Good glycemic control reduces the onset and slows the progression of microvascular complications in Type 1 and Type 2 diabetic patients (DM). Unfortunately, preventing the goal of euglycemia in diabetic patients is the associated three-fold increase in severe hypoglycemia. During the last decade, studies have determined that acquired autonomic nervous system (ANS) failure is implicated in the pathogenesis of hypoglycemia occurring in intensively treated DM. Central to the development of acquired ANS failure is the occurrence of prior episodes of hypoglycemia. Previous work from my own and other laboratories have demonstrated that increases in plasma cortisol can result in acute ANS failure during subsequent stress. These results allow the formulation of a plausible hypothesis stating that an increase in plasma cortisol is a significant mechanism responsible for hypoglycemia-associated autonomic failure. Type 1 diabetic and healthy women have significantly reduced ANS responses during hypoglycemia and exercise. The mechanisms responsible for this large sexual dimorphism is unknown. We hypothesize that estrogen, another steroid hormone, regulates ANS responses and is the major mechanism responsible for this finding. Acquired ANS failure can also occur during exercise. The mechanisms regulating the development of exercise related autonomic failure are unknown, but need to be determined. The studies outlined in this proposal are therefore focused at determining the in-vivo mechanisms regulating ANS counterregulatory failure during hypoglycemia and exercise in healthy and diabetic humans. Studies will be proposed to determine whether antecedent hypoglycemia reduces the metabolic and cardiovascular effects of the critical hormone epinephrine. This information is needed as treatment strategies simply aimed at increasing ANS ressponses during physiologic stress in diabetics will have limited effectiveness if target organs are unresponsive. Experiments will use the glucose clamp technique. ANS responses to hypoglycemia and exercise will be assessed by measuring circulating catecholamines, pancreatic polypeptide, muscle sympathetic nerve activity (MSNA), and heart rate variability. Metabolic counterregulatory mechanisms will be determined by measuring glucose and glycerol turnover, substrate levels, and substrate oxidation via indirect calorimetry.
The specific aims of this proposal are to determine: 1) the mechanisms responsible for cortisol inducing poglycemia-associatedautonomic dysfunction in normnal man and type 1 diabetes, 2) the effects of prior hypoglycemia on subsequent metabolic/cardiovascular responses to epinephrine in healthy and type 2 diabetic man, 3) if dihydroepiandrostenedione can prevent hypoglycemia associated-autonomic dysfunction, and 4) the mechanism responsible for the sexual dimorphism present in ANS counterregulatory responses to hypoglycemia.
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