GLUT1 and Cerebral Glucose Hypometabolism in Human Focal Cortical Dysplasia Is Associated with Hypermethylation of Key Glucose Regulatory Genes
Ghosh C, Westcott R, Skvasik D, Khurana I, Khoury J, Blumcke I, El-Osta A, Najm IM (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Article Number: 107741
DOI: 10.1007/s12035-025-04871-z
Abstract
Focal cortical dysplasia (FCD) is a significant etiological factor in drug-resistant epilepsy, linked with disturbances in neurovascular metabolism. Our study investigated regulation of glucose-transporter1 (GLUT1) and cerebral hypometabolism within FCD subtypes. Surgically excised human brain specimens underwent histopathological categorization. A subset of samples was assessed for DNA methylation changes of glucose metabolism-related genes. We evaluated GLUT1, vascular endothelial growth factor alpha (VEGFα), monocarboxylate-transporter (MCT2), and mammalian target of rapamycin (mTOR) expression, measured glucose-lactate concentrations, and established correlations with patients’ demographic and clinical profiles. Furthermore, we investigated the impact of DNA methylation inhibitor decitabine and hypometabolic condition on the uptake of [3H]-2-deoxyglucose and ATPase in epileptic-brain endothelial cells (EPI-EC). We observed hypermethylation of GLUT1 and glucose metabolic genes in FCD brain/blood samples and could distinguish FCDIIa/b from mild malformations of cortical development (mMCD), with oligodendroglial hyperplasia (MOGHE) and non-lesional brains. Low GLUT1 and glucose-lactate ratios corresponded to elevated VEGFα and MCT2 in FCDIIa/b vs. non-lesional tissues, independent of age, gender, seizure-onset, or duration of epilepsy. Increased mTOR-signaling in FCDIIa/b tissues was evident. Decitabine stimulation increased GLUT1, decreased VEGFα expression, restored glucose uptake and ATPase activity in EPI-ECs, and reduced mTOR and MCT2 levels in human embryonic-kidney cells. We demonstrated: hypermethylation of glucose regulatory genes distinguish FCDIIa/b from mMCD, MOGHE and non-lesional types, glucose uptake reduction is due to GLUT1 suppression mediated possibly by a GLUT1-mTOR mechanism; and DNA methylation regulates cellular glucose uptake and metabolism. Together, these studies may lead to GLUT1-mediated biomarkers and identify early intervention strategies in FCD.
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United States (USA) (US)
Australia (AU)How to cite
APA:
Ghosh, C., Westcott, R., Skvasik, D., Khurana, I., Khoury, J., Blumcke, I.,... Najm, I.M. (2025). GLUT1 and Cerebral Glucose Hypometabolism in Human Focal Cortical Dysplasia Is Associated with Hypermethylation of Key Glucose Regulatory Genes. Molecular Neurobiology. https://doi.org/10.1007/s12035-025-04871-z
MLA:
Ghosh, Chaitali, et al. "GLUT1 and Cerebral Glucose Hypometabolism in Human Focal Cortical Dysplasia Is Associated with Hypermethylation of Key Glucose Regulatory Genes." Molecular Neurobiology (2025).
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