Hypoglycemia occurs frequently during intensive insulin
therapy in patients with both type 1 and type 2 diabetes and remains the single
most important obstacle in achieving tight glycemic control. Using a rodent
model of hypoglycemia, we demonstrated that exposure to antecedent recurrent
hypoglycemia leads to adaptations of brain metabolism so that modest increments
in circulating lactate allow the brain to function normally under acute
hypoglycemic conditions. We characterized 3 major factors underlying this
effect. First, we measured enhanced transport of lactate both into as well as
out of the brain that resulted in only a small increase of its contribution to
total brain oxidative capacity, suggesting that it was not the major fuel.
Second, we observed a doubling of the glucose contribution to brain metabolism
under hypoglycemic conditions that restored metabolic activity to levels
otherwise only observed at euglycemia. Third, we determined that elevated
lactate is critical for maintaining glucose metabolism under hypoglycemia,
which preserves neuronal function. These unexpected findings suggest that while
lactate uptake was enhanced, it is insufficient to support metabolism as an
alternate substrate to replace glucose. Lactate is, however, able to modulate
metabolic and neuronal activity, serving as a “metabolic regulator” instead.