Reflections on the Brain's Energy Crisis During Hypoglycemia

Hypoglycemic metabolism in humans is caused by prolonged starvation, the interruption of the newborn's body metabolism upon separation from maternal circulation, or insulin-induced acute glucose shortage. However, only acute hypoglycemia has the potential to trigger a severe energy crisis in the brain. Signal transmission by pre- and postsynaptic nerve terminals makes the greatest contribution to the brain's energy needs. Moreover, the brain's cognitive function depends on the transmission of multiple signals, and consequently, it is tightly connected with the energy homeostasis in brain tissue. Nevertheless, the energy crisis during acute hypoglycemia is surprising because the brain theoretically has the ability to fuel its energy metabolism using lactate and fatty acids from the circulation. However, these energy-rich substrates are not able to prevent the impairment of cognitive performance during acute hypoglycemia. The reason could be that burning lactate and/or fatty acids does not release redox energy sufficiently for oxidative phosphorylation to compensate for the decreased ATP generation during acute hypoglycemia. In contrast, there is evidence that neuronal firing is supported by glucose as the main fuel. That would enable the rapid supply of ATP to neuronal terminals through non-oxidative glucose degradation.