EXCEED THE SPACE PROVIDED. latrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes. The Pi's focus will ontinue to be on the mechanisms of hypoglycemia-associated autonomic failure (HAAF) in diabetes as we extend the findings from Original Aims 1-4 to Aims 5-8. The concept of HAAF posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to subsequent hypoglycemia in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the sympathoadrenal and the resulting neurogenic symptom responses to subsequent hypoglycemia) and, thus, a vicious cycle of recurrent hypoglycemia. We now plan to test four hypotheses:
Aim 5. A decrease in intraislet insulin is a signal for the normal glucagon response to hypoglycemia. If so, the absence of that signal would plausibly explain the loss of the glucagon response to hypoglycemia in insulin deficient diabetes.
Aim 6. Hypoglycemia sufficient to activate glucose counterregu- latory systems is a signal to glucose-sensitive brain neurons rather than a manifestation of brain metabolic fuel deprivation and, specifically, increased brain synaptic activity (rCBF measured with [15O]water and PET) is demonstrable in the medial prefrontal cortex, thalamus and periaqueductal grey at an arterial plasma glucose concentration of 65 mg/dL before but not after -24 hours of interprandialhypoglycemia. If so, wide- spread brain regions would be implicated in the pathogenesis of HAAF.
Aim 7. The epinephrine simulating p2-adrenergic agonist terbutaline more effectively prevents nocturnal hypoglycemia than a conventional bed- time snack or a commercially available bedtime snack containing uncooked cornstarch in type 1 diabetes.
Aim 8. Glucagon supports the postabsorptive plasma glucose concentration. If so, it may be key to the prevention of hypoglycemia. Insight into these basic issues in human pathophysiology can be expected to lead to clinical strategies that will improve the lives of people with diabetes in both the short- and long-term. PERFORMANCE SITE ========================================Section End===========================================
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