Am J Physiol Endocrinol Metab 282: E125–E131, 2002.
10.1152/ajpendo.00177.2001.
Effects of fatty acids on exercise plus insulin-induced
glucose utilization in trained and sedentary subjects
OSCAR MATZINGER, PHILIPPE SCHNEITER, AND LUC TAPPY
Institute of Physiology, School of Medicine, University of Lausanne, 1005 Lausanne, Switzerland
Received 18 April 2001; accepted in final form 10 September 2001
Matzinger, Oscar, Philippe Schneiter, and Luc
Tappy. Effects of fatty acids on exercise plus insulin-induced
glucose utilization in trained and sedentary subjects. Am J
Physiol Endocrinol Metab 282: E125–E131, 2002; 10.1152/
ajpendo.00177.2001.—Fatty acids are known to decrease in-
sulin-mediated glucose utilization in humans, both at rest
and during exercise. To evaluate the effect of endurance
training in this process, we infused lipids or saline in groups
of sedentary and highly trained subjects. Whole body glucose
utilization and substrate oxidation were monitored during a
2.5-h hyperinsulinemic clamp. During the last 30 min, a
cycling exercise was superimposed. During hyperinsulinemia
at rest, whole body glucose utilization and glucose oxidation
were higher in trained subjects than in sedentary subjects.
Compared with the control experiments with the antilipolytic
agent acipimox, lipid infusion stimulated lipid oxidation to
the same extent in trained as in sedentary subjects. It re-
duced whole body glucose utilization by 37% in trained and
by 41% in sedentary subjects. During exercise, lipid infusion
increased more lipid oxidation in trained than in sedentary
subjects and reduced whole body glucose utilization by 43 ⫾
4% in trained and by 22 ⫾ 4% in sedentary subjects (P ⬍
0.01). The present data indicate that lipid infusion has sim-
ilar effects on lipid oxidation and whole body glucose utiliza-
tion during hyperinsulinemia at rest in trained and seden-
tary subjects. During exercise, however, it increases more
lipid oxidation and produces a more important reduction in
glucose utilization in trained than in sedentary subjects.
These results suggest that endurance training enhances the
inhibitory effect of lipids on whole body glucose metabolism
during exercise.
insulin; exercise; whole body glucose utilization; lipid oxida-
tion
IT HAS BEEN KNOWN FOR A LONG TIME that infusion of a lipid
emulsion impairs glucose tolerance (15) and decreases
insulin-mediated glucose disposal (12) in healthy hu-
mans. Lipids inhibit both glucose oxidation and stor-
age (33) and exert this effect primarily in skeletal
muscle (24). These effects are observed not only at rest
but also during exercise (16, 28) and during the recov-
ery period after an exercise (6).
Endurance training has profound effects on skeletal
muscle substrate utilization. It results in an increased
lipid utilization by working muscles at low to moderate
exercise intensity (17). This increased contribution of
Address for reprint requests and other correspondence: L. Tappy,
Institut de physiologie, Rue du Bugnon 7, CH-1005 Lausanne, Swit-
zerland (E-mail: Luc.Tappy@iphysiol.unil.ch).
http://www.ajpendo.org 0193-1849/02 $5.00 Copyright © 2002 the American Physiological Society
lipid oxidation to total energy expenditure in endur-
ance-trained vs. sedentary individuals is observed at
both the same relative and same absolute workloads (1,
17). Endurance training may affect several key steps in
lipid metabolism to attain such an increase in lipid
oxidation by skeletal muscle: an enhanced lipolysis of
triglyceride stored in adipose tissue and/or within the
muscle fibers, an enhanced uptake of circulating lipids
by working muscle, and an enhanced ␤-oxidation of
fatty acids may all possibly be involved (19). How these
metabolic adaptations to endurance training affect the
interactions between glucose and lipid metabolism re-
mains, however, unknown. The aim of this study was
therefore to assess the effects of endurance training on
the inhibition of whole body glucose metabolism by
lipids at rest and during exercise.
