**1. Introduction**

The significance of hyperglycemia-induced endothelial damage is underlined by its pathogenic role in diabetes complications and the associated costs of diabetes management. The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014 with a steep increase over the age of 50, reaching the peak prevalence of

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25% above 80 years of age [1, 2]. The (direct and indirect) medical costs for patients with diabetes are double the amount compared to expenses for nondiabetic individuals and three times higher in case of cardiovascular diseases such as myocardial infarction or stroke [3]. Currently, diabetes-related healthcare expenditure accounts for 10% of the total healthcare costs and it is estimated to increase by 70% over the next 25 years leading to a serious societal and economic burden [4]. Diabetes complications are responsible for the majority of the associated costs and excess costs gradually increase with the duration of the disease leading to substantially higher expenses after 8–10 years [3, 5]. Hyperglycemia-induced endothelial dysfunction is the major contributor to the development of vascular disease in diabetes mellitus [6]. While insulin resistance may be present in patients with no increase in plasma glucose level and it may contribute to endothelial dysfunction, the major pathway that is responsible for endothelial damage is glucose-induced oxidative stress in diabetes [6, 7].

oxygen consumption and reactive oxygen species (ROS) production in the cells. Still, hyperglycemia is associated with the activation of various ROS-producing pathways and increased oxidant production in endothelial cells [15, 16]. Oxidants play a significant role in the destruction of nitric oxide and other signaling molecules and result in impaired vasoreactivity [10, 17, 18]. Inflammatory pathways may be implicated in the early stages of the injury and they are typically involved in the later stages of the disease and contribute to oxidant production and inflammatory cytokine secretion, which can also change the vascular function [19]. Oxidative stress also induces DNA damage that triggers endothelial cell senescence that might have an impact on vascular function in the later stages of the injury [20]. There are approximately 2–10 trillion (2–10 × 1012) endothelial cells in the human body and they form the endothelial

stem cells (located in the vessel wall) take part in the repair processes but also circulating progenitor cells that arise from the bone marrow are involved in the process [22]. In diabetes, endothelial cell turnover is impaired and it might be a consequence of accelerated aging or reduced renewal of cells [24, 25]. While ROS-mediated injury dominates in the earlier stages of hyperglycemia-induced damage, cell senescence and impairment of endothelial cell turn-

Hyperglycemia induces damage in a select cell population in the body, including mainly the mesangial cells in the kidney, neurons and Schwann cells in peripheral nerves and a subset of endothelial cells: only the microvascular and the arterial endothelial cells show impairment [26]. Interestingly, this dichotomy in the vulnerability is often preserved in *in vitro* experiments: microvascular endothelial cells are more susceptible to glucose-induced injury, whereas venous endothelial cells show reduced oxidant production and damage. This suggests that differences in the pressure, blood flow or vessel function in various parts of the circulation may not be accounted for the susceptibility. It is rather an inherent difference between the cells that explain the vulnerability of the microvasculature [27]. There are differences in the protein and RNA expression patterns, including the miRNA expression profiles, and the different responses of microvascular and macrovascular endothelial cells to various

Differences in glucose uptake may be partially responsible for the susceptibility: most cells tightly regulate the glucose transport rate and prevent the unrestricted uptake, but endothelial and mesangial cells are unable to decrease the transport rate [29, 30]. Glucose overload induces a gradual increase in the mitochondrial membrane potential and the elevated protonic potential increases the superoxide generation by the respiratory chain [31]. The mitochondrial membrane potential is regulated by uncoupling proteins in the cells: these channels release excess protons from the intermembrane space to the matrix and protect against mitochondrial hyperpolarization. Endothelial cells express uncoupling protein 2 (UCP2) and its transport capacity is controlled by oxidative stress: high levels of oxidants open the channel, whereas the absence of oxidants closes the channel [32, 33]. In venous endothelial cells, hyperglycemia upregulates the expression of UCP2 and it effectively protects against mitochondrial

of blood vessels and require constant renewal [21–23]. Mostly, the resident

Hyperglycemia-Induced Endothelial Dysfunction http://dx.doi.org/10.5772/intechopen.71433 181

surface of 500 m2

over may play the leading part in the later stages.

metabolic stimuli may be attributed to this difference [28].

**2.2. Target cells of hyperglycemia**
