Download The Glucose/Fatty Acid Cycle 1963–2003

Regulation in Metabolism Group Colloquium Edited by M.A. Titheradge (Sussex) and P. Ferré (INSERM, Paris). Sponsored by AstraZeneca and Institut de
Recherches Servier. 679th Meeting of the Biochemical Society held at the University of Essex, Colchester, on July 2–4 2003.
The glucose–fatty acid cycle: a physiological
perspective
K.N. Frayn1
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, U.K.
Abstract
Glucose and fatty acids are the major fuels for mammalian metabolism and it is clearly essential that
mechanisms exist for mutual co-ordination of their utilization. The glucose–fatty acid cycle, as it was proposed
in 1963, describes one set of mechanisms by which carbohydrate and fat metabolism interact. Since that
time, the importance of the glucose–fatty acid cycle has been confirmed repeatedly, in particular by elevation
of plasma non-esterified fatty acid concentrations and demonstration of an impairment of glucose utilization.
Since 1963 further means have been elucidated by which glucose and fatty acids interact. These include
stimulation of hepatic glucose output by fatty acids, potentiation of glucose-stimulated insulin secretion by
fatty acids, and the cellular mechanism whereby high glucose and insulin concentrations inhibit fatty acid
oxidation via malonyl-CoA regulation of carnitine palmitoyltransferase-1. The last of these mechanisms,
discovered by Denis McGarry and Daniel Foster in 1977, provides an almost exact complement to the
mechanism described in the glucose–fatty acid cycle whereby high concentrations of fatty acids inhibit
glucose utilization. These additional discoveries have not detracted from the important of the glucose–fatty
acid cycle: rather, they have reinforced the importance of mechanisms whereby glucose and fat can interact.
Introduction
Glucose and fatty acids are the major oxidative fuels in
mammals. In humans they account typically for 80% of
oxidative metabolism. Cells can only dispose of as much ATP
as they have a need for. It is not surprising that powerful
regulatory mechanisms have evolved to co-ordinate control
of the utilization of glucose and fatty acids. It is within this
context that we should see the physiological importance of
the concept of the glucose–fatty acid cycle.
In current literature the ‘glucose–fatty acid cycle’ is often
taken to refer to pathophysiology brought about by elevated
plasma NEFA (non-esterified fatty acid) concentrations.
(Indeed, all too often the term ‘Randle cycle’ is used to refer
Key words: glucose utilization, hepatic glucose output, insulin resistance, insulin secretion, nonesterified fatty acid, tissue triacylglycerol.
Abbreviations used: ACC, acetyl-CoA carboxylase; CPT-1, carnitine palmitoyltransferase-1; NEFA,
non-esterified fatty acid(s); TG, triacylglycerol.
1
e-mail [email protected]
The Glucose/Fatty Acid Cycle 1963–2003
The Glucose/Fatty Acid Cycle
1963–2003: A Tribute to
Sir Philip Randle
to events in skeletal muscle only, thus ignoring what makes
it a cycle, as well as the contributions of Peter Garland, Nick
Hales and Eric Newsholme.) Those who take the trouble to
read the original paper by Philip Randle and his colleagues
[1] will realize that a major part of the paper concerned the
operation of the cycle in normal physiology. Here I would
like to stress how a careful reading of the paper shows that
the authors were amazingly prescient in their views of both
physiology and pathophysiology.
The glucose–fatty acid cycle and normal
physiology
Randle and his colleagues called it a cycle because it describes a series of events that interlink carbohydrate and fat
metabolism. The basic outline is simple and was well understood in the 1960s. In brief, an elevated glucose concentration
stimulates insulin secretion, which then suppresses NEFA
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Figure 1 Substrate and energy balance measured over 5 h following ingestion of three different isoenergetic meals varying in
macronutrient composition
Meal composition is shown below the histogram. Substrate and energy balance are caculated from the amount ingested
and the amount oxidized/expended, measured by indirect calorimetry. Energy balance (solid bars) was identical after
the three meals but oxidation of carbohydrate (hatched bars) and fat (open bars) varied reciprocally in accordance with the
composition of the meal. Data from [45].