METHODS
Subjects
Nine endurance-trained cyclists (group T) and seven
healthy sedentary volunteers (group S) were selected to take
part in this study. All subjects underwent a medical evalua-
tion including history, physical examination, and electrocar-
diogram. They were all in good physical health, were not
taking any medication, were nonsmokers, and had no famil-
ial history of diabetes or obesity (Table 1).
The endurance-trained cyclists were selected on the basis
of having biked ⬎4,000 km/yr for the previous 2 yr. The
sedentary volunteers did not perform any kind of sport (in-
cluding physical activity at work) for the previous 2 yr.
The experimental protocol was approved by the ethics
committee of the Lausanne University Medical School, and
all participants provided informed written consent. Percent
body fat was estimated from skinfold thickness measure-
ments with the use of standard formulas (10).
Maximal oxygen uptake was measured on an electronically
braked cycle ergometer during an incremental exhaustive
exercise test. For the trained subjects, exercise started at a
power output of 150 W, which was increased by 30 W every
minute until exhaustion. The same procedure was used for
sedentary subjects, except that exercise was started at a
power output of 50 W. Respiratory gases were analyzed via
open-circuit indirect calorimetry as described (20) and were
recorded on line.
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
E125
E126 METABOLIC EFFECTS OF FATTY ACIDS AND TRAINING
Table 1. Subjects’ characteristics
Sedentary Group Trained Group
n 7 9
Age, yr 23.4 ⫾ 3.2 24.3 ⫾ 3.3
Body mass, kg 61.5 ⫾ 9.6 68.2 ⫾ 5.1
Height, cm 174.6 ⫾ 5.9 178.7 ⫾ 5.6
BMI, kg/m2 20.3 ⫾ 2.1 21.4 ⫾ 0.9
Body fat, % 14.7 ⫾ 3.8 10.4 ⫾ 2.3
FFM, kg 52.4 ⫾ 8.4 61.1 ⫾ 4.7
V̇O2max, ml/min 2541 ⫾ 217 4591 ⫾ 170
Values are means ⫾ SD. BMI, body mass index; FFM, fat-free
mass; V̇O2 max, maximal oxygen uptake.
Experimental Protocol
Each subject took part in two different protocols separated
by ⱖ2 wk. The order in which the two protocols were per-
formed was randomly assigned. During the 3 days preceding
each protocol, subjects were requested not to perform heavy
physical activity. They were also asked not to consume any
drinks containing caffeine or alcohol during the 24 h preced-
ing each protocol.
In both protocols, subjects were studied in the morning
after an overnight fast. After having voided, subjects lay
quietly supine in bed. Intravenous catheters were placed
percutaneously in an antecubital vein of each arm. One
catheter was used for infusion of [6,6-2H2]glucose, insulin,
dextrose, and a soybean lipid emulsion (20% Lipovenös, Fre-
senius, Stans, Switzerland). The contralateral catheter was
used for periodic collection of blood samples. The heated hand
technique was used, with a thermostabilized box heated
at 50°C, to obtain partially arterialized blood samples.
Throughout the experiments, respiratory gas exchanges were
monitored by open-circuit indirect calorimetry by means of a
transparent hood ventilated with ⬃40 l/min (16). A primed
(4 mg/kg bolus), continuous infusion of [6,6-2H2]glucose,
(40 ␮g 䡠 kg⫺1 䡠 min⫺1; MassTrace, Woburn, MA) was started
immediately after the insertion of the venous cannula. Sixty
minutes later, a hyperinsulinemic euglycemic (0.4 mU 䡠
kg⫺1 䡠 min⫺1) clamp (glucose ⫽ 5 mmol/l) was started (time 0).
Exogenous glucose was labeled with 1.25% [6,6-2H2]glucose
(hot infusate technique) to calculate whole body glucose rate
of disappearance (14).
Two hours after the beginning of the clamp, the subjects
were transferred to an ergometric bicycle (Schiller ergometer
CE 0.124; Baar, Switzerland) where they remained seated for
the next 35 min. A hood was fitted over their heads to allow
collection of expiratory gases and was ventilated with ambi-
ent air at a rate of 250 l/min. After 5 min of preparation and
adaptation of the subject, a cycling exercise at a power output
of 100 W was performed during 30 consecutive minutes.
