The major objective of this grant proposal is to elucidate the mechanism by which changes in the distribution of ions and the subsequent changes in membrane potential influence metabolic processes. First, we want to clarify: 1) the mechanism by which glucagon-induced ion fluxes and membrane potential changes are influencing glucose production, 2) the mechanism by which glucose production is blocked, and 3) the clinical relevance of our studies by testing the effects of hypoglycemic agents and electrolyte movement. In particular, we want to study the mechanism by which glucagon changes ionic distribution and the ionic basis of the changes in membrane potential. We want to clarify the role that individual ions are playing and to identify the ionic pools involved. We want to distinguish between the effects due to ions and those due to membrane potential, and to assess the relative importance of membrane potential changes in metabolic regulation. Most of the prosposed studies are going to be carried out in an isolated in situ perfused liver system.