One Molecule for Mental Nourishment and More: Glucose Transporter Type 1-Biology and Deficiency Syndrome

Abstract

Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood-brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes' Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches.

Keywords: Glut1; SLC2A1; cognitive impairment; epilepsy; flow cytometry; glucose uptake; inborn errors of metabolism; inflammation; ketogenic diet; movement disorders.

Figure 1

Representation of the main glucose transporters into the brain, Glut1 and Glut3, belonging to facilitated, “passive” transporters (encoded by members of the SLC2 gene family). Transport across cell membranes is depicted by arrows; localization and known defects of Glut1 are shown by green rectangular symbols (based on [12,15]). Legend: Glu, glucose; CSF, cerebrospinal fluid.

Figure 2

A model of the Glut1 structure with 12 TM domains, and the main functional sites: ATP binding sites, the phosphorylation site, and the sugar binding site in position N317 of the TM8 domain.

Figure 3

Representation of glucose and lactate fluxes through the BBB. Glucose transporters: Glut1 (depicted in green) is expressed in endothelial cells (part of BBB) and in glial cell membrane; Glut3 (yellow) is expressed in neuron membrane. MCT (monocarboxylate transporters family) is depicted in blue: different isoforms (MCT1, MCT2, MCT4) are expressed in endothelial cells (part of the BBB), neurons, astrocytes, and oligodendrocytes.

Figure 4

Immune challenge induces metabolic activation with increased GLUT1 expression, glucose uptake and glycolysis. The transition of monocytes to macrophages is characterized by further increases in Glut1 expression and glycolysis. Naive (unactivated) monocytes are metabolically quiescent, with low basal metabolic activity and ATP derived primarily via oxidative phosphorylation (OxPhos). Classically activated macrophages (M1) induce aerobic glycolysis, resulting in lactate production and the increased production of inflammatory cytokines. Alternatively activated macrophages (M2) trigger a metabolic profile with OxPhos and an anti-inflammatory response. TNF: Tumor necrosis factor; IL-6: Interleukin 6; IL-1RA: interleukin-1 receptor antagonist.

Figure 5

Aberrantly activated oncogenes deregulate the import of glucose through Glut1 into cancer cells. The solid purple arrows depict the metabolites and metabolic reactions. Dashed arrows depict regulatory effects of signal transduction components. Legend: Glut1, glucose transporter 1; HK, hexokinase; GLS1, glutaminase 1; PRPS2, phosphoribosyl pyrophosphate synthetase 2; CAD, carbamoyl-phosphate synthetase 2; RTK, receptor for tyrosine kinase; ASCT2/SN2, glutamine transporter gene.