Because there was a significant degree of hyperventilation
during the initial period of exercise, only the last 10 min of
exercise were recorded. Plasma bicarbonate concentrations
remained steady during this period.
Protocol 1: lipid infusion. This test was performed to as-
sess insulin-mediated glucose disposal at rest and during
exercise in presence of elevated plasma free fatty acid (FFA)
concentrations (condition L). A continuous infusion of 20%
Lipovenös (1 ml/min) was started 60 min before the begin-
ning of insulin infusion and was continued throughout the
test to maintain elevated plasma FFA concentrations.
Protocol 2: administration of acipimox. This test (condition
Acx) was performed to assess insulin sensibility at rest and
AJP-Endocrinol Metab • VOL 282 • JANUARY 2002 •
during exercise in the presence of very low FFA plasma
levels. All subjects received 250 mg of the antilipolytic agent
acipimox (Olbetam; Pharmacia & Upjohn, Dübendorf, Swit-
zerland) at the beginning of the test and again 2 h later to
efficiently suppress plasma FFA concentrations.
Analytical Procedures
Plasma glucose was determined by the oxidase method,
using a Beckman Glucose Analyzer II (Beckman Instru-
ments, Fullerton, CA). Plasma FFA concentrations were
determined by a colorimetric assay kit (Wako, Freiburg,
Germany). Plasma lactate concentrations were measured
enzymatically (18). Plasma insulin concentrations were mea-
sured by radioimmunoassay (kit from Biodata Guidonia,
Montecello, Italy, with ⬍14% cross-reactivity with proinsu-
lin). Urinary urea concentration was analyzed enzymatically
using a Beckman urea analyzer (Beckman Instruments).
Plasma [6,6-2H2]glucose was measured by gas chromatogra-
phy-mass spectrometry, as described (32).
The rates of glucose appearance (Ra) and disappearance
(Rd) were calculated from plasma [6,6-2H2]glucose enrich-
ment using hot infusate equations (14).
Endogenous glucose production was calculated as glucose
Ra ⫺ the rate of exogenous dextrose infusion.
The percent reduction in glucose Rd induced by lipids
between protocols 1 (lipids, L) and 2 (acipimox, Acx) was
calculated as
RdAcx ⫺ RdL
% reduction ⫽ 䡠 100
RdAcx
Statistical Analysis
All results are expressed as means ⫾ SE unless stated
otherwise. Comparisons between groups were performed by
multiple way analysis of variance. Post hoc comparisons were
made using Fisher’s protected least significant difference.
Statistical significance was set at ␣ ⫽ 0.05.
RESULTS
Plasma Hormones and Substrate Concentrations
During the initial 2 h at rest, plasma glucose was
clamped at the following values: trained subjects dur-
ing lipid infusion (TL), 5.54 ⫾ 0.29 mmol/l; trained
subjects after acipimox (TAcx), 5.44 ⫾ 0.35 mmol/l;
sedentary subjects during lipid infusion (SL), 5.55 ⫾
0.23 mmol/l; and sedentary subjects after acipimox
(SAcx), 5.57 ⫾ 0.63 mmol/l. During the next 30 min,
with a cycling exercise at a power output of 100 W, the
following plasma glucose concentrations were main-
tained: TL, 5.29 ⫾ 0.54 mmol/l; TAcx, 5.32 ⫾ 0.62
mmol/l; SL, 5.6 ⫾ 0.52 mmol/l; and SAcx, 5.58 ⫾ 0.4
mmol/l. Steady-state plasma insulin concentrations at
rest were similar under all four conditions (TL, 260.8 ⫾
10.9 pmol/l; TAcx, 223.3 ⫾ 7.1 pmol/l; SL, 275.1 ⫾ 6.8
pmol/l; SAcx, 256.5 ⫾ 6.5 pmol/l). They were minimally
affected by exercise (Fig. 1). Steady-state plasma FFA
concentrations were similarly increased to high physi-
ological values in TL (0.395 ⫾ 0.12 mmol/l) and SL
(0.415 ⫾ 0.28 mmol/l); they were suppressed to the
same extent in both groups with acipimox (TAcx,
0.033 ⫾ 0.004 mmol/l; SAcx, 0.035 ⫾ 0.003 mmol/l; P ⬍
0.0001 vs. TL and SL; Fig. 2).
