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Content may be subject to copyright.
Eccentric exercise induces transient insulin
resistance in healthy individuals
J. P. KIRWAN, R. C. HICKNER, K. E. YARASHESKI, W. M. KOHRT, B. V. WIETHOP,
AND J. 0. HOLLOSZY
Section
of
Applied Physiology, Department
of
Internal Medicine, and Irene Walter Johnson Institute
of
Rehabilitation, Washington University School
of
Medicine, St. Louis, Missouri 63110
KIRWAN, J. P., R. C. HICKNER, K. E. YARESHESKI, W. M.
KOHRT, B. V. WIETHOP, AND J. 0. HOLLOSZY. Eccentric exer-
cise induces transient insulin resistance in healthy individuals. J.
Appl. Physiol. 72(6): 2197-2202, 1992.-Euglycemic-hyperin-
sulinemic clamps were performed on six healthy untrained indi-
viduals to determine whether exercise that induces muscle dam-
age also results in insulin resistance. Clamps were performed
48 h after bouts of predominantly 1) eccentric exercise [30 min,
downhill running, -17% grade, 60 * 2% maximal 0, consump-
tion (VO 2 max)], 2) concentric exercise (30 min, cycle ergometry,
60 -+ 2% \~o~~J,
or 3) without prior exercise. During the
clamps, euglycemia was maintained at 90 mg/dl while insulin
was infused at 30 mu. mm2
l
min-l for 120 min. Hepatic glucose
output (HGO) was determined using [ 6,6-2H] glucose. Eccentric
exercise caused marked muscle soreness and significantly ele-
vated creatine kinase levels (273 t 73, 92 t 27, 87 t 25 IU/l
for the eccentric, concentric, and control conditions, respec-
tively) 48 h after exercise. Insulin-mediated glucose disposal
rate was significantly impaired (P < 0.05) during the clamp
performed after eccentric exercise (3.47 t 0.51 mg
l
kg-l
l
min-‘) compared with the clamps performed after concentric
exercise (5.55 it 0.94 mg. kg-’
l
min-‘) or control conditions
(5.48 t 1.0 mg
l
kg-’ . min). HGO was not significantly differ-
ent among conditions (0.77 t 0.26, 0.65 & 0.27, and 0.66 t 0.64
mg . kg-‘. min-’ for the eccentric, concentric, and control
clamps, respectively). The insulin resistance observed after ec-
centric exercise could not be attributed to altered plasma corti-
sol, glucagon, or catecholamine concentrations. Likewise, no
differences were observed in serum free fatty acids, glycerol,
lactate, ,8-hydroxybutyrate, or alanine. These results show that
exercise that results in muscle damage, as reflected in muscle
soreness and enzyme leakage, is followed by a period of insulin
resistance.
glucose disposal; muscle damage; euglycemic-hyperinsulinemic
clamps; hormones; metabolites
A NUMBER OF STUDIES
have shown that humans who ex-
ercise regularly have increased insulin sensitivity
(2, 12,
18, 20, 21,
25,
32).
Much of the improvement has been
attributed to the effects of the last bout of exercise. In-
deed, when endurance-trained subjects stop exercising,
there is a reversal of this enhanced insulin effect
(12,18).
King et al.
(18)
showed that, over a lo-day period, this
reversal is due to a decrease in insulin sensitivity with no
change in responsiveness. It has also been suggested that
an acute bout of exercise results in improved insulin ac-
tion in untrained individuals
(24).
This effect also ap-
pears to be short-lived and is lost between
48
h and 5 days
after the last exercise bout.
However, enhanced insulin action after acute exercise
is not a consistent finding. Recently, we observed an in-
creased insulin response to hyperglycemia without a con-
comitant increase in glucose disposal after an exhausting
bout of treadmill running (19). The increased insulin re-
sponse appeared to be the result of exercise-induced
muscle damage. To further investigate the possibility
that exercise that results in muscle damage may in fact
cause insulin resistance, we designed the present study in
which insulin action was measured under conditions of
hyperinsulinemia and euglycemia after I) downhill run-
ning, which involves a considerable amount of eccentric-
type contractions, shown to induce microtrauma to skele-
tal muscle
(11,14,31);
2) cycle ergometry, predominantly
concentric contractions; and 3) no exercise.
METHODS
Subjects.
Six healthy untrained individuals (3 males, 3
females) volunteered to participate in this study after
signing an informed consent in accordance with the Uni-
versity Guidelines for the Protection of Human Subjects.
