Figure 4. Preconditioning through recurrent hypoglycemia leads to cellular adaptation and HAAF.

Hypoglycemia is a state of energy depletion that leads to metabolic stress. Sympathetic activation leads to symptoms of hypoglycemia awareness and the adrenomedullary response. The normal response to hypoglycemia is a cellular adaptation, assuming the energy depletion and metabolic stress was not enough to induce cell death. The mechanism by which cellular adaptation occurs is unclear but may include the use of alternate fuels (such as lactate) and/or an enhanced glucose transport/phosphorylation/metabolism. During a subsequent hypoglycemic episode, the adapted cell experiences less marked energy depletion and less metabolic stress thus making the cells less susceptible to death. Less intracellular energy depletion leads to impaired sympathetic activation resulting in hypoglycemia unawareness and a reduced adrenomedullary response to subsequent hypoglycemia, collectively known as hypoglycemia associated autonomic failure (HAAF). Preconditioning through recurrent hypoglycemia, paradoxically, acts to render an individual more prone to, but less vulnerable to, an episode of severe hypoglycemia.