Glucose transporters in brain in health and disease

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INVITED REVIEW

Glucose transporters in brain in health and disease Hermann Koepsell 1 Received: 2 July 2020 / Revised: 20 July 2020 / Accepted: 24 July 2020 # The Author(s) 2020

Abstract Energy demand of neurons in brain that is covered by glucose supply from the blood is ensured by glucose transporters in capillaries and brain cells. In brain, the facilitative diffusion glucose transporters GLUT1-6 and GLUT8, and the Na+-D-glucose cotransporters SGLT1 are expressed. The glucose transporters mediate uptake of D-glucose across the blood-brain barrier and delivery of D-glucose to astrocytes and neurons. They are critically involved in regulatory adaptations to varying energy demands in response to differing neuronal activities and glucose supply. In this review, a comprehensive overview about verified and proposed roles of cerebral glucose transporters during health and diseases is presented. Our current knowledge is mainly based on experiments performed in rodents. First, the functional properties of human glucose transporters expressed in brain and their cerebral locations are described. Thereafter, proposed physiological functions of GLUT1, GLUT2, GLUT3, GLUT4, and SGLT1 for energy supply to neurons, glucose sensing, central regulation of glucohomeostasis, and feeding behavior are compiled, and their roles in learning and memory formation are discussed. In addition, diseases are described in which functional changes of cerebral glucose transporters are relevant. These are GLUT1 deficiency syndrome (GLUT1-SD), diabetes mellitus, Alzheimer’s disease (AD), stroke, and traumatic brain injury (TBI). GLUT1-SD is caused by defect mutations in GLUT1. Diabetes and AD are associated with changed expression of glucose transporters in brain, and transporter-related energy deficiency of neurons may contribute to pathogenesis of AD. Stroke and TBI are associated with changes of glucose transporter expression that influence clinical outcome. Keywords Glucose transporter . Brain . GLUT1 . GLUT2 . GLUT3 . GLUT4 . SGLT1 . Diabetes . Parkinson’s disease . Stroke . Traumatic brain injury . GLUT1 deficiency syndrome

Abbreviations AA AD AβP AMG AMPK APP ARH BBB BCCAO CCI CHI

Ascorbic acid Alzheimer’s disease Amyloid beta-peptide α-Methyl-D-glucoside AMP-activated protein kinase Amyloid precursor protein Hypothalamic arcuate nucleus Blood-brain barrier Bilateral common carotic artery occlusion Controlled cortical impact Closed head injury

This article is part of the special issue on Glucose Transporters in Health and Disease in Pflügers Archiv—European Journal of Physiology * Hermann Koepsell [email protected] 1

Institute for Anatomy and Cell Biology, University of Würzburg, Koellikerstr 6, 97070 Würzburg, Germany

CGN 2DOG DIO DMH EGP ER FDOG FDOG-6-P FPI GABA GE GI GK GlcNAc GLUT1-DS HA HBSP HFD HIF HSP

Cerebellar granule neuron 2-Deoxy-D-glucose Diet-induced obesity Dorsomedial hypothalamus Endogenous glucose production Endoplasmic reticulum 2-Fluoro-2-deoxy-D-glucose FDOG phosphorylated in position 6 Fluid percussion injury