release from adipose tissue depots. This removes competition
for substrate utilization in muscle, so that glucose utilization
may be stimulated by insulin, unimpeded by high concentrations of fatty acids. When plasma NEFA concentrations are
high, usually it is because glucose and insulin concentrations
are low, and fatty acids then naturally become the major fuel
for skeletal muscle. The original contribution from Randle
et al. was the demonstration that there is an additional
level of control: elevated fatty acid oxidation in muscle
will reduce glucose uptake and oxidation. This much all
makes perfect physiological sense. The ‘coarse’ control of
the reciprocal utilization of glucose and fatty acids in the
body is brought about through insulin secretion: fine-tuning
is provided in skeletal muscle, by the mechanism Randle et al.
elucidated in a series of studies prior to the ‘cycle’ paper. The
intimate but reciprocal relationship between carbohdyrate
and fat oxidation in vivo is illustrated in Figure 1. After
isoenergetic meals of differing macronutrient composition,
energy balance is identical, but the carbohydrate and fat
balances that contribute to energy balance change reciprocally
in accordance with meal composition.
The inhibitory effect of elevated NEFA concentrations
on glucose utilization by skeletal muscle has been shown
repeatedly in human experiments in vivo. The experimental
paradigm invariably involves infusion of an intravenous
TG (triacylglycerol) emulsion together with heparin, which
releases the enzyme lipoprotein lipase into the circulation.
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Lipoprotein lipase rapidly hydrolyses circulating TG to
raise plasma NEFA concentrations. Under these conditions,
the plasma NEFA concentration is often reported to be
elevated to supra-physiological levels, although these may
be artefactual, caused by continuing lipolysis in vitro [2].
It should also be noted that this is not a pure elevation of
plasma NEFA concentrations: plasma TG, monoacylglycerol
[3] and glycerol concentrations are also raised. Nevertheless,
the results are consistent: whole-body or, more specifically,
muscle glucose utilization is impaired [4,5], typically after
delay of about 2 h [6].
Since 1963, further aspects of the mutual interrelationships of glucose and fatty acids have come to light.
These include the effects of fatty acids themselves upon
glucose-stimulated insulin secretion, the effects of fatty
acids upon hepatic glucose metabolism and the mechanism
discovered by the late Denis McGarry and Daniel Foster in
1977 [7], whereby high glucose and insulin concentrations
can suppress fatty acid oxidation – the exact complement to
the mechanism described by Randle and colleagues. Again,
all these can be seen as further ‘fine-tuning’ of the balance
between glucose and fatty acid metabolism.
Fatty acids and insulin secretion
The recognition that fatty acids may act directly upon the
pancreatic β-cell to regulate glucose-stimulated insulin
The Glucose/Fatty Acid Cycle 1963–2003
Figure 2 Plasma insulin concentrations in response to glucose, in the presence of elevated concentrations of specific NEFA
Glucose was infused from 210 min to stimulate insulin secretion. The effect of elevation of fatty acids compared with
the control was highly significant (P < 0.001) and the effects of the various types of fatty acid were also different from
one another (P < 0.01). Data are from eight normal subjects, reproduced from Diabetologia, “Interaction between specific
fatty acids, GLP-1 and insulin secretion in humans”, C. Beysen, F. Karpe, B.A. Fielding, A. Clark, J.C. Levy and K.N. Frayn,
c Springer-Verlag GmbH & Co., with permission. Elevated NEFA: 䉱, monounsaturated;
vol 45, pp. 1533–1541, fig. 3, 2002 䊉, polyunsaturated; 䉭, saturated; 䊊, control (no elevation of fatty acid concentrations).
secretion is not new [8,9] but has received a boost with
more intensive study in recent years. It is now clear that
the effect of fatty acids upon glucose-stimulated insulin
secretion is biphasic. Initially fatty acids potentiate the effects
of glucose. After some hours of prolonged exposure to high
fatty acid concentrations (somewhere between 12 and 24 h)
this changes to an inhibition [10]. Since prolonged high fatty
acid concentrations are a feature of pathophysiology rather
than normal daily life, we might imagine that the normal
physiology of this system is that high levels of fatty acids, if
present together with an elevated glucose concentration, tend
to limit their own utilization by some stimulation of insulin
secretion [11,12]. It is also clear that there is a critical need for
fatty acids for the β-cell to be able to respond to glucose [13].