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 METABOLIC EFFECTS OF FATTY ACIDS AND TRAINING
Fig. 1. Plasma glucose and insulin concentrations in trained (T) and
sedentary (S) subjects during lipid infusion (L) or after acipimox
infusion (Acx). Exercise at 100 W (Ex) was performed during the last
30 min.
Plasma lactate concentrations were similar in the
two groups under both Lipovenös and acipimox at rest:
TL, 1.319 ⫾ 0.035 mmol/l; TAcx, 1.358 ⫾ 0.055 mmol/l;
SL, 1.147 ⫾ 0.042 mmol/l; and SAcx, 1.212 ⫾ 0.039
mmol/l. During exercise, plasma lactate concentrations
markedly increased in sedentary subjects with both
Lipovenös and acipimox (P ⬍ 0.001 under both condi-
Fig. 2. Plasma free fatty acid (FFA) concentrations in T and S
subjects during L or after Acx. Exercise at 100 W was performed
during the last 30 min.
AJP-Endocrinol Metab • VOL 282 • JANUARY 2002 •
E127
Fig. 3. Plasma lactate concentrations. Same symbols as for Fig. 1.
tions) but remained unchanged in trained individuals
(Fig. 3).
Indirect Calorimetry
Basal carbohydrate oxidations were lower during
lipid infusion (TL, 12.16 ⫾ 0.74 vs. SL, 13.72 ⫾ 2.52
mmol 䡠 kg⫺1 䡠 min⫺1) than after acipimox (TAcx, 17.55 ⫾
2.46 vs. SAcx, 16.64 ⫾ 1.54 mmol 䡠 kg⫺1 䡠 min⫺1, P ⬍
0.05 in both groups) (Fig. 3). Carbohydrate oxidation
rates during hyperinsulinemia at rest were also lower
during lipid infusion (TL, 16.43 ⫾ 1.24 vs. SL, 15.01 ⫾
1.16 mmol 䡠 kg⫺1 䡠 min⫺1) than after acipimox (TAcx,
25.05 ⫾ 2.05 vs. SAcx, 23.36 ⫾ 2.33 mmol 䡠 kg⫺1 䡠 min⫺1,
P ⬍ 0.01 in both groups). During exercise, carbohy-
drate oxidation increased significantly in all protocols.
It was, however, significantly lower in trained than in
sedentary subjects with both lipid infusion (P ⫽
0.0005) and acipimox (P ⫽ 0.0071). Compared with the
values obtained after acipimox, lipid infusion reduced
carbohydrate oxidation during exercise by 27.6% in
trained subjects [not significant (NS)] and by 38.5% in
sedentary subjects (NS) (Fig. 4).
Lipid oxidation at rest mirrored carbohydrate oxida-
tion. Basal lipid oxidation rate was 67% higher in TL
than in TAcx, and 73% higher in SL than in SAcx.
During hyperinsulinemia at rest, lipid oxidation rate
was 307% higher in TL than in TAcx, and 404% higher
in SL than in SAcx. Lipid oxidation rates during this
period were comparable in trained and sedentary sub-
jects in both protocols. During exercise, lipid oxidation
increased markedly in trained subjects, but only mod-
estly in sedentary subjects. Lipid oxidation rates were
263% higher in TL than in SL (P ⬍ 0.0004) and 283%
higher in TAcx than in SAcx (NS) (Fig. 4).
