Figure 6

Schematic illustration of the hypothesized effect of metformin on the glycocalyx barrier. The endothelial glycocalyx is considered to form a highly hydrated mesh of polysaccharide structures and adsorbed plasma proteins on the luminal side of all blood vessels. A. Under normal physiological conditions, the structure of the glycocalyx layer is stable and its molecular composition represents a dynamic balance between continued biosynthesis versus shedding of glycans in combination with the absorption and release of plasma proteins. A healthy glycocalyx has been shown to constitute a significant barrier for the circulating blood. While its sieving properties hinder the access of 70 kDa dextrans (Dex70), 40 kDa dextrans (Dex40) appear to have unlimited access to the entire glycocalyx domain. B. The balance between glycocalyx synthesis and breakdown is, however, disrupted in diabetes. This results in an impairment of the barrier properties of the glycocalyx, causing a diminished exclusion of the circulating blood and permeation of Dex70. Reactive oxygen species (ROS) are indicated to be involved in the glycocalyx breakdown. C. Two weeks of metformin treatment is associated with a partial recovery of the diabetes-associated disrupted glycocalyx barrier. While exclusion of circulating plasma is still impaired, the exclusion of Dex70 is significantly increased. As a result, the access of Dex70 into the glycocalyx is hindered and Dex70 stays mainly confined to the circulation. While the mechanisms underlying the glycocalyx improvement by metformin remain to be elucidated, alleviation of oxidative stress is suggested to play a role. Diagrams are not drawn to scale.