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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.
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