In this issue of Diabetes Care, McCoy et al.(1) report 3.4-fold higher mortality in patients with diabetes who selfreported severe hypoglycemia (that which required the assistance of another person) 5 years earlier. They suggest that patient-related outcomes such as hypoglycemia would augment risk stratification and management of patients with diabetes.

Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes (2). It causes recurrent morbidity in most people with type 1 diabetes and many with advanced type 2 diabetes and is sometimes fatal. It impairs defenses against subsequent hypoglycemia and, thus, causes a vicious cycle of recurrent hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and, therefore, full realization of the benefits of glycemic control. Although it can be caused by an episode of marked absolute therapeutic hyperinsulinemia, iatrogenic hypoglycemia is typically the result of the interplay of mild-to-moderate absolute or even relative therapeutic hyperinsulinemia and compromised physiological and behavioral defenses against falling plasma glucose concentrations (2). The compromised physiological defenses include attenuated adrenomedullary epinephrine responses that, in the setting of absent insulin and glucagon responses, cause the clinical syndrome of defective glucose counterregulation with its 25-fold or greater increased risk of severe hypoglycemia during aggressive glycemic therapy. The compromised behavioral defense is the failure to ingest carbohydrates, which results from attenuated sympathoadrenal (largely sympathetic neural) responses that cause the clinical syndrome of hypoglycemia unawareness with its sixfold or greater increased risk of severe hypoglycemia during aggressive glycemic therapy. Defective glucose counterregulation and hypoglycemia unawareness are the components of hypoglycemia-associated autonomic failure (HAAF) in diabetes. HAAF is a form of functional sympathoadrenal failure,