Glucose Ra
During the last 15 min of hyperinsulinemia at rest,
glucose Rd values were TL, 6.74 ⫾ 0.51 mg 䡠 kg⫺1 䡠
min⫺1; TAcx, 10.71 ⫾ 0.74 mg 䡠 kg⫺1 䡠 min⫺1 (P ⬍ 0.0001
vs. TL); SL, 4.09 ⫾ 0.66 mg 䡠 kg⫺1 䡠 min⫺1 (P ⬍ 0.0001
vs. TL); and SAcx, 6.89 ⫾ 0.34 mg䡠kg⫺1 䡠min⫺1 (P ⫽
0.0001 vs. TAcx, P ⫽ 0.0045 vs. SL) (Fig. 4). Glucose Rd
values during the last 10 min of exercise were TL,
11.68 ⫾ 1.01 mg䡠kg⫺1 䡠min⫺1; TAcx, 20.93 ⫾ 1.69
mg䡠kg⫺1 䡠min⫺1 (P ⬍ 0.0001 vs. TL); SL, 9.56 ⫾ 0.75
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E128 METABOLIC EFFECTS OF FATTY ACIDS AND TRAINING
Fig. 4. Net substrate oxidation in basal conditions, during hyperin-
sulinemia at rest (Clamp), and during hyperinsulinemia at exercise
(Exercise at 100 W). ffm, Fat-free mass. *P ⬍ 0.05, **P ⬍ 0.01 TAcx
vs. TL; #P ⬍ 0.05, ##P ⬍ 0.01 SAcx vs SL.
mg䡠kg⫺1 䡠min⫺1 (NS vs. TL); and SAcx, 12.21 ⫾ 0.73
mg䡠kg⫺1 䡠min⫺1 (P ⬍ 0.0001 vs. TAcx, NS vs. SL) (Fig. 5).
The percent reduction in glucose Rd induced by lipids
at rest was 37.2 ⫾ 2.1% in trained subjects and 38.9 ⫾
10.9% in sedentary subjects (NS). During exercise, it
was 43.6 ⫾ 3.7% in trained subjects and 21.9 ⫾ 3.9% in
sedentary subjects (P ⬍ 0.01) (Fig. 6).
DISCUSSION
Endurance training increases the utilization of lipids
as an energetic substrate to the working skeletal mus-
cle (1, 17). The aim of this study was to assess whether
Fig. 5. Glucose rate of disappearance in basal conditions, during
hyperinsulinemia at rest and during hyperinsulinemia at exercise.
See text for other significances. *P ⬍ 0.05, **P ⬍ 0.01 TAcx vs. TL;
#P ⬍ 0.05, ##P ⬍ 0.01 SAcx vs. SL.
AJP-Endocrinol Metab • VOL 282 • JANUARY 2002 •
Fig. 6. Percent reduction in glucose rate of disappearance (GRD)
induced by lipid infusion in trained and sedentary subjects. **P ⬍
0.01 vs trained.
these metabolic adaptations to endurance training al-
ter the inhibitory effects of lipids on whole body glucose
utilization. For this purpose, we studied highly endur-
ance-trained athletes and sedentary individuals. The
important difference in physical fitness between the
two groups of subjects tested was indeed documented
by the markedly higher maximal oxygen uptake ob-
served in trained athletes as well as by the increase in
lactate concentrations during a moderate exercise in
sedentary subjects. The rationale for studying these
two groups of individuals lies in the increased capacity
of endurance-trained subjects to oxidize lipids during
an exercise performed at the same absolute workload
(1, 17). We therefore expected that infusion of a lipid
emulsion during an exercise performed at physiological
high insulin concentrations would produce a similar
increase in plasma FFA concentrations in trained and
sedentary subjects but a more important stimulation of
lipid uptake and oxidation in skeletal muscle of trained
subjects. To avoid possible differences in the antilipo-
lytic effects of insulin and in stimulation of lipolysis
during exercise between the two groups of subjects,
control experiments with pharmacological inhibition of
lipolysis were performed. This allowed us to evaluate
the effects of lipids on glucose disposal by calculating
the relative reduction in glucose disposal between the
lipid and antilipolytic (acipimox) protocols.
Our results indicate that our experimental design
was indeed adequate for our purpose. Insulin infusion
resulted in similar plasma insulin concentrations in
trained and sedentary subjects both during lipid infu-
sion and after acipimox. Lipid infusion allowed the
maintenance of plasma FFA concentrations in the nor-
mal postabsorptive range throughout the hyperinsu-
linemic and exercise procedures. Moreover, absolute
plasma FFA concentrations were quite comparable be-
tween trained and sedentary subjects. Acipimox ad-
ministration nearly completely suppressed adipose tis-
sue lipolysis throughout the procedure, as indicated by
steady, low plasma FFA concentrations during the 220
min of the experiments. Finally, plasma glucose con-
centrations were adequately clamped at comparable
values in all protocols.
