The proposed studies will address the changes in ion transport involved in the regulation of glucose metabolism in hepatocytes. It is clear that alterations in ion transport are an important part of the cell response to glucoregulatory hormones and to alterations in substrate entry. Because of the central role of the liver in glucose metabolism, the study of the interaction between membrane transport, hormonal stimulation and metabolic regulation in hepatocytes will have special relevance to the pathophysiology of diabetes. In addition, such studies will have more general relevance to similar processes in a variety of epithelia, particularly the kidney. The following issues will be addressed: 1. Substrate delivery- Cell adjustments to alanine/sodium contransport: It is clear that the cell loses potassium when increased alanine entry occurs. We will define the nature of the efflux pathway, determine the signal that triggers the K efflux, and explore the role of this pathway in the gluconeogenic response. 2. Insulin-The role of Na/H exchange: Insulin is known to stimulate Na-H exchange in some tissues as well as K uptake into muscle and liver cells. We will investigate whether Na-H exchange is turned on in hepatocytes and explore the role of this transporter in mediating other insulin effects. 3. Adrenergic agents-The roles of protein kinase C and calcium: We will establish the role of protein kinase C in mediating the transport effects of alpha adrenergic agents. The effects on K transport will be studied and the possibility that Na/H exchange is stimulated will be explored.
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