The recovery of weanling mice from insulin-induced hypoglycemic stupor–coma after injection of sodium -l(+)-lactate (18 mmol/kg) was as rapid (10 min) as in litter-mates treated with glucose (9 mmol/kg). Stimulated by this dramatic action, we studied the effects of lactate injection on brain carbohydrate and energy metabolism in normal and hypoglycemic mice; blood and liver tissue were also studied. Ten minutes after lactate injection in normal mice, plasma lactate levels increased by 15 mmol/L; plasma glucose levels were unchanged, but the β-hydroxybutyrate concentration fell 59%. In the brains of these animals, glucose levels increased 2.3-fold, and there were significant increases in brain glycogen (10%), glucose-6-phosphate (27%), lactate (68%), pyruvate (37%), citrate (12%), and malate (19%); the increase in α-ketoglutarate (32%) was not significant. Lactate injection reduced the cerebral glucose-use rate 40%. These changes were not due to lactate-induced increases in blood [HCO−3] and pH (examined by injection of 15 mmol/kg sodium bicarbonate). Although lactate injection of hypoglycemic mice doubled levels of glucose in plasma and brain (not significant) and most of the cerebral glycolytic intermediates, values were far below normal (still in the range seen in hypoglycemic animals). By contrast, citrate and α-ketoglutarate levels returned to normal; the large increase in malate was not significant. Reduced glutamate levels increased to normal, and elevated aspartate levels fell below normal. Thus, recovery from hypoglycemic stupor does not necessarily depend on normal levels of plasma and/or brain glucose (or glycolytic intermediates). Near normal levels of the Krebs citric acid cycle intermediates suggest that changes in these metabolites, amino acids, or derived substrates relate to the dramatic recovery of hypoglycemic mice after lactate injection.
Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation