Carbohydrate and lipid metabolism are under tight hormonal control by insulin, glucagon and the autonomic nervous system. Following a chronic stress, such as infection, carbohydrate and lipid metabolism are markedly accelerated with associated changes in insulin, glucagon, the sympathetic nervous system and other hormones. This increase in carbohydrate metabolism is not readily suppressed by exogenous nutritional support. Although in vivo studies suggest that gluconeogenesis is increased in infection, in vitro data suggest that hepatic gluconeogenic potential is decreased. An explanation for this paradox is that the hormonal and substrate changes commonly seen in infection may compensate for the hepatic impairment. Glucagon and insulin are potent regulators of glucose metabolism and they have been implicated in directing the increase in glucose production seen in sepsis. The first goal of this proposal is to determine if sepsis alters hepatic insulin sensitivity and the role of basal insulin in regulating hepatic glucose production. The second goal is to determine what role the hyperglucagonemia seen in sepsis plays in directing the gluconeogenic response to infection. The third goal of this proposal is to determine whether the capacity of the liver to remove and metabolize glucose is altered by infection. Experiments will be carried out in dogs which have received either a sterile or an E-coli-containing fibrinogen clot in the peritoneum 36 hrs prior to the study. Hormone levels will be controlled both by surgical (pancreatectomy) and pharmacological (somatostatin) methods. Hepatic glucose metabolism (glycogenolysis, gluconeogenesis, glucose uptake) will be measured using combined tracer and A-V difference techniques. This proposal is a first step in defining some of the many factors that are responsible for the acceleration of gluconeogenesis in stressful situations, more specifically in the infectious state. In addition, it will determine if infection modifies the ability of the liver to take up glucose or to respond to factors, which normally play an important role in stimulating hepatic glucose uptake. The combination of both tracer and balance techniques will allow assessment of the rates of hepatic glucose uptake, glycogenolysis and gluconeogenesis and the factors that are important in determining their relative rates. A knowledge of the factors that regulate hepatic metabolism in infection and the identification of the processes involved will contribute to our understanding of the role they might play in directing the metabolic response to infection and the metabolic fate of nutritional support.

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Vanderbilt University Medical Center
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