Glucose sensing and uptake in the brain

Abstract

Event Abstract Back to Event Glucose sensing and uptake in the brain Shlomo Sasson1* 1 Hebrew University, Department of Pharmacology, Institute of Drug Research, School of Pharmacy, Faculty of Medicine, Israel Glucose is the main metabolic fuel of the central nervous system and its transport across the blood-brain barrier (BBB) and in neural cells is mediated by glucose transporters. The main glucose transporter in the endothelial cells in brain blood vessels and capillaries is GLUT-1, whereas both GLUT-1 and GLUT-3 are expressed in neural cells. Under normal glycemic conditions the rate of glucose transport across the BBB meets the metabolic requirements of the brain. However, mild hypoglycemic conditions lead to over-expression and increased abundance of GLUT-1 protein both on the lumen and basolateral membranes of the capillary endothelial cells enabling an efficient extraction of glucose to the deprived brain. In contrast, sustained hyperglycemia evokes the opposite response. The content and plasma membrane abundance of GLUT-1 in endothelial cells of brain blood capillaries is significantly reduced and the capacity of the cells to transport glucose to the brain is controlled. This mechanism protects the central nervous system from deleterious effects of hyperglycemia. The following two figures show the glucose-dependent and time-course of the autoregulatory response of cultured endothelial cells to varying glucose concentrations in the cultures medium. The physiological and pathophysiological role of this mechanism will be discussed. In the second part of the presentation another aspect of the gluco-sensing mechanism of the brain will be discussed: careful examination of the expression pattern of glucose transporters in various areas on the brain vasculature reveals a predominate expression of GLUT-2 in circumventricular areas. Unlike GLUT-1 or GLUT-3 that exhibit low Km for D-glucose (2-5 mM), the GLUT-2's Km value is above 20 mM. These kinetic properties of GLUT-2 allow free diffusion of glucose through the cells in a direct proportion to the concentration of the ambient glucose. Moreover, unlike GLUT-1, this transporter is not subjected to the glucose-dependent autoregulation. The physiological significance of GLUT-2 expression in circumventricular areas in the regulation of food intake and weight gain was revealed upon silencing of this transporter intracerebroventricularly in rats. The food intake and cumulative body weight gain in these animal was significantly lower than in controls rats. It is therefore suggested that exposure of centers in circumventricular areas (e.g., ARC) to ambient glucose following its transport via GLUT-2 provide a sensitive sensing mechanism to glycemic changes, which leads to autonomic efferent signals towards insulin-producing β-cells in Islets of Langerhans in the pancreas and other organs involved in energy balance. It is also suggested that these centers control the expression of hypothalamic orexigenic and anorexigenic peptides. GLUT