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This Week's Citation Classic CC/NUMBER 31 AUGUST 3, 1981 Randle P J, Garland P B, Hales C N & Newsholme E A. The glucose fattyacid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785-9, 1963. [Department of Biochemistry, University of Cambridge, Cambridge, England] was added) decreased by ketone The 'glucose fatty-acid cycle' describes the bodies. Studies of the effects of anoxia reciprocal relationship between the catabolism of glucose and lipid fuels in animals. between 1956 and 1961 identified Evidence was given that release and oxidamembrane transport, hexokinase, and tion of lipid fuels inhibits metabolic phosphofructokinase as rate-limiting degradation of glucose in muscles, and conreactions for glucose uptake and versely that metabolic effects of glucose inglycolysis in in vitro preparations of hibit release of lipid fuels and thereby heart and diaphragm muscles. Work in facilitate uptake and oxidation of glucose. the latter half of 1961 and early 1962 The physiologic and pathologic significance of this concept is discussed. [The SCI® indishowed that metabolism of fatty acids cates that this paper has been cited over 800 (and ketone bodies) inhibited these times since 1963.] reactions and additionally pyruvate dehydrogenase. The effects of fatty acids (and ketone bodies) were quantitatively very similar to the changes efPhilip J. Randle fected by starvation or induction of Department of Clinical Biochemistry alloxan-diabetes in the rat. John Radcliffe Hospital "In consequence, much of 1962 was Oxford 0X2 6HE taken up with obtaining evidence for England increased intracellular provision of fatty acids in heart and diaphragm muscles of diabetic or starved animals. By June 16, 1981 the end of 1962, we were convinced "My collaborators were all graduate that we had sufficient evidence to students in the department of biochemjustify writing a conceptual paper on istry at Cambridge. They have each regulatory interactions between glumade distinguished careers. Peter cose and fatty-acid metabolism and Garland is head of the department of their physiologic and pathologic signifibiochemistry in Dundee, Nick Hales is cance. This paper was written in head of the department of clinical January 1963. biochemistry at Cambridge, and Eric "Perhaps this paper has been cited Newsholme is lecturer in biochemistry frequently because it summarised, at and fellow of Merton College in Oxan opportune moment, a phase in the ford development of understanding of the "As a graduate student at Camprocess of fuel selection in mammalian bridge, I had worked on the rat muscle. I hope that it adequately diaphragm assay for insulin and anti-inrepresented and acknowledged the sulin factors in blood plasma. This excontribution of colleagues in other perience convinced me that the route laboratories. The main controversy to an understanding of the factors over the glucose fatty-acid cycle since which modify the action of insulin in then has been its applicability to muscle was through identification of skeletal muscle, and its quantitative rate-limiting reactions in the tissue and importance in the whole animal. of the biochemistry of their regulation. However, recent work by M.J. Rennie The pioneer of this general experimenand J . O . Holloszy has shown its applital approach was the late E.W. Suthercability to red skeletal muscle and reland 1 emphasised its importance in vivo.2 In 1956, I had the good fortune to Much of my own work since 1963 has observe that glucose uptake and been concerned with detailed biog l y c o l y s i s in diaphragm muscle are inchemical mechanisms relevant to the Creased by anoxia and (provided insulin general concept." 1 Sutherland E W. The effect of the hyperglycaemic factor of the pancreas and of epinephrine on glycogenolysis. Recent Progr Hormone Res 5-441-59, 1950. 2 Rennle M J & Hollozy J O. Inhibition of glucose uptake and glycogenolysis by availability of oleate in welloxygenated perfused skeletal muscle Biochemical J. 168:16l-70, 1977. 248