HYPOGLYCEMIA - THE LIMITING FACTOR IN THE MANAGEMENT OF IDDM

Iatrogenic hypoglycemia is the limiting factor in the management of in sulin-dependent diabetes mellitus (IDDM). It causes recurrent physical morbidity, some mortality, and recurrent or even persistent psychosoc ial morbidity. The principles of glucose counterregulation, the physio logical mechanisms that normally very effectively prevent or correct h ypoglycemia, are now known. Decrements in insulin, increments in gluca gon, and, in the absence of the latter, increments in epinephrine stan d high in the hierarchy of redundant glucose counterregulatory factors . Iatrogenic hypoglycemia in IDDM is the result of the interplay of ab solute or relative therapeutic insulin excess and compromised glucose counterregulation. Syndromes of compromised glucose counterregulation include defective glucose counterregulation (the result of combined de ficiencies of the glucagon and epinephrine responses to falling glucos e levels), hypoglycemia unawareness (loss of the warning, neurogenic s ymptoms of developing hypoglycemia), and elevated glycemic thresholds (lower glucose levels required) for autonomic activation and symptoms during effective intensive therapy. These have been conceptualized as examples of hypoglycemia-associated autonomic failure, a functional di sorder distinct from classical diabetic autonomic neuropathy, in IDDM. Recent antecedent iatrogenic hypoglycemia appears to be a major facto r in the pathogenesis of hypoglycemia unawareness; there is increasing evidence that this syndrome is reversible with scrupulous avoidance o f hypoglycemia. It probably also contributes substantially to the synd rome of elevated glycemic thresholds during intensive therapy. However , factors in addition to recent antecedent hypoglycemia play an import ant role in the pathogenesis of the syndrome of defective glucose coun terregulation. Pending the prevention and cure of IDDM, we need to lea rn to replace insulin in a much more physiological fashion and/or to p revent, correct, or compensate for compromised glucose counterregulati on if we are to eliminate hypoglycemia from the lives of people with I DDM without compromising glycemic control. In the meantime, we must co ntinue to seek better insight into the fundamental mechanisms of compr omised glucose counterregulation and to develop practical preventive c linical strategies and practice hypoglycemia risk factor reduction wit h our patients.