The prevention or correction of hypoglycemia normally involves both decrements in insulin and increments in glucose counterregulatory hormones, particularly glucagon and epinephrine (3). The secretion of all three of these hormones is altered in T1DM and advanced T2DM.

Iatrogenic hypoglycemia is the result of the interplay of absolute or relative therapeutic insulin excess and compromised glucose counterregulation in T1DM (3). As glucose levels fall (exogenous) insulin levels do not decrease and glucagon levels do not increase. The latter is also the result of insulin deficiency (4). Thus, the first and second defenses against hypoglycemia are lost. Further, the epinephrine response, the third defense, is typically attenuated, i.e., the glycemic threshold for its release is shifted to lower plasma glucose concentrations. The latter is generally the result of recent antecedent hypoglycemia although sleep, and to some extent prior exercise, causes a similar phenomenon (3). The combination of absent glucagon and attenuated epinephrine responses causes defective glucose counterregulation which is associated with a 25-fold or greater increased risk of severe hypoglycemia (5,6). The reduced autonomic (adrenomedullary and sympathetic neural) response causes hypoglycemia unawareness – loss of the warning, largely neurogenic, symptoms of developing hypoglycemia – which, because it compromises the behavioral defense (e.g., food ingestion), is also associated with a high frequency of hypoglycemia (7).

The concept of hypoglycemia-associated autonomic failure (HAAF) in T1DM (3,8) and advanced T2DM (3,9) posits that recent antecedent hypoglycemia causes both defective glucose counterregulation (by reducing epinephrine responses in the setting of absent insulin and glucagon responses) and hypoglycemia unawareness (by reducing sympathoadrenal and thus neurogenic symptom responses) (see figure 1). Perhaps the most compelling support for the concept of HAAF is the finding, in three independent laboratories (10-12), that as little as 2-3 weeks of scrupulous avoidance of hypoglycemia reverses hypoglycemia unawareness and, at least in part, improves the reduced epinephrine component of defective glucose counterregulation in most affected patients.

HAAF may explain why hypoglycemia becomes progressively more limiting to glycemic control over time in T2DM as patients approach the insulin-deficient end of the spectrum of T2DM (3,9).