To clarify the physiology and pathophysiology of human metabolic regulation, in the contex of regulatory reduncancy and hierachy and with respect to the relative roles of the sympathochromaffin (adrenergic) system vis-a-vis- other regulatory systems, it is planned: 1) To validate further an """"""""islet clamp"""""""" technique (somatostatin with glucagon and insulin replacement to be used to determine the relative roles of insulin, glucagon, or both in selected aspects of normal and abnormal metabolic regulation. 2) To define the normal mechanisms of glucoregulation during moderate exercise, focusing on catecholamines, insulin, glucagon and muscarinic withdrawal alone and in concert, and the mechanisms of exercise-associated hypoglycemia in relation to adequate and defective hypoglycemic glucose counterregulation in patients with insulin dependent diabetes mellitus. 3) To explore the concept of CNS adaptation to antecedent glycemia by examining its rate of development, quantitating glycemic thresholds for counterregulatory and symptomatic responses to glucose decrements in normal and diabetic individuals and determining the effect of antecedent glycemia on glycemic thresholds for reduction of glucose utilization by the brain. 4) To dissect the mechanisms of metabolic effects of epinephrine and norepinephrine with respect to lipolysis, adrenergic receptor subtypes, hormonal versus neurotransmitter receptors and the relevance of receptor measurements on circulating cells in normal and diabetic persons. In addition to the islet clamp, in vivo methods will include glucose and glycerol kinetics, positron emission tomography and epinephrine dose-response studies coupled with isotope derivative measurements of norepinephrine and epinephrine, immunoassays of hormones and fluorometric determinations of metabolic intermediates as well as ligand binding measurements of Alpha- and Beta-adrenergic receptors and their linked adenylate cyclases. In vitro methods will include assessment of lipolytic sensitivity of fat obtained by aspiration. The findings are expected to be relevant to human metabolic regulatory physiology per se, the treatment of diabetes mellitus and the pathogenesis, and thus the prevention, of hypoglycemia.
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