Three hypoglycemia-associated clinical syndromes in people with insulin-dependent diabetes mellitus (IDDM)—defective glucose counterregulation, hypoglycemia unawareness, and elevated glycemic thresholds for symptoms and activation of counterregulatory systems during effective intensive therapy—have much in common. They segregate together, are associated with increased frequency of severe iatrogenic hypoglycemia, and share several pathophysiological features, including reduced autonomic nervous system responses to a given degree of hypoglycemia. In the setting of reduced glucagon responses, the reduced adrenomedullary epinephrine responses play a key role in the pathogenesis of iatrogenic hypoglycemia in affected patients. Thus, these syndromes are examples of hypoglycemia-associated autonomic failure in IDDM, a disorder distinct from classical diabetic autonomic neuropathy. The pathogenesis of hypoglycemiaassociated autonomic failure is not known, need not be the same in all three syndromes, and could be multifactorial even in a given syndrome. The recent finding that short-term antecedent hypoglycemia results in reduced symptomatic and autonomic (including adrenomedullary) responses to subsequent hypoglycemia in nondiabetic humans leads logically to the following hypothesis concerning one potential pathogenetic mechanism: recent antecedent iatrogenic hypoglycemia is a major cause of hypoglycemiaassociated autonomic failure in IDDM, and hypoglycemia-associated autonomic failure, by reducing both symptoms of and defenses against developing hypoglycemia, results in recurrent severe hypoglycemia, thus creating a vicious cycle. If this hypothesis is confirmed, it will suggest strategies to reduce the frequency of iatrogenic hypoglycemia in people with IDDM.

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