This study was approved by the Human Studies Com-
mittee of Washington University School of Medicine.
Selected physical characteristics are shown in Table
1.
All subjects had a normal response to a 75-g oral glucose
tolerance test.
Exercise.
Maximal 0, consumption
(VO~~J
was de-
termined by use of an incremental treadmill protocol.
Gas volumes were measured by a dry gas meter (Parkin-
son-Cowan). 0, (Applied Electrochemistry S-3A) and
CO, (Beckman LB-2) concentrations were determined
by use of a semiautomated on-line system. Heart rate
was monitored by electrocardiogram with a modified V5
lead. Skinfold measurements were obtained for estima-
tion of percent body fat, as described by Jackson and
Pollock
(15).
The eccentric exercise bout consisted of 30 min of
downhill running on a treadmill declined at -17%. The
subjects ran at an intensity designed to elicit
-60%
vo
2 m8X. Expired air was collected using a Daniels valve
and meteorological balloons at. IO-min intervals during
exercise, and 0, consumption (VO,) was measured with a
mass spectrophotometer (Perkin-Elmer MGA
1100).
Ventilation was determined using a Collins gasometer.
0161-7567192 $2.00 Copyright 0 1992 the American Physiological Society 2197
2198
ECCENTRIC EXERCISE INDUCES INSULIN RESISTANCE
TABLE
1.
Subject characteristics
Age,
yr 29.Ok2.0
Height, cm 168.6k2.7
Weight, kg 71.Ok5.1
BMI, kg/m2 24.8k1.3
Body fat, % 20.m3.9
vo
2max9
ml
l
kg-’
l
min-’ 46.1S.2
Values are means + SE of 6 subjs. BMI, body mass index; VO, max,
maximal 0, consumption.
The concentric exercise bout consisted of 30 min of
cycling on an electronically braked cycle ergometer
(Lode, Groningen, Holland) at an intensity similar to
that for the downhill
run,
i.e., ~60%
VO,
max.
VO,
was
measured at lo-min intervals, as described for the eccen-
tric exercise bout.
Euglycemic-hyperinsulinemic clamps.
Three euglyce-
mic-hyperinsulinemic clamps were performed on each
subject in a counterbalanced design. The clamps were
performed 48 h after
1)
downhill running, 2) cycling, or
3) a period of no exercise. Clamps were performed 1 wk
apart, with the excepti .on that when the downhill running
clamp was performed, a 3-wk interval separated the tests
to allow recovery from the muscle damage resulting from
eccentric exercise.
On the morning of the clamp, the subjects reported to
the Clinical Research Center of the Washington Univer-
sity Medical Center at 0700 h after an overnight fast. The
clamps were performed according to the procedures de-
scribed by De Fronzo et al. (8). A polyethylene catheter
was inserted into a dorsal hand vein that was warmed in a
heated box (75°C) for sampling of arterialized blood (23).
A second catheter was placed in an antecubital vein for
infusion of insulin, glucose (20% dextrose), [6,6-2H]-
glucose, and potassium chloride.
To measure hepatic glucose output (HGO), a [6,6-
2H] glucose (96% Tracer Technology, Somerville, MA)
prime (18 pmol/kg) was given at the beginning of a 2-h
baseline equilibration period, followed by a constant in-
fusion (0.22 pmol
l
kg-l
l
min-‘), which was maintained
throughout baseline and the 2-h . euglycemi .c clamp pe-
riod. After tracer equilibration a primed-continuous in-
fusion (30 mU
l
mm2
l
min-‘) of regular porcine insulin
(Squibb-Nova, Princeton, NJ) was begun and was main-
tained throughout the clamp. Blood samples for gluco
se
kinetics were collected before the tracer infu sion and at
lo-min intervals during the last 30 min of the baseline
period and the last 40 min of the hyperinsulinemic clamp
period. Plasma glucose levels were clamped at 90 mg/dl
during hyperinsulinemia by use of a variable glucose in-
fusion. Blood samples for plasma glucose and insulin
determination were drawn at 5- and 15min intervals,
respectively, during the clamp. Blood samples for addi-
tional hormone, metabolite, and substrate measure-
ments were obtained before an .d at 110 min of the eugly-
cemic clamp.
Blood analysis.
Plasma glucose concentration was
measured immediately by the glucose oxidase method
(Beckman Instruments, Fullerton, CA). Blood samples
for hormone, substrate, and metabolite measurements
were kept chilled on ice [except for serum free fatty acids
(FFA)], centrifuged at 4°C and stored at -8OOC for sub-
sequent analysis. Samples for insulin were assayed in
duplicate by a double-antibody radioim munoassay (2 7) .
