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The role of GLUT1 in the endothelium

Boek - Dissertatie

Maintenance of optimal blood glucose concentration to support optimal functioning of all tissues in the human body is a vital metabolic featureof the organism. Glucose levels that are too high lead to insulin resistance (Saltiel and Kahn, 2001), whereas hypoglycemia threatens brain function and can induce loss of consciousness (Mergenthaler et al., 2013). Regulation of glycemia is dependent on the secretion of hormones, mainlyinsulin and glucagon, which either promote the storage of excessive glucose in muscle and liver, either stimulate its release by these organs. Although this suffices to keep whole body glucose levels constant, this process takes minutes and seems to be too slow and too systemic to allowa fast adaptation to small and local changes in glucose.Glucose is transported throughout the body via an ingenious network of blood vessels - formed by nicely aligned endothelial cells (ECs). The surface of this cell layer, each cell being in direct contact with the blood, can reach up till 350m2 (Pries et al., 2000). Their function is to regulate blood flow, to provide a barrier between the blood and the surrounding tissue, and to allow oxygentransport. It was generally assumed that these ECs passively allow the passage of nutrients to hungry tissues and are not involved in metabolic control. Only very recently, people have shown that ECs can actively control endothelial-to-tissue lipid transport by a mechanism involving VEGFB-mediated induction of FATP lipid transporters (Carmeliet et al., 2012; Hagberg et al.,2010), but it is still under debate whether the same holds true for glucose transport (De Bock et al., 2013a). Clearly, the vessel wall is an important target for insulin action, and it determines the availability of insulin in the interstitium thereby acting as a rate-limiting step for insulin-stimulated glucose uptake by the muscle (Barrett and Liu, 2013; Kubota et al., 2011). Nevertheless, nobody has ever considered the idea that - because of its privileged location next to the blood stream and becauseof its extended surface area that reaches up till the most distal and hidden places in the body - the endothelium could potentially represent a glucose sensing organ that actively controls glucose levels. This project aims to explore the novel concept that ECs act as nutrient sensors. These sensorsshould be able to adequately DETECT small and local perturbations in blood glucose concentrations and are able to adequately RESTORE euglycemia by releasing the glucose they have stored inside.
Jaar van publicatie:2019
Toegankelijkheid:Closed