AAMP AIM 6: MAPPING THE BRAIN GLUCOSE SENSOR

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Iatrogenic hypoglycemia - the limiting factor in the glycemic management of diabetes - causes recurrent morbidity (and some mortality) in the short-term and precludes full realization of established microvascular and potential macrovascular benefits of glycemic control in the long-term. The concept of hypoglycemia-associated autonomic failure (HAAF) in insulin deficient diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to a given level of subsequent hypoglycemia in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic and thus the neurogenic symptom response to subsequent hypoglycemia) and thus a vicious cycle of recurrent iatrogenic hypoglycemia. Although there is substantial support for the clinical impact of HAAF, its fundamental mechanisms are unknown. Accordingly, we are testing hypotheses relevant to the mechanism(s) and mediator(s) of HAAF and the mechanisms of two of its fundamental components, loss of the glucagon response to hypoglycemia and glycemic thresholds for autonomic and symptomatic responses that are shifted to lower plasma glucose concentrations. These hyptheses include: 1)Hypoglycemia sufficient to activate glucose counterregulatory systems is a signal to glucose-sensitive brain neurons (identified by increments in regional cerebral blood flow measured with [15O]water and PET) rather than a manifestation of brain metabolic fuel deprivation which occurs only at lower plasma glucose concentrations, and activation of these brain glucose sensors is shifted to lower plasma glucose concentrations following hypoglycemia. 2) To the extent cortisol is the mediator of HAAF,cortisol elevations (during euglycemia)comparable to those that occur during hypoglycemia reduce autonomic neuroendocrine and neurogenic symptom responses(assessed with hyperinsulinemic stepped hypoglycemic clamps)to subsequent hypoglycemia. 3) To the extent the glucagon response to hypoglycemia involves an interaction between a decrement in intraislet insulin and a low a-cell glucose concentration, a rapid decrease in insulin secretion(induced with the KATP channel agonist diazoxide)does not cause increased glucagon secretion during euglycemia but diazoxide-induced suppression of basal insulin secretion prevents the glucagon response to hypoglycemia. 4) While the adrenal medullae(the source of the biologically active epinephrine response)are also a source of the norepinephrine response to hypoglycemia, hypoglycemia per se (insulin constant) stimulates the sympathetic nervous system (quantitated with the forearm norepinephrine spillover technique), as well as the adrenal medullae,and neurogenic(autonomic)symptoms are the result of the perception of physiological changes mediated by sympathetic neural as well as adrenomedullary activation. Insight into these basic physiological issues directly relevant to HAAF can be expected to lead to clinical strategies that will minimize the frequency of iatrogenic hypoglycemia and thus improve the lives of people with diabetes in both the short- and the long-term.