A network of insulin peptides regulate glucose uptake by astrocytes: Potential new druggable targets for brain hypometabolism

Astrocytes are major players in brain glucose metabolism, supporting neuronal needs on demand through mechanisms that are not yet entirely clear. Understanding glucose metabolism in astrocytes is therefore of great consequence to unveil novel targets and develop new drugs to restore brain energy balance in pathology. Contrary to what has been held for many years, we now present evidence that insulin, in association with the related insulin-like growth factor I (IGF-I) modulates brain glucose metabolism through a concerted action on astrocytes. Cooperativity of insulin and IGF-I relies on the IGF-I receptor (IGF-IR), that acts as a scaffold of Glucose Transporter 1 (GluT1) regulating its activity by retaining it in the cytoplasm or, in response to a concerted action of insulin and IGF-I, translocating it to the cell membrane. Regulated translocation of GluT1 to the cell membrane by IGF-IR involves an intricate repertoire of protein-protein interactions amenable to drug modulation, particularly by interfering with IGF-IR/GluT1 interactions. We propose that this mechanism accounts for a substantial proportion of basal and regulated glucose uptake by astrocytes as GluT1 is the major glucose transporter in these brain cells. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'