Insulin action and secretion in endurance-trained
and untrained humans
D. S. KING,
G. P. DALSKY,
D. R. VAN HOUTEN,
AND
Section of Applied Physiology
Research Center, Washington
M. A. STATEN,
J. 0. HOLLOSZY
l
l
l
l
l
l
clamp; insulin
sensitivity;
INSULIN ACTION is enhanced in endurance-trained
individuals. This is evidenced by lower or unchanged plasma
glucose levels during an oral or intravenous glucose tol-’
erance test, despite a markedly reduced plasma insulin
response (2, 20, 22, 24, 28). Ftihermore
studies using
the euglycemic clamp procedure have shown that insulinstimulated glucose disposal is increased in trained subjects at plasma insulin concentrations in the 60. to lOO&+‘ml range (7,15,27,30). These findings have generally
been interpreted as indicating that exercise training results in an increase in sensitivity to insulin. However,
the measurement of insulin action at a single submaximal
insulin concentration
does not distinguish between increased insulin sensitivity (i.e., a decrease in the insulin
concentration required for half-max .imal response) and
increased insulin responsiveness (i.e 9 an increase in the
0161-7567/%7
CLUTTER,
and Division of Metabolism, Department of Medicine, and General Clinical
University School of Medicine, St. Louis, Missouri 63110
KING,D.S., G. P. DALSKY, M.A. STATEN, W.E. CLUTTER,
D. FL VAN HOUTEN,ANDJ.O.HOLLOSZY.
Insulinactionand
secretion in endurance-trained and untrained humans. J. Appl.
Physiol. 63(6): 2247-2252,1987.-To
evaluate insulin sensitivity and responsiveness, a two-stage hyperinsulinemic euglycenhic clamp procedure (insulin infusions of 40 and 400 mUa
mm20min-‘) wais performed on 11 endurance-trained and 11
untrained volunteers. A 3-h hyperglycemic clamp procedure
(plasma glucose kl80 mg/dl) was used to study the insulin
response to a fixed glycemic stimulus in 15 trained and 12
untrained subjects. During the 40-mU rn-‘. min-l insulin infusion, the glucose disposal rate was 10.2 k 0.5 mg kg fat-free
mass (FFM)-’ min-1 in the trained group compared with 8.0 &
0.6 mg gkg FFM” min-l in the untrained group (P < 0.01). In
contrast, there was no significant difference in maximally stimulated glucose disposal: 17.7 2 0.6 in the trained vs. 16.7 & 0.7
mg kg FFM’l . min-’ in the untrained group. During the hyperglycemic clamp procedure, the incremental area for plasma
insulin was lower in the trained subjects for both early (O-10
minz 140 * 18 vs. 223 * 23 &Jo ml-’ .min; P < 0.005) and late
(10-180 min. 4,582 t 689 vs. 8,895 k 1,316 PU ml-’ l rein; P c
0.005) insulin secretory phases. These data demonstrate that
1) the improved insulin action in healthy trained subjects is
due to increased sensitivity to insulin, with no change in
responsiveness to insulin, and 2) trained subjects have a smaller
plasma insulin response to an identical glucose stimulus than
untrained individuals.
euglycemic clamp; hyperglycemic
insulin responsiveness; exercise
W. E
$1.50 Copyright
0
response to a maximally stimulating
insulin concentration) (21). In this context, we used both a submaximal
and a maximally stimulating
Insulin concentration during a euglycemic clamp procedure (9) to determine
whether the enhanced insulin action in trained humans
is due to an increased sensitivity to insulin, to increased
responsiveness, or to a combmation
of increased sensitivity and responsiveness.
The plasma glucose response during glucose tolerance
tests varies considerably among individuals and has been
reported to be reduced in endurance-trained
humans (2,
13, 22). This makes it difficult to determine the effects
of endurance training on pancreatic function. We therefore used the hyperglycemic clamp procedure (9) to compare the insulin response to an identical glucose stimulus
in trained and untrained humans.
