Alteration in brain glucose metabolism induced by hypoglycaemia in man

Glucose is the usual fuel of brain tissue. As hypoglycaemia develops, a level of glycaemia is reached where glucose transport from the circulation is no longer sufficient to meet metabolic demands, and the brain signals for peripheral counter-regulatory responses and symptoms of hypoglycaemia ensue. The glycaemic threshold for these events can be shifted to lower glucose concentrations following a single episode of hypoglycaemia, and compensating central nervous system adaptations have been postulated in man. In nondiabetic subjects, rates of brain glucose uptake are initially impaired at a systemic glucose concentration of 3.6 mmol/l; whereas after 56 h of intermittent hypoglycaemia (3.0 mmol/l) brain uptake is preserved at normal rates even at 2.5 mmol/l. Increments in counter-regulatory hormones and symptoms are also triggered at lower glucose concentrations following recurrent hypoglycaemia. In 24 patients with insulin-dependent diabetes stratified into three equal groups by HbA1c value, those in the lowest third of HbA1c range had rates of brain glucose uptake at 3.0 mmol/l that were equivalent to rates measured at 5.3 mmol/l. Patients in the other HbA1c groups had rates of brain glucose uptake during hypoglycaemia that were reduced by 30% relative to normoglycaemia-comparable to reductions seen in non-diabetic subjects. Thus, alterations in glucose uptake occur in the brain in order to maintain normal brain metabolism following experimental and clinical hypoglycaemia. Because of this enhanced glucose uptake, the brain has no need to signal for counter-regulatory responses and hypoglycaemia unawareness occurs.