Glucose transporter 1 deficiency impairs glucose homeostasis, cell proliferation, and morphology in human embryonic kidney cells 293.

Glucose represents a major source of energy for mammalian cells. In such cells, glucose uptake is facilitated by the presence of various glucose transporters (GLUTs). Amongst the different GLUT isoforms expressed in mammalian cells, GLUT1 is a major isoform expressed during development, but becomes restricted to a select number of cell types in adult cells, which include red blood cells, brain microvascular endothelial cells, or astrocytes. GLUT1 deficiency syndrome (GLUT1DS) is an autosomal dominant neurological disease characterized by reduced cerebral glucose and lactate uptake in patients. We previously documented the impact of GLUT1DS on the glucose uptake and homeostasis in human pluripotent stem cell-derived brain microvascular endothelial cells and astrocytes. Although such cells showed similarities in terms of impaired glucose uptake, we also noticed differences in their metabolic adaptation to such impairment. This study aims to assess the impact of GLUT1DS on non-cerebral cells by investigating the impact of impaired GLUT1 in GLUT1-deficient human embryonic kidney cells (GLUT1D-HEK293). Our results suggest that GLUT1D-HEK293 cells were viable but displayed altered cell doubling and cell morphology, reduced glucose uptake and consumption (with no apparent compensation by other GLUT isoforms), while accompanied by a severe reduction in cell glycolytic activity and a marked deficit in ATP production. Taken together, our study demonstrates that the impairment of GLUT1 activity in human cells shares common phenotypic outcomes between various cell types but also displays unique cellular responses when it comes to metabolic adaptation to energy deficit, partially explaining the impact on tissues in GLUT1DS patients.