(A) In response to an isolated fall in blood sugar, the brain senses hypoglycemia at a glucose concentration of approximately 65 mg/dl and activates the sympathetic nervous system. This activation results in stimulation of the adrenal chromaffin cells, which in turn leads to the release of epinephrine and NPY. Epinephrine release following a single episode of hypoglycemia increases the activity of tyrosine hydroxylase, resulting in the replenishment of epinephrine secretory stores. (B) In response to repeated episodes of hypoglycemia, the brain senses hypoglycemia at a lower glucose concentration than that following exposure to a single episode. This results in activation of the sympathetic nervous system, followed by stimulation of adrenal chromaffin cells. Because NPY released during previous episodes of hypoglycemia has reduced tyrosine hydroxylase activity, the epinephrine secretory capacity of the chromaffin cells is reduced, resulting in a blunted counterregulatory response.