Blood samples for epinephrine and norepinephrine deter-
mination were collected in tubes containing reduced glu-
tathione and ethylene glycol-bis(P-aminoethyl ether)-
N,N,N’-N’-tetraacetic acid. The samples were assayed
by a single-isotope derivative (radioenzymatic) method
(33). Blood samples for cortisol (10) and glucagon (9)
were dispensed into tubes containing aprotinin (FBA
Pharmaceuticals, New York, NY). Blood lactate (22),
glycerol (30), ,@hydroxybutyrate (30), and alanine (5)
were determined enzymatically from perchloric acid ex-
tracts. Serum FFA were determined using an enzymatic
calorimetric procedure (NEFA C kit, Wako Chemicals,
Dallas, TX).
Blood samples for [ 6,6-2H] glucose determination were
centrifuged, and the plasm a
(200 I-L
,l) was deproteinized
with 300 ~1 of cold ac etone. A fter fu rther centrifugation,
the supernatant was removed and evaporated and the
pentaacetate derivative of glucose was formed by addi-
tion of 100 ~1 of acetic anhydride-pyridine
(19).
Glucose
was separated at 180°C on a 3% OV column, and its 2H
isotopic abundance was measured by positive ion-chemi-
cal ionization mass spectrometry by use of selective ion
monitoring of mass-to-charge ratios of 333 and 331.
Calculations and statistics.
Glucose appearance rate
(Ra) was calculated from plasma [ 6,6-2H] glucose enrich-
ments and rate of tracer infusion by use of the equation
{R a = [(APE infusate/APE plasma glucose)-11
l F),
where APE is atoms percent excess, described previously
by Jahoor (16). In this case,
F
represents the isotope in-
fusion rate (pg
l
kg-’
l
min-l). HGO was calculated as Ra
minus the glucose infusion rate. Glucose disposal rates
were calculated as glucose infusion rate plus HGO.
Differences among the experimental conditions were
examined by repeated-measures analysis of variance.
Specific mean differences were identified by a Newman-
Keuls post hoc test. All values are expressed as means t
SE. The
was 0.05. acceptable level for statistical significance
RESULTS
Exercise.
Exercise intensity was determined from
VO,
measurements obtained during each bout. Downhill run-
ning elicited a
VO,
of 26.9 t 4.2 ml
l
kg-l
l
min-’ or 60 t
2% of vo, m8x) whereas the cycle ergometry elicited a
VO,
of 26.8 t 4.0 ml
l
kg-‘. min-’ or 60 t 2% of Vo2 m8x. These
values were not significantly different. The eccentric ex-
ercise trial resulted in marked muscle soreness in the
quadriceps, gluteal, and lower leg muscles. The soreness
was progres sive and appeared to peak 48-72 h after exer-
cise. No soreness was reported after the concentric exer-
cise trial. Serum creatine kinase (CK) values (Fig. 1)
were obtained 48 h after exercise and were significantly
elevated (P < 0.05) after eccentric exercise (87 t 25,92 t
27, and 273 t 73 IU/l for the control, concentric, and
eccentric exercise trials, respectively).
Euglycemic- hyperinsulinemic clamps.
Fasting plasma
glucose (97 t 2,98 t 2, and 98 t 2 mg/dl for the control,
concentric, and eccentric exercise trials, respectively)
and fasting plasma insulin (5.0 t 1.0,5.0 t 1.1, and 5.3 t
ECCENTRIC EXERCISE INDUCES INSULIN RESISTANCE
CONTROL CONCENTRIC ECCENTRIC
FIG. 1. Plasma creatine kinase levels 48 h after eccentric and con-
centric exercise and under control conditions with no exercise. *Signifi-
cantly different from concentric and control,
P < 0.05.
TABLE
2. Effects of exercise on basal Ra and
effect of
exercise and hyperinsulinemia on HGO during euglycemia
Control Concentric
Exercise Eccentric
Exercise
Basal Ra,
mg
l
kg-’
l
min-’
HGO,
mg
l
kg-’
l
min-’
2.2OkO.19 1.99kO.24 2.3320.13
0.66kO.64 0.65kO.27 0.77kO.26
Values are means t SE of 6 subjs. Ra, glucose appearance rate;
HGO, hepatic glucose output.
