Stimulation of gluconeogenesis by glucagon and norepinephrine in the perfused chicken liver

The effects of glucagon and norepinephrine on gluconeogenesis by perfused chicken liver were studied with fluorimetric monitoring of the redox states of the intracellular pyridine nucleotides. Glucagon stimulated glucose production from precursors entering the pathway both above and below the level of triose phosphates without causing a detectable effect on the redox states of pyridine nucleotides. Glucagon stimulation was not abolished by subsequent infusion of octanoate or ethanol. The presence of a pyruvate/lactate mixture plus NH4Cl resulted in a maximum efficacy of glucagon. Glucose production from lactate and fructose was stimulated by norepinephrine. Norepinephrine always caused a change towards increased reduction of pyridine nucleotides with an increase in the beta-hydroxybutyrate/acetoacetate ratio, but displayed no stimulation of glucose and lactate production from pyruvate. As a result of octanoate infusion with lactate, the changes induced by norepinephrine were reversed. The responses to norepinephrine and phenylephrine were decreased markedly in liver perfused with a calcium-free medium and/or with phentolamine. Infusion of calcium into the calcium-deficient liver caused an abrupt elevation of glucose production together with a reduction of pyridine nucleotides, and the original response to norepinephrine was recovered. The results demonstrate that the effects of glucagon and norepinephrine on gluconeogenesis are not identical, and that norepinephrine stimulation is mediated through an alpha-adrenergic and calcium-dependent mechanism in which redox changes of mitochondrial pyridine nucleotides are involved.