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For isolated rat hepatocytes, glucagon, The presence in liver of both phosphofructokinase (EC 2.7.1.11) and fructose diphosphatase (EC 3.1.3.11) provides for the possibility of a substrate cycle and the apparent futile hydrolysis of ATP. Until recently, it was considered that the reactions of glycolysis and gluconeogenesis were mutually exclusive and that minimal flux occurred through phosphofructokinase during periods of gluconeogenesis in liver. In recent studies in this laboratory significant rates of flux through phosphofructokinase were observed concomitant with gluconeogenesis (1) and these rates were directly proportional to the extracellular glucose concentration. Thus, at physiologically normal glucose concentrations (i.e., 5.5 mM), the rate of flux through phosphofructokinase varied from 4 to 36% of the flux rate through fructose diphosphatase, depending upon the nature and concentration of the gluconeogenic substrate.Furthermore, it was found that glucagon and cAMP stimulate glucose formation from galactose, dihydroxyacetone, xylitol, and fructose by influencing the rate of reactions involving fructose 6-phosphate (1). Both agents were found to inhibit flux through phosphofructokinase and simultaneously to enhance flux through fructose diphosphatase.The identification of a glucagon-mediated site of regulation of hepatic gluconeogenesis between triose phosphate and glucose (1) supports earlier speculation from this laboratory (2-4) and others (5-9) that a control site occurs in this region. In addition, the identification of a control site at phosphofructokinase-fructose diphosphatase may explain observations by Haugaard and Haugaard (10), repeated and confirmed recently by Tepperman and Tepperman (11), that glucagon specifically acts to inhibit incorporation of carbon from glucose, but not fructose, into fatty acids in rat liver slices.In the present work further regulatory control at the phosphofructokinase-fructose diphosphatase site is examined.Both epinephrine and cGMP are effective stimulants of gluconeogenesis and appear to act in a manner similar to that previously described for glucagon and cAMIP (1

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