1.2 pU/ml for the control, concentric, and eccentric exer-
cise trials, respectively) levels were similar among trials.
Basal glucose Ra was also similar for the three clamps
(Table 2).
During the euglycemic clamps, plasma glucose was
maintained at 88 t 0.3, 88 t 1.0, and 89 t 0.7 mg/dl for
the eccentric exercise, concentric exercise, and control
trials, respectively. Coefficients of variation for plasma
glucose were 2.0 t 0.3,3.7 t 0.3, and 2.6 t 0.4% for eccen-
tric exercise, concentric exercise, and control trials, re-
spectively. Plasma insulin levels during the clamps were
32 t 5, 38 t 4, and 35 t 4 PI-J/ml for eccentric exercise,
concentric exercise, and control trials, respectively, and
no significant differences were observed among trials.
During the final 30 min of the clamps, glucose disposal
rates (Fig. 2) were significantly reduced after eccentric
exercise (3.47 t 0.51 mg. kg-‘. min-‘) compared with the
concentric exercise (5.55 t 0.94 mg
l
kg-’
l
min-l) and
control trials (5.48 t 1.0 mg
l
kg-l
l
min-l). Thirty min-
utes of moderate-intensity cycling exercise had no effect
on glucose disposal measurements obtained 48 h after
the exercise bout. HGO during hyperinsulinemia ap-
peared to be elevated slightly during clamps performed
after the exercise bouts; however, these differences were
not significantly different (Table 2).
A4etabolites and hormones.
Resting concentrations of
lactate, FFA, glycerol, ,&hydroxybutyrate, and alanine
2199
CONTROL CONCENTRIC ECCENTRIC
FIG. 2. Mean glucose disposal rates during hyperinsulinemic-eugly-
cemic clamps performed 48 h after eccentric and concentric exercise
and under control conditions with no exercise. *Significantly different
from concentric and control,
P < 0.05.
TABLE
3. Effects of exercise and hyperinsulinemia
on metabolite concentrations
Control
Basal Clamp
Concentric Eccentric
Exercise Exercise
Basal Clamp Basal Clamp
Glucose, 97 89
mg/dl -+2 +l
Lactate, 0.8 1.1*
mm01 11 kO.01 -to.13
FFA, 515 88"
pm01 /l 252 k5
Glycerol, 0.11 0.13
mm0111 kO.03 kO.04
,&Hydrox, 0.16 0.15
mm01 /l -to.04 kO.05
Alanine, 0.38 0.39
mmol/l kO.02 kO.02
98 88 98
+2 +I 22
0.9 1.1 0.9
20.11 kO.08 kO.09
541 74* 441
282 k9 k74
0.22 0.20 0.30
kO.07 kO.07 kO.08
0.18 0.10 0.17
kO.06 kO.01 kO.05
0.38 0.036 0.36
kO.03 kO.03 kO.04
88
+O
0.9
kO.38
84"
+9
0.22
kO.06
0.10
kO.02
0.35
lto.03
Values are means f. SE of 6 subjs. FFA, free fatty acids; ,8-Hydrox,
/3-hydroxybutyrate. * Significantly different from the preclamp basal
value for the same condition.
were not different among trials (Table 3). During the
hyperinsulinemic-euglycemic clamp, FFA levels were sig-
nificantly depressed (P < 0.05) for all three trials and
were not different among the trials. Lactate levels were
increased during all three clamps, but the increase was
statistically significant only during the control trial. Lac-
tate concentrations during hyperinsulinemia were not
significantly different among trials. Changes in glycerol,
,&hydroxybutyrate, and alanine were not statistically sig-
nificant.
Resting catecholamine, glucagon, and cortisol levels
were not different among trials (Table 4). The insulin
infusions led to a small increase in both norepinephrine
and epinephrine. These increases were not significant
and were not different among the trials. Both glucagon
and cortisol were unchanged during the clamps, and no
differences were found for either hormone when the re-
sponse was compared among trials.
2200
ECCENTRIC EXERCISE INDUCES INSULIN RESISTANCE
TABLE
4. Effects
of
exercise and hyperinsulinemia
on concentration
of
plasma hormones
Concentric Eccentric
Control Exercise Exercise
Basal Clamp Basal Clamp Basal Clamp
Cortisol, 8.6 8.8 9.9 9.2 7.0 6.5
mg/dl kl.7
H.1
k2.7 ~12.4
+l.l
+0.7
Epinephrine, 39.8 45.3 37.7 39.5 34.8 39.8
Pdml
k6.2 k9.4 k7.6 t5.4 k5.4 IL 10.4
Norepinephrine, 166.8 182.8 163.5 208.5 154.7 180.5
Pdml
~120.6 220.0 k35.6 Ik35.0 k14.0 k22.2
Glucagon,
108.4 111.2 114.5 101.9 112.5 100.6
rig/ml k15.4 k16.8 k18.1 k12.2 k22.9 k13.5
Values are means +
SE
of 6 subjs.
