The endothelial border to health: Mechanistic evidence of the hyperglycemic culprit of inflammatory disease acceleration

Abstract

The endothelial cell (EC) layer constitutes a barrier that controls movements of fluid, solutes and cells between blood and tissue. Further, the endothelial layer regulates vascular tone and directs local humoral and cellular inflammatory processes. The strategic position makes it an important player for maintenance of health and for development of a number of diseases. Endothelial dysfunction is known to be an important component of type 2 diabetes, but is also assumed to be involved in many other diseases, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and cardiovascular diseases. We here suggest that the EC plays a pivotal role in disease pathophysiology through initiation, potentiation, and maintenance of several inflammatory mechanisms. Our contention is based on the observation that hyperglycemia-intermittent or sustained, local or systemic-is a major culprit for several endothelial dysfunctions. There is also mounting epidemiological evidence that dietary intake of refined sugars is important for the development of a number of diseases beyond obesity and type 2 diabetes. Various diseases involving inflammatory and immunological components are accelerated by hyperglycemic events because the endothelium transduces "high glucose" signaling into significant pathophysiological phenomena leading to reduced endothelial barrier function, compromised vascular tone regulation and inflammation (e.g., cytokine secretion and RAGE activation). In addition, endothelial extracellular proteins form epitopes for potential specific antibody formation upon interactions with reducing sugars. This paper reviews the endothelial metabolism, biology, inflammatory processes, physical barrier functions, and summarizes evidence that although stochastic in nature, endothelial responses to hyperglycemia are major contributors to disease pathophysiology. We present molecular and mechanistic evidence that both biological and physical barriers, protein function, specific immunity, and inflammatory processes are compromised by hyperglycemic events and thus, hyperglycemic events alone should be considered risk factors for numerous human diseases. © 2017 IUBMB Life, 69(3):148-161, 2017.

Integrated hypothesis of dental caries and periodontal diseases

“…It is well known that hyperglycaemia in diabetes causes inflammatory damage to human tissues, in particular the capillary endothelial cells [for review, 96,97]. The reason why endothelial cells are particularly vulnerable to hyperglycaemia is that these cells are defective in transporting glucose over the cell membrane, which leads to toxic concentrations of glucose inside the cell.…”

Postprandial Triglycerides, Oxidative Stress, and Inflammation

“…Exposure to elevated plasma glucose in patients with type 2 diabetes mellitus is associated with both an increased level of ROS and a drop in cell antioxidant defense, enzymatic as well as non-enzymatic [4,5]. In addition to serving as a barrier to control movements of fluid, solutes and cells between blood and tissue, the endothelial layer also play a key role in regulating vascular tone and inflammatory processes [40]. While the impact of hyperglycemia on endothelial cell metabolism is beyond the scope of this presentation it should be noted that, at normal fasting plasma glucose concentrations (4-6 mM, 72-108 mg/dL), the glucose transporter GLUT-1 is already functioning at saturation level [41].…”

Endothelial Dysfunction in Type 2 Diabetes: Targeting Inflammation

“…In diabetes, hyperglycemia can induce inflammation via different mechanisms [42]. The metabolic defects underlying diabetes cause mitochondrial superoxide overproduction in endothelial cells of blood vessels.…”