Our earlier work characterized the ability of glucagon, epinephrine, norepinephrine, cortisol and insulin to independently regulate glucose production (glycogenolysis and gluconeogenesis) and ketogenesis in vivo. The general aim of the proposed experiments is to continue that work, with a focus on 1) the acute and chronic interaction of the hormones, 2) the role which they play in hypoglycemic counterregulation and 3) the way in which they interact with signals from the CNS. Experiments will be carried out using conscious dogs fasted for 18 to 42h in which hormone levels, substrate levels, and neural input to the liver will be controlled using surgical and pharmacologic methods. To control epinephrine and cortisol adrenalectomy and hormone replacement will be used; to control insulin, glucagon and growth hormone somatostatin infusion and hormone replacement will be used; to control neural input to the liver """"""""head"""""""" glucose clamping, denervation, vagal cooling or alpha and beta blockade will be used. Glucose production (glycogenolysis and gluconeogenesis) will be measured using tracer and A-V difference techniques. Gluconeogenesis will also be assessed using HPLC techniques to quantify the SA of various metabolites in liver biopsies. Ketogenesis will be determined using A-V difference methods. We will examine the interaction of epinephrine with an acute rise in cortisol or an acute rise in glucagon. Further, we will assess epinephrine's ability to protect glucagon from insulin's inhibitory action. We will also examine the role of gluconeogenic substrate mobilization in modulating the glycogenolytic and gluconeogenic responses to norepinephrine and epinephrine. We will examine the effects of insulin in livers that have increased gluconeogenic rates as a result of norepinephrine infusion, fasting or denervation. We will assess the sensitivity of the brain to arterial insulin and we will determine whether pre-exposure of the brain to insulin can modify its response to hypoglycemia. We will determine the mechanism by which glucagon's action is augmented during hypoglycemia. We will also assess the mechanism by which peripheral insulin levels become rate limiting for glucose production by the liver. Lastly, we will begin to assess the role of the sympathetic and parasympathetic nervous systems in regulating hepatic glucose production and ketogenesis. Taken together these studies should further our understanding of hypoglycemic counterregulation and they will shed light on the interplay between the endocrine and nervous systems in the regulation of glucose and fat metabolism in vivo.
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