DISCUSSION
The principal finding in this study was that exercise
that induces muscle trauma and soreness results in a
marked decrease (37%) in insulin-mediated whole body
glucose disposal. This degree of insulin resistance
48
h
after exercise is quite remarkable. The effect was inde-
pendent of any measurable alteration in metabolite con-
centrations or the hormonal milieu, as evidenced by the
data reported in Tables 3 and
4.
We previously showed that an acute bout of exhaust-
ing treadmill running caused an increased insulin re-
sponse during a hyperglycemic clamp
(19).
The exhaust-
ing bout of treadmill running caused some muscle sore-
ness and elevated CK levels. Although the hyperglycemic
clamp does not permit a clear-cut conclusion regarding
insulin action, the findings suggested that exercise of this
nature may cause insulin resistance. The euglycemic-hy-
perinsulinemic clamp procedure used in the present
study provides more specific information on the action of
insulin by controlling the glycemic and insulinemic stim-
uli for glucose disposal. Thus the reduced rate of glucose
disposal after eccentric exercise provides more conclu-
sive evidence that exercise of this nature leads to insulin
resistance.
These data also show that relatively short-duration
moderate-intensity cycling exercise had no measurable
effect (either positive or negative) on insulin action at
submaximal insulin levels
48
h after the exercise bout.
These data do not agree with previous conclusions by
Mikines et al.
(24)
regarding the duration of the effect of
the last bout of exercise on insulin sensitivity. However,
the length of the exercise bout in the two studies was
considerably different
(30
vs.
60
min), and this may have
contributed to the contradictory conclusions. The fact
that concentric exercise did not negatively affect glucose
uptake suggests that it is the eccentric nature of the exer-
cise that leads to insulin resistance.
Eccentric exercise involves lengthening of the muscle
fibers as tension is developed and has been shown to
produce pronounced and delayed muscle trauma
(11,14,
31).
A number of investigators
(11, 17,28)
showed ultra-
structural changes in skeletal muscle after eccentric ex-
ercise, including evidence of disrupted sarcomeres,
Z-
band streaming, necrotic fibers, increased lysosomal ac-
tivity, and infiltration of damaged fibers by macrophages
and/or mononuclear cells. Elevated CK levels and mus-
cle soreness are routinely used as clinical indicators of
muscle damage
(34).
The occurrence of muscle soreness
and elevated CK levels after eccentric, but not concen-
tric, exercise indicates that the eccentric exercise did
cause muscle trauma. Thus, damage to skeletal muscle
resulting from eccentric exercise appears to have contrib-
uted to the insulin resistance observed in this study. This
conclusion is supported by our observation (unpublished
data) that insulin-resistant individuals do not have ele-
vated CK levels and do not generally complain of muscle
soreness.
The observation of insulin resistance after trauma is
not new
(4, 13).
This phenomenon, termed “stress dia-
betes,” is associated with decreased glucose disposal and
elevated plasma glucose concentrations arising from re-
duced insulin action (4). Inadequate suppression of HGO
at submaximal insulin concentrations contributes to the
high plasma glucose concentrations. Elevated counter-
regulatory hormones, including cortisol, glucagon, epi-
nephrine, and norepinephrine, have been reported to me-
diate the response
(1).
The degree of trauma and muscle
damage associated with this phenomenon is considerably
greater than that after exercise. In the present study,
slightly less hepatic suppression was present after eccen-
tric exercise. However, differences in HGO were not sta-
tistically significant, and so we cannot say that hepatic
insulin resistance was present. The relatively small sam-
ple size may have contributed to the absence of statistical
significance; however, a power calculation indicated that
47 subjects would be required to avoid making a type II
error. It is unrealistic in this type of study to include such
a large number of subjects. Furthermore, because all
subjects showed the same trend in HGO, we believe that
the data reflect the physiological response to the treat-
ment under the conditions of the study. None of the
counter-regulatory hormones measured was elevated at
rest or during the clamp performed after eccentric exer-
cise. Thus, although inhibition of insulin action at the
level of the peripheral tissue as a result of elevated coun-
terregulatory hormones cannot be ruled out, it does not
appear that the hormones measured were responsible for
the impaired glucose disposal.
