The overall objective of this study is to clarify the mechanisms involved in the deposition of hepatic glycogen during the intravenous and oral administration of carbohydrate in several metabolic states. We propose to use a combined in vivo/in vitro approach: the in vivo studies, to be carried out in conscious dogs using the venous occlusion technique for sampling of mixed hepatic venous blood, are designed to delineate the relative importance of specific signals and substrates (glucose itself, insulin, glucagon, gluconeogenic precursors, putative gut factors) to the amount of glycogen deposited during carbohydrate administration. Studies in vitro, to be carried out in perfused rat liver, are designed to delineate the intracellular mechanisms by which the various factors interact to determine glycogen deposition rates when carbohydrate (and non-carbohydrate glucose precursors) are plentiful. The interpretation of the perfused liver studies will be performed using the minimal model approach: A mathematical model of glycogen metabolism is developed which allows us to estimate mass flux rates through the glycogen metabolic pathway from the time course of metabolic intermediates measured in the perfused liver system during substrate administration and hormonal stimulation. Estimating flux rates using the model is an approach to the study of intracellular mechanisms of control which does not require the assumption that enzyme activities measured in vitro, in broken cells are representative of activities in the perfused tissue. The integrated portrait of control mechanisms of glycogen metabolism obtained in these studies will be compared with control of glycogen deposition in the liver of the diabetic animal, and the animal with genetic insulin resistance.
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