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Control of Gluconeogenesis in Liver

III. Effects of L-lactate, pyruvate, fructose, glucagon, epinephrine, and adenosine 3′,5′-monophosphate on gluconeogenic intermediates in the perfused rat liver
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      The levels of intermediary metabolites in the perfused liver have been measured to determine the location of the rate-limiting step for gluconeogenesis from lactate and the site at which glucagon, epinephrine, and cyclic AMP exert control.
      The reaction limiting maximum gluconeogenesis from lactate is situated between pyruvate and phosphopyruvate. Glucagon or epinephrine, acting through cyclic AMP, appears to activate a reaction in this portion of the pathway. At less than saturating levels of lactate, the rate of gluconeogenesis is determined by the activities of the above reaction and also of lactate dehydrogenase. The latter step is not under hormonal control. Gluconeogenesis is not limited by the supply of NAD+ or NADH and is virtually independent of the oxidation-reduction potential of the extramitochondrial NAD+-NADH couple as reflected by the lactate-pyruvate ratio of the tissue. The liver has potent mechanisms to restore a displaced oxidation-reduction potential to normal.
      Glucagon does not stimulate gluconeogenesis or inhibit lactate formation from fructose or dihydroxyacetone. It is suggested that a sparing of pyruvate oxidation or inhibition of the pyruvate kinase reaction is not responsible for the gluconeogenic action of glucagon and that effects, if any, of glucagon on reactions at the level of triose phosphate dehydrogenase, fructose diphosphatase, or glucose 6-phosphatase are of no physiological importance.

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