Glucocorticoid Inhibition of Glucose Uptake by Peripheral Tissues: Old and New Evidence, Molecular Mechanisms, and Physiological Significance

GLUCOCORTICOID INHIBITION OF GLUCOSE UPTAKE BY PERIPHERAL TISSUES: OLD AND NEW EVIDENCE, MOLECULAR MECHANISMS, AND PHYSIOLOGICAL SIGNIFICANCE ALLAN MUNCK* Classical Hypotheses on the Actions ofGlucocorticoids on Carbohydrate and Protein Metabolism Over the past forty years or so endocrinologists have been actively studying the actions of glucocorticoids on glucose metabolism. Most of their efforts have been directed at the stimulatory action on hepatic gluconeogenesis . Largely neglected have been what I shall endeavor to show are the equally important, and now equally well documented, inhibitory actions on glucose utilization by extrahepatic tissues. The widely accepted view that stimulation ofhepatic gluconeogenesis from amino acids accounts satisfactorily for most ofthe observed effects of glucocorticoids on carbohydrate metabolism emerged during the 1930s from the work ofBritton and Silvette [1], ofEvans [2], and ofLong and his collaborators. It received definitive formulation in 1940 in the paper by Long, Katzin and Fry [3] thathas since served as a springboard for almost all work in this area. The strongest evidence for this view came from balance studies showing that the increase in total carbohydrate brought about by injection of adrenalectomized, fasted rats with glucocorticoids could be roughly accounted for by a concomitant increase in production ofurea, the principal by-product in the conversion ofamino acids to carbohydrates [2, 3]. From the amounts of amino acid required, it seemed unlikely that the amino acids could have come solely from liver proteins but must also have been * Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755· Some of this work was supported by a research grant (AM 03535) from the National Institute of Arthritis and Metabolic Diseases, the source of my Research Career Development Award (AMK3 -16). 265 derived from catabolic processes in extrahepatic tissues. It has since been shown that as a result of glucocorticoid action the liver ifanything gains protein, while many extrahepatic tissues lose protein and other constituents [4]. Thus, paradoxically, the glucocorticoids simultaneously exert both anabolic and catabolic actions. At about the time the gluconeogenic actions were being established, reports also began to appear of a separate action of glucocorticoids on glucose utilization. In the paper already referred to, Long et al. [3] concluded from measurements of respiratory quotient that adrenal cortical extract decreases the rate of oxidation of glucose. (Landau [5] who has analyzed carefully the assumptions involved in drawing conclusions from measurements of respiratory quotient, and from balance studies such as those described above, points out the shortcomings of the generally accepted interpretations of these experiments. He notes, for example, that decreased glucose oxidation does not necessarily mean decreased utilization , and that ureaproduction or excretion does not always give a stoichiometric measurement ofgluconeogenesis from amino acids. While accepting these strictures, it is well to keep in mind that the classical interpretations do not lead to any major discrepancies. AsI shall discusspresently, the questions that have arisen regarding the reality and the physiological significance of the effects on glucose utilization can be seen in the light of modern work to have been largely the result ofexperimental difficulties.) Some of the clearest evidence for decreased glucose utilization came again from balance studies. For example, Ingle [6] showed that in forcedfed rats treated with cortisone to a point where significant glycosuria occurred , the amount ofglucose excreted under the influence ofthehormone was much larger than could be attributed to increased gluconeogenesis from protein. Such a discrepancy strongly suggests that the hormone decreases glucose utilization. By the early 1940s, glucocorticoids thus appeared to have two fairly well-established actions: (a) they increased hepatic production of glucose from amino acids, with a concomitant breakdown ofprotein from extrahepatic tissues; and (b) they decreased glucose uptake, presumably in extrahepatic tissues. Two general hypotheses were proposed regarding the source of these effects. The first, due to Long et al. [3], held that the primary action ofthe glucocorticoids is a stimulation of protein catabolism, with increased 266 Allan Munck · Inhibition ofGlucose Uptake Perspectives in Biology and Medicine · Winter 1971 carbohydrate levels following as a consequence of gluconeogenesis from the resulting amino acids. Originally Long and his co-workers did not attempt to specify the site of hormone action, which could clearly be either on peripheral tissues, with direct stimulation ofprotein breakdown, or on...