enzymes and cytoprotective proteins, may be key components to prevent and treat cardiovascular diseases.…”

Blood glucose management in the patient undergoing cardiac surgery: A review

“…Insulin resistance also promotes atherosclerosis by increasing triglycerides, apolipoprotein B, and low-density lipoproteins. In addition, concentrations of very low-density lipoproteins are generated in response to increased synthesis of apolipoprotein B [23] . Coronary events in diabetics result from a prothrombotic state.…”