Glutamate Prevents Altered Mitochondrial Function Following Recurrent Low Glucose in Hypothalamic but Not Cortical...

Astrocytes contribute to glutamatergic signalling, which is required for hypoglycaemia counterregulation and is impaired by recurrent insulin-induced hypoglycaemia. This study examined the glutamate response of astrocytes when challenged with acute and recurrent low glucose (RLG) exposure. The metabolic responses of cortical (CRTAS) and hypothalamic (HTAS) primary rat astrocytes were measured in acute and recurrent low glucose using extracellular flux analyses. RLG caused mitochondrial adaptations in both HTAS and CRTAS, many of which were attenuated by glutamate exposure during low glucose (LG) treatments. We observed an increase in capacity of HTAS to metabolise glutamine after RLG exposure. Demonstrating astrocytic heterogeneity in the response to LG, CRTAS increased cellular acidification, a marker of glycolysis in LG, whereas this decreased in HTAS. The directional change in intracellular Ca²⁺ levels of each cell type, correlated with the change in extracellular acidification rate (ECAR) during LG. Further examination of glutamate-induced Ca²⁺ responses in low glucose treated CRTAS and HTAS identified sub-populations of glucose-excited- and glucose-inhibited-like cells with differing responses to glutamate. Lastly, release of the gliotransmitter ATP by HTAS was elevated by RLG, both with and without concurrent glutamate exposure. Therefore, hypothalamic astrocytes adapt to RLG by increasing glutamate uptake and oxidation in a manner that prevents RLG-induced mitochondrial adaptations.