Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity

Abstract

Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium that are associated with diabetes and cardiovascular disease, including changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. Hyperglycemia is a characteristic feature of type 1 and type 2 diabetes and plays a pivotal role in diabetesassociated microvascular complications. Although hyperglycemia also contributes to the occurrence and progression of macrovascular disease (the major cause of death in type 2 diabetes), other factors such as dyslipidemia, hyperinsulinemia, and adipose-tissue-derived factors play a more dominant role. A mutual interaction between these factors and endothelial dysfunction occurs during the progression of the disease. We pay special attention to the possible involvement of endoplasmic reticulum stress (ER stress) and the role of obesity and adipose-derived adipokines as contributors to endothelial dysfunction in type 2 diabetes. The close interaction of adipocytes of perivascular adipose tissue with arteries and arterioles facilitates the exposure of their endothelial cells to adipokines, particularly if inflammation activates the adipose tissue, and thus affects vasoregulation and capillary recruitment in skeletal muscle. Hence, an initial dysfunction of endothelial cells underlies metabolic and vascular alterations that contribute to the development of type 2 diabetes.

Relationship between adipocytokines and cardiovascular risk factors in patients with type 2 diabetes mellitus

“…The rising incidence of T2DM has resulted in CVD becoming the leading cause of morbidity and mortality worldwide (1). This increased risk of CVD is due to a complex cluster of risk factors associated with T2DM including insulin resistance, hyperglycemia, diabetic dyslipidemia, hypertension, hyperinsulinemia, systemic inflammation and adipose tissue-derived factors (2). Changes in the mass and metabolism of adipose tissue may be related to insulin resistance and visceral obesity commonly associated with T2DM (3).…”

“…Furthermore, decreased adiponectin levels were found to be associated with a higher incidence of T2DM (5). Leptin is the first identified endocrine product of adipose tissue and was found to regulate vascular function through local and central mechanisms (2). The primary role of leptin is to provide a signal to the central nervous system concerning the balance of body energy, which helps to control appetite and food intake, and to maintain stable body weight.…”

Reduction of both number and proliferative activity of human endothelial progenitor cells in obesity

“…Not only could adipose-tissue-derived mediators add to vascular dysfunction 2 but also obesity is associated with a number of comorbidities, including hypertension, hyperlipidemia, systemic inflammation and overt diabetes, all of which could trigger endothelial dysfunction. [2][3][4] Endothelial cell loss through damage/apoptosis induced by atherogenic risk factors 5,6 requires replenishment of endothelial cells in the vessel wall. In this process, two mechanisms are likely to be responsible for postnatal vasculogenesis in physiological and pathophysiological neovascularization: (1) an increased mitotic response and turnover of nearby located endothelial cells and/or (2) reendothelialization by the attachment of endothelial progenitor cells (EPCs).…”

“…[2][3][4] Endothelial cell loss through damage/apoptosis induced by atherogenic risk factors 5,6 requires replenishment of endothelial cells in the vessel wall. In this process, two mechanisms are likely to be responsible for postnatal vasculogenesis in physiological and pathophysiological neovascularization: (1) an increased mitotic response and turnover of nearby located endothelial cells and/or (2) reendothelialization by the attachment of endothelial progenitor cells (EPCs). 7 This cell type was first identified about a decade ago, 8 has been shown to circulate in human peripheral blood and expresses both progenitor and endothelial marker proteins.…”

Inflammation and Genetics of Inflammation in Cardiovascular Diseases

“…So, endothelial dysfunction (ED) initiated by both infectious and non-infectious processes (e.g. metabolic syndromeMetS) is now recognized to play a critical role in the initiation and progression of atherosclerotic vascular disease (Al-Quasi et al, 2008;Bakker et al, 2009;Lamon & Hajjar, 2008). CRP, which levels raise during inflammation contributes to the induction of endothelial cell activation and dysfunction (Deveraj et al, 2010;Grad et al, 2007;Schwartz et al, 2007;Teoh et al, 2008;Venogupal et al, 2003).…”