Glucose Transporter 1 Deficiency Impairs Glucose Metabolism and Barrier Induction in Human Induced Pluripotent Stem Cell‐Derived Astrocytes

Glucose is a major source of energy for the brain. At the blood-brain barrier (BBB), glucose uptake is facilitated by glucose transporter 1 (GLUT1). GLUT1 Deficiency Syndrome (GLUT1DS), a haploinsufficiency affecting SLC2A1, reduces glucose brain uptake. A lot of effort has been made to characterize GLUT1DS at the BBB, but the impact on astrocytes remains unclear. In this study, we investigated the impact of GLUT1DS on astrocyte differentiation and function in vitro, using human induced pluripotent stem cells GLUT1DS (GLUT1DS-iPSCs) differentiated into astrocyte-like cells (iAstros). GLUT1 expression is decreased during the differentiation of iPSCs into astrocytes, with neural progenitor cells showing the lowest expression. The presence of a truncated GLUT1 did not compromise the differentiation of iPSCs into iAstros, as these cells could express several key markers representative of the astrocyte lineage. GLUT1DS-iAstros failed to express full-length GLUT1 at protein levels while showing no signs of impaired GLUT4 expression. However, GLUT1DS-iAstros showed decreased glucose uptake and lactate production compared to control-iAstros, reduced glycolysis, and mitochondrial activity as well as ATP deficit. In addition to reduced energy production, astrocytes displayed a reduced extracellular glutamate release. As previously observed, one iAstros clone (C7) showed the most severe phenotype from all groups. Our study provides an insightful view of the contribution of GLUT1 in astrocytes' energetic metabolism and raises the possible contribution of these cells in the astrocyte-neuron metabolic coupling. Our future direction is to understand better how GLUT1DS impacts astrocytes and neurons within their metabolic coupling.