Decreased insulin binding to skeletal muscle and inter-
ference with glucose transporter translocation in the
plasma membrane are among the factors that may help
explain the decreased glucose uptake after exercise-in-
duced muscle trauma. However, the magnitude of the
decrease in whole body glucose disposal (37%) relative to
the localized muscle trauma appears too great to be en-
tirely accounted for by actual damage to the muscle cells.
Some systemic factor released as a result of the exercise-
induced muscle trauma could possibly also play a role in
inducing the insulin resistance. Previous reports of a cir-
culating inhibitor of insulin action suggest that this fac-
tor may be involved in uncoupling the ability of insulin to
stimulate glucose transport at a point beyond the binding
of insulin to the insulin receptor on the plasma mem-
brane
(26).
It has been suggested that the enhanced insulin action
associated with exercise may be due to an increase in
muscle glycogen storage capacity and facilitates replace-
ment of glycogen depleted during exercise (3). Although
ECCENTRIC EXERCISE INDUCES INSULIN RESISTANCE 2201
prolonged or exhausting exercise is generally followed by
glycogen supercompensation in the active muscles (7),
this is not always the case, especially when the exercise
induces muscle damage. O’Reilly et al. (29) showed that
muscle glycogen repletion is inhibited for up to
10
days
after eccentric exercise. Costill et al.
(6)
also found signifi-
cantly impaired glycogen resynthesis in muscle 72 h after
eccentric exercise. They suggested that inflammatory
cells compete with muscle for the available glucose and,
thus, less glucose is available for storage. Our data do not
support this suggestion but, instead, suggest that less
glucose is available for storage because of impaired glu-
cose uptake by the muscle.
In conclusion,
volves primarily we have
eccentric shown that
work results exe
in rcise that in-
marked tran-
sient insulin resistance that is evident
48
h after the ex-
ercise bout. Thus, in clinical trials, it is not advisable to
evaluate the effectiveness of exercise in promoting en-
hanced insulin action if the exercise protocol results in
muscle trauma or soreness. In addition, failure to re-
synthesize glycogen stores for several
tric exercise may be due to impaired
glucose uptake by skeletal muscle.
days after eccen-
insulin-mediated
9.
10.
11.
12.
13.
14.
15.
16.
17.
We are grateful to the nursing staff of the General Clinical Research
Center at Washington University School of Medicine for technical as-
sistance; Dr. Ron Gingerich and staff at the RIA Core Laboratories of
the Diabetes Research Training Center for the cortisol, glucagon, and
metabolite assays; and Suresh Shah and Krishan Jethi for the catechol-
amine and FFA assays.
This research was supported by National Institutes of Health (NIH)
Diabetes Research and Training Grant AM-20579 and Grant 5
MOlRR-00036 from the General Clinical Research Center Branch, Di-
vision of Research Facilities and Resources. J. P. Kirwan was sup-
ported by NIH Research Services Award AG-00078. K. E. Yarasheski
was supported by NIH Research Career Development Award AG-
00444.
Address for reprint requests: J. P. Kirwan, National Coaching and
Training Centre, University of Limerick, Limerick, Ireland.
Received 6 May 1991; accepted in final form 19 December 1991.
18.
19.
20.
21.
22.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
BESSEY,
P. Q., J. M.
WAGERS,
T. T.
AOKI, AND
D. W.
WILMORE. 23*
Combined hormonal infusion stimulates the metabolic response to
injury.
Ann. Surg. 200: 264-281,
1984.
BJORNTORP,
P., M.
FAHLEN,
G.
GRIMBY,
A.
GUSTAFSON,
J.
HOLM,
P.
RENSTROM, AND
T.
SCHERSTEN.
Carbohydrate and lipid metabo-
24
’
lism in middle-aged, physically well-trained men. Metabolism 21:
1037-1043, 1972.
BOGARDUS,
C., P.
THUILLEZ,
E.
RAWSSIN,
B.
VASQUEZ,
M.
NARI-
MIGA, AND
S.
AZHAR.
Effect of muscle glycogen depletion on in vivo
25
l
insulin action in man.
J.
CLin.
Invest.
72: 1605-1610, 1983.
BRANDI,
L. S., M.
FREDIANI,
M.
OLEGGINI,
F.
MOSCA,
M.
