The Control of Gluconeogenesis: the Work of John Exton

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Control of Gluconeogenesis in Liver. I. General Features of Gluconeogenesis in the Perfused Livers of Rats (Exton, J. H., and Park, C. R. (1967) J. Biol. Chem. 242, 2622–2636) Control of Gluconeogenesis in Liver. II. Effects of Glucagon, Catecholamines, and Adenosine 3′,5′-Monophosphate on Gluconeogenesis in the Perfused Rat Liver (Exton, J. H., and Park, C. R. (1968) J. Biol. Chem. 243, 4189–4196) John H. Exton was born in Auckland, New Zealand in 1933. He received his medical degree from the University of New Zealand in 1958 and his Ph.D. in biochemistry from the University of Otago, New Zealand in 1963. Exton then left New Zealand for Nashville, Tennessee to do postdoctoral research in the Department of Physiology at the Vanderbilt University School of Medicine with Charles R. Park and Journal of Biological Chemistry (JBC) Classic author Earl Sutherland (1Rall T.W. Sutherland E.W. J. Biol. Chem. 1958; 232 (JBC Classics:): 1065-1076Abstract Full Text PDF PubMed Google ScholarSutherland E.W. Rall T.W. J. Biol. Chem. 1958; 232: 1077-1092(http://www.jbc.org/cgi/content/full/280/42/e39)Abstract Full Text PDF PubMed Google Scholar). Along with Park, who will be featured in an upcoming JBC Classic, Exton worked on elucidating the pathways of gluconeogenesis, the formation of glucose from non-sugar carbon substrates like pyruvate, lactate, glycerol, and certain amino acids. Gluconeogenesis occurs principally in the liver and is essential for survival in starvation; it also plays a major role in the disposal of lactate and maintenance of glucose during exercise. The process is controlled directly or indirectly by many hormones, including insulin, glucagon, catecholamines, and glucocorticoids. Exton and Park published a series of papers in the JBC on the control of gluconeogenesis using the isolated, perfused rat liver. This allowed them to study the process and its regulation without the interference of other changes in the body. Two of those papers are reprinted here as JBC Classics. The first paper studied the basic process of gluconeogenesis (i.e. the conversion of lactate, pyruvate, glycerol, alanine, and a mixture of amino acids to glucose) and demonstrated that physiological increases in these substrates alone led to increased glucose production by the liver, indicating the importance of substrate supply in the regulation of gluconeogenesis. Comparison of the rates of gluconeogenesis from lactate, pyruvate, fructose, and dihydroxy-acetone suggested that the rate-limiting step for lactate gluconeogenesis was located between pyruvate and triose phosphate in the gluconeogenic pathway. Measurements of the conversion of [14C]pyruvate to glucose and CO2 were used in a mathematical analysis to determine the flow of isotope from this substrate into the gluconeogenic pathway and the Krebs cycle. In the second paper, the stimulatory effects of glucagon and catecholamines on lactate gluconeogenesis were analyzed. Physiological concentrations of glucagon were effective in stimulating gluconeogenesis. However, blood levels of epinephrine were not, leading to the proposal that the stimulatory effects of the sympathetic nervous system were due to the release of norepinephrine from adrenergic nerve endings in the liver. Exogenous cyclic AMP stimulated gluconeogenesis, consistent with this being the mediator of the effect of glucagon. Studies of gluconeogenesis from fructose indicated that glucagon/cyclic AMP stimulated the pathway somewhere between pyruvate and phosphoenolpyruvate in the gluconeogenic pathway. In 1966, Exton became an Assistant Professor of Physiology at Vanderbilt and was promoted to Associate Professor in 1968. Later, in 1970, he became Professor of Molecular Physiology and Biophysics and in 1989 he became a Professor of Pharmacology. Exton remains at Vanderbilt where he studies signal transduction. Exton has received many honors for his research including the Lilly Award from the American Diabetes Association, a Doctor Honoris Causa from the Autonomous University of Barcelona, the Drummond Award from the University of Calgary, and the Sutherland Award, Vanderbilt's highest research award. He is also a University National Scholar, New Zealand, and a Commonwealth Scholar, United Kingdom, as well as a fellow of the American Association for the Advancement of Science and a member of the National Academy of Science. He was named an investigator of the Howard Hughes Medical Institute in 1976 and has served as an Associate Editor for the Journal of Biological Chemistry since 1988.