One feature of this mechanism that has caused some interest
is that, at least in perifused or isolated islets, the effect of fatty
acids upon glucose-stimulated insulin secretion is fatty acidspecific [14]. Saturated fatty acids cause more potentiation
than do unsaturated ones [15]. This has led to speculation
that dietary saturated fatty acids might tend to lead to insulin
resistance through chronic stimulation of insulin secretion.
However, when tested in vivo in humans, the effect is not
so clear cut, perhaps because of interaction with glucagonlike peptide-1 secretion; in fact the greatest effect is then
seen with monounsaturated fatty acids [16] (Figure 2). The
mechanism for the stimulatory effect of fatty acids upon
glucose-stimulated insulin secretion is not yet entirely clear
although a cell-surface G-protein-coupled receptor for fatty
acids has recently been described in β-cells [17]. The longerterm inhibitory effects seem to reflect accumulation of TG
and long-chain acyl-CoA in the β-cell with possible direct
effects of the latter on ATP-channel activity [18].
Fatty acids and hepatic glucose production
The effect of fatty acids upon hepatic glucose metabolism
was first shown in vivo in humans by Ferrannini and
colleagues [4]. They showed that elevated circulating NEFA
concentrations stimulated hepatic glucose output in the
presence of relative insulinopaenia. This effect has been
the subject of many investigations (e.g. [6,19–21]). It has
also been debated to a considerable extent. Hepatic glucose
production in the fasted state is via two routes: glycogenolysis
and gluconeogenesis. Some studies suggest that fatty acids
stimulate one or other of these processes, but that ‘hepatic
autoregulation’ adjusts the other to compensate so that total
glucose output is unaffected [19,22]. On balance, however,
what seems clear is that fatty acids will counteract the normal
insulin-suppression of hepatic glucose output [20,22,23].
At first sight this seems like pathophysiology rather than
physiology. Inappropriately elevated fatty acid concentrations – as seen in type 2 diabetes, for example [24] – stimulate
glucose production, and glucose intolerance is worsened.
But there is an alternative view. The interactions between
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glucose and fatty acids seem mainly to ensure preferential
use of glucose when available, and preservation of fat stores.
That could be said for the potentiation of glucose-stimulated
insulin secretion by fatty acids: high fatty acid concentrations
will down-regulate themselves. Just the same is true for the
effect on hepatic glucose output. We should remember that
the substrates for gluconeogenesis are mainly glucose-derived
(i.e. recycled glucose from peripheral tissues in the form
of lactate, pyruvate and alanine), so fatty acids are simply
replacing carbohydrate-derived substrates as a fuel for hepatic
metabolism and thereby regulating their own usage.
The suppression of hepatic glucose output by insulin has
been attributed, by some, to an indirect effect, possibly via
lowering of NEFA supply to the liver [25,26]. This does not
seem to be borne out in the liver-specific insulin-receptorknockout mouse: insulin-induced suppression of hepatic
glucose output was lost, despite normal lowering of plasma
NEFA by insulin [27]. But that is a very unphysiological system [28] and, on balance, a substantial role of NEFA in normal regulation of hepatic glucose output remains probable.
Malonyl-CoA and fatty acid oxidation
Finally, in ‘updating’ the normal physiology that the glucose–
fatty acid cycle underlies, one must appreciate the beautiful
complementarity of the regulation of fatty acid oxidation by
glucose, achieved through malonyl-CoA inhibition of CPT-1
(carnitine palmitoyltransferase-1). Although McGarry et al.
first described this as a mechanism whereby carbohydrate
availability reduced ketogenesis in the liver [7], we now recognize that the same mechanism operates in muscle and perhaps
other tissues. The muscle-specific isoform of CPT-1 is actually more sensitive to inhibition by malonyl-CoA than is
the liver isoform [29]. An interesting feature to emerge
from more recent work is that there also two isoforms of
ACC (acetyl-CoA carboxylase; producing malonyl-CoA),
one (ACC-1 or ACC-α) expressed in tissues that synthesize
fatty acids (e.g. liver, adipose tissue), the other (ACC-2 or
ACC-β) expressed in non-lipogenic tissues such as skeletal
and cardiac muscle. ACC-2 is generally expressed along with
the muscle isoform of CPT-1 [29]. There can be little doubt
that the purpose of ACC-2 is to produce malonyl-CoA
purely for the purpose of regulation of fatty acid oxidation.