CERRI,
C.
BONI,
N.
PECORI,
G.
BUZZIGOLI, AND
E.
FERRANNINI.
Insulin resis-
26
’
tance after surgery: normalization by insulin treatment.
Clin. Sci.
Lond. 79: 443-450,199O.
CAHILL,
G. F.,
JR.,
M. G.
HERRERA,
A. P.
MORGAN,
J. S. 27
SOELDNER,
J.
STEINKE,
P,
LEVY,
G. A.
RERCHAND, JR., AND
D. M. ’
KIPNIS.
Hormone-fuel interrelationships during fasting.
J. Clin. 28
.
Invest.
45: 1751-1769, 1966.
COSTILL,
D. L., D. D.
PASCOE,
W. J.
FINK,
R. A.
ROBERGS,
S. I.
BARR, AND
D.
PEARSON.
Impaired muscle glycogen resynthesis 29.
after eccentric exercise.
J. Appl. Physiol. 69: 46-50,
1990.
COSTILL,
D. L., W. M.
SHERMAN,
W. J.
FINK,
C.
MARESH,
M.
WITTEN, AND
J. M.
MILLER.
The role of dietary carbohydrates in
muscle glycogen resynthesis after strenuous running.
Am. J. Clin. 30.
Nutr. 34: 1831-1836,
1981.
DE FRONZO,
R. A., J. D.
TOBIN, AND
R.
ANDRES.
Glucose clamp
techniaue: a method for auantifvine insulin secretion and resis-
31.
tance.
Am. J. Physiol. 237 (Endocrinol. Metab. Gastrointest. Physiol.
6):
E214-E223, 1979.
ENSINCK,
J. W. Immunoassays for glucagon. In:
Glucugon. Hand-
book
of
Experimental Pharmacology,
edited by P. Lefebvre. New
York: Springer-Verlag, 1983, vol. 66, p. 203-221.
FARMER,
R. W.,
AND
C. E.
PIERCE.
Plasma cortisol determination:
radioimmunoassay and competitive binding compared.
Clin. Chem.
20: 411-414, 1974.
FRIDEN,
J. M., M.
SJOSTROM, AND
B.
EKBLOM.
Myofibrillar dam-
age following intense eccentric exercise in man.
Int. J. Sports Med.
4: 170-176,
1983.
HEATH,
G. W., J. R.
GAVIN
III, J. M.
HINDERLITER,
J. M.
HAG-
BERG,
S. A.
BLOOMFIELD, AND
J. 0.
HOLLOSZY.
Effects of exercise
and lack of exercise on glucose tolerance and insulin sensitivity.
J.
Appl. Physiol. 55: 512-517, 1983.
HENDERSON,
A. A., K. N.
FRAYN,
C. S. B.
GALASKO, AND
R. A.
LITTLE.
Dose-response relationships for the effects of insulin on
glucose and fat metabolism in injured patients and control sub-
jects.
Clin. Sci. Lond. 80: 25-32,
1991.
HIKIDA,
R., R.
STARON,
F.
HAGERMAN,
W.
SHERMAN, AND
D. L.
COSTILL.
Muscle fiber necrosis associated with human marathon
runners.
J. Neurol. Sci. 59: 185-203, 1983.
JACKSON,
A. S.,
AND
M. L.
POLLOCK.
Generalized equations for
predicting body density of men.
Br. J. Nutr. 40: 497-504, 1978.
JAHOOR,
F., E. J.
PETERS, AND
R. R.
WOLFE.
The relationship
between gluconeogenic substrate supply and glucose production in
humans.
Am. J. Physiol. 258 (Endocrinol. Metab. 21):
E288-E296,
1990.
JONES,
D. A., D. J.
NEWHAM,
J. M.
ROUND, AND
S. E. J.
TOLFREE.
Experimental human muscle damage: morphological changes in
relation to other indices of damage.
J. Physiol. Lond. 375: 435-448,
1986.
KING,
D. S., G. P.
DALSKY,
W. E.
CLUTTER,
D. A.
YOUNG,
M. A.
STATEN,
P. E.
CRYER, AND
J. 0.
HOLLOSZY.
Effects of exercise and
lack of exercise on insulin sensitivity and responsiveness.
J. Appl.
Physiol. 64: 1942-1946, 1988.
KIRWAN,
J. P., R. E.
BOUREY,
W. M.
KOHRT,
M. A.
STATEN, AND
J. 0.
HOLLOSZY.
