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Review
. 2020 Sep;472(9):1299-1343.
doi: 10.1007/s00424-020-02441-x. Epub 2020 Aug 13.

Glucose transporters in brain in health and disease

Hermann Koepsell  1
Affiliations
Review

Glucose transporters in brain in health and disease

Hermann Koepsell. Pflugers Arch. 2020 Sep.

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: Brain; Diabetes; GLUT1; GLUT1 deficiency syndrome; GLUT2; GLUT3; GLUT4; Glucose transporter; Parkinson’s disease; SGLT1; Stroke; Traumatic brain injury.

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Figures

Fig. 1
Fig. 1
Schematic depiction of a brain capillary, an associated astrocyte, and an interacting neuron with the most relevant glucose transporters. Capillary endothelial cells that are connected by tight junctions form the blood-brain barrier. In the insets, glucose transporters are depicted that mediate d-glucose transport across the indicated membranes. The main direction of d-glucose translocation is shown by red arrows. Transporters are denoted by capital letters when their locations were described in humans and rodents. Lowercase letters were used when the transporter locations were only described in rodents
Fig. 2
Fig. 2
Barriers between blood and CSF and between brain interstitium and CSF containing glucose transporters. A barrier between blood in the choroid plexus and CSF in brain ventricles is formed by epithelial cells covering the choroid plexus. Tanycytes form a barrier between blood in CVOs and CSF in brain ventricles. A barrier between brain interstitium and CSF is formed by ependymal cells including tanycytes that line brain ventricular walls. Tight junctions are indicated in red. Different concentrations of d-glucose in the compartments are indicated by the density of gray dots
Fig. 3
Fig. 3
Role of astrocytes for transfer of d-glucose and l-lactate from blood to nerve cells supplying energy in the form of ATP. During hypoglycemia or nutrition through a ketogenic diet, energy may be derived from l-lactate supplied with the blood. l-Lactate may be also generated by astrocytes and contribute to neuronal energy supply under normal conditions as proposed by the astrocyte-lactate-neuron shuttle hypothesis. MCT1 monocarboxylate transporter 1, MCT2 monocarboxylate transporter 2
Fig. 4
Fig. 4
Involvement of glucose transporters and a glucose sensor in d-glucose sensing by neurons that are excitated by d-glucose (GE neurons). a A metabolism-dependent mechanism detected in rodents is shown. Increased d-glucose uptake at high extracellular glucose by a Glut transporter leads to an increase of intracellular glucose promoting ATP synthesis. Elevated intracellular ATP blocks an ATP-dependent K+ channel resulting in a decrease of the membrane potential. This promotes opening of the voltage-dependent Ca2+ channel VDCC. Increased intracellular Ca2+ induces the release of neurotransmitters. b A metabolism-independent mechanism observed in rodents is shown. Na+-d-glucose cotransport by Sglt1, Sglt2, or Sglt3b or binding of d-glucose to the glucose activated Na+/H+ ion channel Sglt3a leads to a depolarization of the plasma membrane and to an increase of Ca2+ uptake via VDCC. The increased intracellular Ca2+ concentration triggers the release of neurotransmitters. Ψ membrane potential
Fig. 5
Fig. 5
Involvement of glucose transporters in d-glucose sensing by neurons that are deactivated by d-glucose (GI neurons). Metabolism-dependent mechanisms detected in rodents are depicted in which a decrease of the extracellular d-glucose concentration leads to reduced d-glucose uptake by the glucose transporters Glut1, Glut2, Glut3, and/or Glut4. Decreased intracellular d-glucose promotes changes in metabolism resulting in a decrease and increase of intracellular ATP and AMP, respectively. a A mechanism based on the decrease of intracellular ATP is shown. Due to decreased intracellular ATP, the activity of the Na+-K+ATPase is reduced. This leads to a depolarization of the plasma membrane. The depolarization activates VDCC leading to an increase of intracellular Ca2+ that promotes neurotransmitter release. b Two mechanisms that are promoted by the increase of intracellular AMP activating AMP-dependent kinase AMPK are shown. Activation of AMPK may lead to a depolarization of the plasma membrane by blocking the chloride channel CFTR or the two-pore-domain potassium channel K2P. Opening of VDCCs leads to an increase of intracellular Ca2+ that triggers neurotransmitter release
Fig. 6
Fig. 6
Locations of neurons, tanycytes, and ependymocytes in respect to brain ventricles, CVOs, and brain capillaries allowing glucose sensing in blood, CSF, and brain interstitium. The tuberal region of the hypothalamus with a CVO in the median eminence is depicted. Tanycytes sense the glucose concentration in the CSF within the brain ventricle and activate neurons. In addition, tanycytes and neurons sense the interstitial concentration of d-glucose close to leaky capillaries located in CVOs and the arcuate hypothalamic nucleus. Neurons also sense glucose concentrations in brain interstitium. Tanycytes are also supposed to be involved in the transfer of glucose from regions close to leaky capillaries and from capillaries of the BBB to the CSF. DMH dorsomedial nucleus, VMH ventromedial hypothalamic nucleus, ARH arcuate hypothalamic nucleus, ME median eminence
Fig. 7
Fig. 7
Hypothesis how decreased expression of glucose transporters in brain leading to a decreased intracellular d-glucose concentration in neurons may promote the emergence of AD. A reduced concentration of d-glucose in neurons decelerates the biosynthetic pathway of hexosamine (HBSP) leading to a decreased O-glycosylation of proteins tau and APP with N-acetylglucosamine. The glycosylation of these proteins is neuroprotective because it decreases hyperphosphorylation of tau that promotes the formation of tau oligomers and decreases Aβ formation by degradation of APP. The effects of downregulation of cerebral glucose transporters are indicated by red arrows. GlcNAc N-acetylglucosamine, UDP-GlcNAc uridine 5′-diphosphate-N-acetylglucosamine, OGT O-GlcNAc transferase, OGA O-GlcNAcase, APP amyloid precursor protein
Fig. 8
Fig. 8
Chronical order of onset and duration of cerebral hypoxemia, upregulation of transcription factor HIFα, the HIF1α target proteins erythropoetin and Glut1, and IGF1 after stroke. The scheme is based on data in rats employing a BCCAO model of stroke [61]
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