Glucose transporter type 1 deficiency syndrome (Glut1DS) is a neurodevelopmental disorder caused by impaired cerebral glucose transport and clinically characterized by absence-type seizures, neurodevelopmental delays, movement disorders, and cognitive deficits. The consequences of chronic cerebral glucose deficiency for glial metabolism and myelin homeostasis remain poorly understood. In this study, we combined metabolic profiling, diffusion MRI, transcriptomic and lipidomic analyses to delineate the metabolic, molecular, and microstructural alterations induced by Glut1 haploinsufficiency in a Glut1+/− mouse model. Glut1+/− mice exhibited a global decrease in glucose, glycogen, and lactate levels across multiple brain regions, consistent with impaired glucose uptake and astrocytic energy metabolism. In addition to widespread metabolic deficits, diffusion MRI revealed selective microstructural abnormalities confined to the dorsolateral striatum, a critical hub for locomotor control. These changes were characterized by increased mean diffusivity and reduced mean kurtosis, indicative of reduced tissue microstructural complexity. Striatal transcriptomic profiling revealed a reactive astrocytic signature along with coordinated downregulation of genes involved in oligodendrocyte function, myelination, and galactolipid biosynthesis. Lipidomic analysis further identified selective reductions in myelin-enriched lipid classes, including hexosylceramides and ethanolamine plasmalogens, consistent with alterations in lipid pathways relevant to myelin organization and stability. Importantly, chronic L-lactate supplementation initiated during early postnatal development partially rescued motor deficits in young adult Glut1+/− mice.

Collectively, these findings support a model in which chronic glucose transport deficiency is associated with alterations in glial metabolic homeostasis and myelin-related pathways, while highlighting lactate supplementation as a potential therapeutic strategy in Glut1DS.