In summary, we now recognize more aspects in which
fatty acid and glucose metabolism are inter-related than
were known in 1963. But none of these detracts from the
basic aspects of the glucose–fatty acid cycle as it was originally applied to explaining normal physiology: they simply
reinforce the powerful need of the organism to regulate
oxidation of these two major fuels.
The glucose–fatty acid cycle and
pathophysiology
TG accumulation in tissues
Most citations of the 1963 paper [1] refer to elevated
NEFA concentrations inhibiting glucose utilization. In fact
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the paper was very clear in discussing elevated fatty acid
supply, and Randle et al. recognized the potential importance
of TG accumulation within tissues (especially muscle) in
contributing acyl groups for β-oxidation:
“We suggest that there is a distinct biochemical syndrome . . .
due to breakdown of glycerides in adipose tissue and
muscle, the symptoms of which are a high concentration of plasma NEFA, impaired sensitivity to insulin . . . ”
Again, this was amazingly prescient. A close relationship
between muscle TG accumulation and insulin resistance is
now well established [30,31]. There is debate about whether
TG accumulation in muscle is the cause or an effect of insulin
resistance. Observations of impaired fatty acid oxidation in
muscle in insulin-resistant states might suggest the latter [32–
34], but when muscle TG concentrations are manipulated
acutely by altering NEFA supply, insulin resistance runs
in parallel [35]. It has been suggested that acyl-CoAs are
the active species in mediating insulin resistance in this
context [36,37]; parenthetically, it should be noted that Randle
and colleagues also anticipated this: “One possibility . . . is
inhibition of the enzymes concerned by acyl coenzyme
A compounds” [1]. More recently, imaging techniques to
measure liver TG content have also shown close relationships
with insulin resistance [38,39]. This can also be linked to
the longer-term suppressive effect of fatty acids on glucosestimulated insulin secretion, referred to above: this effect may
relate to TG accumulation within the pancreatic islet [40].
In fact, in animal models in which the tissue TG content
is varied (e.g. by adenoviral expression of leptin to reduce
fat stores), there is a close relationship between whole-body
insulin sensitivity and the TG content of muscle, liver and
pancreas [41].
Metabolic ‘inflexibility’
The concept of ‘metabolic inflexibility’ has recently been
discussed in association with insulin resistance [42–44].
The idea is that tissues (such as skeletal muscle) normally
adapt their use of metabolic fuels in a dynamic manner
according to nutrient supply. Skeletal muscle, for instance,
oxidizes mainly fatty acids in the postabsorptive state but
mainly glucose in the postprandial state. David Kelley and
colleagues proposed that insulin resistance is characterized
by ‘metabolic inflexibility’. They illlustrated this with data
from studies of human leg glucose oxidation in vivo. In
the postabsorptive state, glucose oxidation (relative to fat
oxidation, as measured by the local respiratory quotient)
is not reduced in insulin-resistant obese or type 2 diabetic
subjects; in fact it is higher than in lean, insulin-sensitive
subjects. But when the postprandial state is simulated by
infusion of glucose and insulin, then glucose oxidation rises
sharply in the leg of lean subjects, whereas it does not change
in obese and diabetic subjects, with the result that under
hyperinsulinaemic conditions muscle glucose oxidation is
lower in insulin-resistant than in insulin-sensitive subjects
The Glucose/Fatty Acid Cycle 1963–2003
[42]. The explanation may well relate to the glucose–fatty
acid cycle. This condition of metabolic inflexibility is closely
associated with muscle TG accumulation [43,44]. It could be
that lipid fuel supply to the muscle is dominated by the intracellular lipid deposits, and continues to be available even in the
presence of high external glucose and insulin concentrations.
The concept of metabolic flexibility (insulin sensitivity) and
inflexibility (insulin resistance) may, in fact, be an alternative
way of looking at the glucose–fatty acid cycle.
I thank the Wellcome Trust and the Humane Research Trust for
funding our work in this area.
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Received 11 June 2003
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