Effects of treadmill exercise to exhaustion on the
insulin response to hyperglycemia in untrained men.
J. Appl. Phys-
iol. 70: 246-250, 1991.
LEBLANC,
J., A.
NADEAU,
D.
RICHARD, AND
A.
TREMBLAY.
Studies
on the sparing effect of exercise on insulin requirements in human
subjects.
Metabolism 30: 1119-l 124, 1981.
LOHMANN,
D., F.
LIEBOLD,
W.
HEILMANN,
H.
SENGER, AND
A.
POHL.
Diminished insulin response in highly trained athletes.
Me-
tabolism 27: 521-524, 1978.
LOWRY,
0. H., J. V.
PASSONEAU,
F. X.
HASSELBERGER, AND
D. V.
SHULTZ.
Effect of ischemia on known substrates and cofactors of
the glycolytic pathway of the brain.
J. Biol. Chem. 239: 18-30,1964.
MCQUIRE,
E. A. H., J. H.
HELDERMAN,
J. D.
TOBIN,
R.
ANDRES,
AND
M.
BERMAN.
Effects of arterial versus venous sampling on
analysis of glucose kinetics in man.
J. Appl. Physiol. 41: 565-573,
1976.
MIKINES,
K. J., B.
SONNE,
P. A.
FARRELL,
B.
TRONIER, AND
H.
GALBO.
Effect of physical exercise on sensitivity and responsive-
ness to insulin in humans.
Am. J. Physiol. 254 (Endocrinol. Metab.
17):
E248-E259, 1988.
MIKINES,
K. J., B.
SONNE,
B.
TRONIER, AND
H.
GALBO.
Effects of
acute exercise and detraining on insulin action in trained men.
J.
Appl. Physiol. 66: 704-711, 1989.
MISBIN,
R. I., A.
GREEN,
I. M.
ALVAREZ,
E. C.
ALMIRA,
G. L.
DOHM, AND
J. F.
CARO.
Inhibition of insulin-stimulated glucose
transport by factor extracted from serum of insulin-resistant pa-
tient.
Diabetes 37: 1217-1225, 1988.
MORGAN,
D. R.,
AND
A.
LAZAROW.
Immunoassay of insulin: two
antibody system.
Diabetes
12: 115-126, 1963.
NEWHAM,
D. J., G.
MCPHAIL,
K. R.
MILLS, AND
R. H. T.
ED-
WARDS.
Ultrastructural changes after concentric and eccentric con-
tractions of human muscle.
J. Neurol. Sci. 61:
109-122, 1983.
O’REILLY,
K. P., M. J.
WARHOL,
R. A.
FIELDING,
W. R.
FRONTERA,
C. N.
MEREDITH, AND
W. J.
EVANS.
Eccentric exercise-induced
muscle damage impairs muscle glycogen repletion.
J. Appl. Physiol.
63: 252-256, 1987.
PINTER,
J. K., J. A.
HAYASKI, AND
J. A.
WATSON.
Enzymatic assay
of glycerol, dihydroxyacetone and glyceraldehyde.
Arch. Biochem.
Biophys. 121: 404-414, 1967.
SCHWANE,
J. A., S. R.
JOHNSON,
C. B.
VANDENAKKER, AND
R. B.
2202
ECCENTRIC EXERCISE INDUCES INSULIN RESISTANCE
ARMSTRONG. Delayed-onset muscular soreness and plasma CPK
and LDH activities after downhill running. Med. Sci.
Sports Exer-
cise 15: 51-56, 1983.
32.
SEALS, D.R.,J.M. HAGBERG, W.K. ALLEN, B.F. HURLEY,G. P.
DALSKY, A.A. EHSANI,AND J.O. HOLLOSZY. Glucosetolerancein
young and older athletes and sedentary men.
J. Appl. Physiol. 56:
1521-1525, 1984.
33.
SHAH, S. D., W. E. CLUTTER, AND P. E. CRYER. External and inter-
34.
nal standards in the single isotope derivative (radioenzymatic) as-
say of plasma norepinephrine and epinephrine in normal humans
and persons with diabetes mellitus or chronic renal failure.
J. Lab.
Clin. Med. 106: 624-629, 1985.
SHELL, W. E., J. K. KJEKSHUS, AND B. E. SOBEL. Quantitative
assessment of the extent of mycardial infarction in the conscious
dog by means of analysis of serial changes in serum creatine phos-
phokinase activity.
J. Clin. Inuest. 50: 2614-2625, 1971..
