The Croonian Lecture, 1963 Gluconeogenesis

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Abstract
Gluconeogenesis is a major metabolic process. Its extent depends on physiological circumstances, being low when the diet is rich in carbohydrate and the body in a state of rest, but high on a low-carbohydrate diet or after heavy physical exercise when lactate is to be reconverted to carbohydrate. Two in vitro systems[long dash] slices of kidney cortex and pigeon liver homogenates[long dash]were used to study various aspects of gluconeogenesis. The capacity of the kidney cortex to form glucose from various substrates including amino acids increases within a few days on feeding a low-carbohydrate diet. It also increases after heavy physical exercise (swimming). Experiments on pigeon liver homogenates and kidney cortex slices indicate that feedback control occurs in the stage of fructose-diphosphatase and of pyruvate carboxylase. Fructose-diphosphatase is inhibited by excess substrate and by adenosine monophosphate (AMP). Gluconeogenic precursors release this inhibition by causing a conversion of fructose-diphosphate into a-glycerophosphate and of AMP to adenosine triphosphate (ATP). Aceto-acetate and crotonate were found to accelerate glucose synthesis from lactate in kidney cortex slices. This supports the assumption that the activity of pyruvate carboxylase is controlled by the concentration of acetyl coenzyme A or a related acyl coenzyme A compound as demonstrated on pure enzyme preparations by Keech and Utter. The pyruvate carboxylase reaction controls gluconeogenesis from lactate, pyruvate and amino acids forming pyruvate. Fructose-diphosphatase step controls gluconeogenesis from amino acids and other compounds which form triosephosphate without the involvement of pyruvate carboxylase. A further control point of gluconeogenesis is the step initiating the degradation of precursors. The feedback mechanisms represent a "fine control." Other control mechanisms ("coarse control") operate by varying the enzyme concentrations.

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