Fig. 3.

Brain exposure to glucose excursions at a late stage of damage. This schematic illustrates both circulating and central glucose excursions in response to meals in a hypothetical individual with increased fasting glucose level. (1) The increased time spent in hyperglycemia induces damage to pericytes and endothelial dysfunction of brain arterioles, resulting in chronic hypoperfusion and decreased blood to brain glucose transport. Downregulation of glucose transporters may also contribute to decreased glucose transport, although human evidence for this is lacking. (2) This protective mechanism works to lower central glucose relative to circulating concentration. This means that the brain may experience hypoglycemia at a normal circulating glucose level, a phenomenon known as relative cerebral hypoglycemia. (3) The ensuing exposure to hypoglycemia can disable endocrine counter-regulation to subsequent hypoglycemia. (4) Exposure to subsequent hypoglycemia is exaggerated and the ensuing energy crisis may induce neuroglycopenia and the accumulating damage could move the brain toward neuropathology.