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 METABOLIC EFFECTS OF FATTY ACIDS AND TRAINING
During the initial 2-h period of hyperinsulinemia,
while subjects were resting quietly in the supine posi-
tion, insulin-mediated glucose disposal was 65% higher
in trained vs. sedentary subjects during lipid infusion
and 55% higher after acipimox. This observation was
expected and reflects the well-known effect of physical
fitness and endurance training to increase insulin sen-
sitivity (4, 7). Infusion of lipids, which produced similar
increases in plasma FFA concentrations and in lipid
oxidation rates in trained and sedentary subjects, also
produced the same relative inhibition of insulin-medi-
ated glucose disposal in both groups of subjects. This
indicates that elevated plasma FFA concentrations are
equally effective in impairing insulin actions in trained
and sedentary subjects at rest.
The mechanisms by which elevated FFAs produce
insulin resistance are still controversial. It was pro-
posed by Randle et al. (26) that an elevated concentra-
tion of FFA stimulates FFA oxidation in skeletal and
cardiac muscle. According to the hypothesis enunciated
by these investigators, fat oxidation gives rise to in-
creased intracellular concentrations of acetyl-CoA,
ATP, and citrate, which in turn inhibit glycolysis and
the entry of pyruvate into the tricarboxylic acid cycle.
It results in an increase in intracellular glucose 6-phos-
phate, which in turn inhibits hexokinase and cellular
glucose uptake. Several observations, however, sug-
gest that FFA may decrease insulin sensitivity through
other mechanisms unrelated with lipid oxidation.
Boden et al. (2) observed that an infusion of lipids in
healthy humans rapidly increased glucose oxidation at
the expense of lipid oxidation; inhibition of nonoxida-
tive glucose disposal, however, was delayed by several
hours, suggesting that this effect was not directly re-
lated to lipid oxidation. Furthermore, glucose 6-phos-
phate concentrations were not decreased in skeletal
muscle biopsies obtained 6 h after the beginning of
lipid infusions. Roden et al. (27) studied skeletal mus-
cle metabolism with nuclear magnetic resonance spec-
troscopy in healthy subjects during lipid infusion. They
observed that lipids suppressed glycogen synthesis and
decreased the intracellular concentrations of glucose
6-phosphate. Interestingly, it was also reported that
skeletal muscle glucose 6-phosphate concentrations
are not increased in humans or Rhesus monkeys with
type 2 diabetes (25). In view of these observations, it is
proposed that FFAs exert a direct inhibitory effect in
the insulin resistance induced by lipids. Inhibition of
insulin receptor substrate 1 associated with phospha-
tidylinositol 3-kinase activity may be involved in this
effect (9).
During exercise, lipid infusion resulted in similar
plasma FFA concentrations in trained and sedentary
subjects, but in markedly higher lipid oxidation rates
in trained subjects. This reflects the well-known effect
of training on muscle fuel oxidation (17). The major
novel observation of this study was that, despite simi-
lar plasma FFA concentrations, the reduction by lipids
of whole body glucose disposal during exercise was
about twice as important in trained as in sedentary
subjects.
AJP-Endocrinol Metab • VOL
E129
Several explanations can be proposed for the en-
hanced effect of lipids on glucose metabolism in en-
durance-trained individuals. Infused lipids initially
combine with circulating apolipoproteins to form li-
poproteins similar to very-low-density lipoproteins in
the circulation (5). The triglycerides present in these
particles are subsequently hydrolyzed to fatty acids by
lipoprotein lipase in the capillaries of skeletal muscle
and adipose tissue. Endurance training significantly
increases the synthesis of lipoprotein lipase in skeletal
muscle (21, 30) and, hence, is expected to enhance the
proportion of infused triglycerides, which are taken up
as FFA by skeletal muscle. A role of lipoprotein lipase
in insulin sensitivity is indeed supported by the recent
observation of transgenic mice overexpressing lipopro-
tein lipase being markedly insulin resistant (13).
It is recognized that FFAs enter the skeletal muscle
cell by a carrier-mediated process (3). Three puta-
tive fatty acid transporters have been identified so far
[fatty acid translocase (FAT/CD36), plasma membrane
fatty acid binding protein (FABPPM), fatty acid trans-
port protein]. If cellular FFA uptake was increased as
a consequence of endurance training, it might result in
an increase in intracellular long-chain fatty acyl-CoA
concentrations, the putative mediator of glucose trans-
port inhibition. An upregulation of fatty acid transport-
ers by exercise training has indeed been suggested.
Several reports indicate that chronic muscle stimula-
tion increases FABP (24) and FAT/CD36 (3) or FABP
and FAT/CD36 (26) in rats. Other studies, however,
failed to observe an effect of training on these param-
eters (11, 34). Our present observation indicates that
similar FFA concentrations are equally effective in
reducing insulin-mediated glucose metabolism in
trained and sedentary subjects at rest and exert an
enhanced inhibition only during exercise. If the effects
of FFA were primarily exerted through an increase in
intracellular long-chain fatty acyl-CoA, this would im-
ply an acute increase in skeletal muscle FFA transport
during muscle contraction. Such an effect of muscle
contraction on FFA uptake has indeed been suggested
(11) but remains to be demonstrated.
Lipid oxidation was significantly higher in endur-
ance-trained individuals. This may be secondary to an
increased uptake of FFA in skeletal muscle. An en-
hanced activity of the enzyme carnitine palmitoyl-
transferase I may also be involved (31). Interestingly,
lipid oxidation was higher in endurance-trained indi-
viduals during exercise even when acipimox was used
to inhibit adipose tissue lipolysis. This observation is
consistent with the report that endurance training
increases oxidation of intramuscular triglycerides (29).
Altogether, our results indicate that the inhibitory
effects of lipids on whole body glucose utilization are
enhanced in endurance-trained subjects during exer-
cise plus hyperinsulinemia but not during hyperinsu-
linemia alone. As discussed earlier, an increased up-
take of FFA in skeletal muscle due to stimulation of
lipoprotein lipase and/or FABP appears the most likely
explanation for this effect. The hypothesis that an
increased lipid oxidation per se inhibits glucose uptake
282 • JANUARY 2002 • www.ajpendo.org
E130 METABOLIC EFFECTS OF FATTY ACIDS AND TRAINING
has never been actually disproved; it appears, however,
unlikely in regard to the observation that chronic in-
hibition of lipid oxidation causes accumulation of in-
tramyocellular triglycerides and insulin resistance in
rats (8). In the present study, the inhibitory effects of
lipids being more important in trained subjects only
during exercise but not at rest suggests that muscle
contraction per se may stimulate transfer of lipids from
lipoprotein particles into the muscle fiber and its con-
version into long-chain acyl-CoA in trained individu-
als. It remains, however, possible that our observation
was merely due to the fact that endurance training per
se has profound effects on skeletal muscle. It increases
muscle capillary density (22) and GLUT-4 content (23)
and, hence, can be expected to facilitate glucose utili-
zation. This increased insulin sensitivity is readily
observed in the endurance-trained subjects of our
study. Because lipid suppressed glucose utilization to
the same absolute values in both trained and seden-
tary subjects, it is also possible that the dose of lipids
administered exerted a maximal inhibition of glucose
utilization in both groups but that the higher percent-
age of reduction observed in trained individuals merely
reflected a large initial glucose utilization.
In conclusion, these results indicate that the inhibi-
tory effects of lipids on whole body glucose utilization
are increased in endurance-trained subjects during
exercise plus hyperinsulinemia but not during hyper-
insulinemia at rest. This suggests that endurance
training and muscle contraction upregulate regulatory
steps in muscle lipid uptake and metabolism, which
are operative in reducing glucose transport and oxida-
tion.
This study was supported by a grant from the Swiss National
Science Foundation (no. 32–56700.99).
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