METHODS
Subjects. A total of 15 endurance-trained
(9 males and
and 13 untrained (10 males and 3 females)
subjects gave their written consent to participate in the
studies described below, which were approved by the
Washington University
Human Studies Committee. All
the trained subjects had been involved in endurance
training for several years, and at the time of study they
were exercising >5 times/wk, with each exercise session
lasting ~45 min. Twelve of the trained subJects were
runners and three were cyclists. Eleven trained and 11
untrained subjects underwent the euglycemic clamp procedure. The hyperglycemic clamp was performed on 15
trained subjects and on 12 untrained subjects. Some
descriptive data on these subjects are given in Table 1.
Determination
of maximal O2 uptake capacity. The
maximal O2 uptake (VO zmaX) of the untrained subjects
and of the runners was determined using a- running
protocol on a motorized treadmill, whereas the VOW mu of
the trained cyclists was determined using aI cycle-ergometer test (14).
Skinfold measurements. Skinfold measurements were
made at six sites using a Lange caliper. In the-males the
six sites measured were at the triceps, subscapular, pectoral, suprailiac, umbilical, and front thigh. In females
the skinfold I thickness at midaxilla was substituted for
the pectoral site. Percent body fat was estimated according to the formulas of Yuhasi (32).
Dietary records. All subjects were instructed to eat a
6 females)
1987 the
American
Physiological
Society
2247
2248
TABLE
INSULIN
Euglycemic
30&l
175.7k2.9
67.6k2.9
v
Ht, cm
wt,
AND SECRETION
1. Subject characteristics
Trained
4%
ACTION
kg
Clamp
Hyperglycemic
Untrained
Trained
Untrained
25t1
179.4zkl.9
75.6k3.3
99.4k12.0
29&l
175.1t2.4
67.6k2.5
84.4k7.3
25&l
178.1zk1.8
72.9k2.2
95.4zk10.9
15.4k1.3
57.4k2.2
17.3zk2.3
46.6t2.2*
Skinfold sum,
80.3k8.9
B;;fat,
14.6k1.3
58.4k2.9
17.Ok2.1
46.6t1.9”
11
11
%
~hriu,
Clamp
ml kg-’ min-’
l
l
n
15
12
Values are means & SE; n, no. of subjects. vo2-,
maximal 0,
uptake. * Untrained significantly different from trained (P < 0.005).
diet containing ~150 g of carbohydrate for 3 days before
the clamp procedures. Compliance was verified by detailed dietary records that were analyzed using a computer program (Datadiet Nutrient Analysis, IPC Datadiet; Camarillo, CA).
Euglyycemic and hyperglycemic clamp procedures. Subjects reported to the General Clinical Research Center
at Washington University Medical Center at 0700 after
an overnight fast and, in the case of the trained subjects,
-16 h after an exercise bout of typical intensity and
duration. A polyethylene
catheter was placed into an
antecubital vein for infusion of 20% glucose during the
hyperglycemic clamp procedure and for infusion of 20%
glucose, Insulin, and KC1 during the euglycemic clamp
procedure. A second catheter was inserted in a retrograde
manner into a dorsal hand vein; the subject’s hand was
placed in a box heated to 70°C for sampling of arterialized
blood (25). After allowing 30 min for temperature equilibration, three blood samples were withdrawn for determination of fasting glucose and insulin concentrations.
For measurement of insulin action, a two-stage hyperinsulinemic-euglycemic
clamp procedure was used (9).
Insulin (porcine, Squibb Novo, Princeton, NJ) was diluted in 0.9% saline; 4 ml of the subject’s blood were
added to each 100 ml of saline to protect against insulin
adherence to glassware and tubing. After samples for
fasting glucose and insulin were drawn, two sequential,
primed, continuous infusions of insulin at rates of 40 and
400 mUa mm2 min-‘, each lasting 120 min, were performed. Plasma glucose concentration
was determined
every 5 min using the glucose oxidase method (Beckman
Instruments,
Fullerton, CA). The arterialized
plasma
glucose concentration
was clamped at 90 mg/dl during
the 240 min of insulin infusion by adjusting the glucose
infusion rate with a variable-speed infusion pump (Harvard Apparatus, Millis, MA). Blood samples for determination of plasma insulin concentration were drawn at
15min intervals, The plasma potassium concentration
was measured frequently throughout
the euglycemic
clamp procedure, and a replacement infusion of KC1 was
given to maintain plasma potassium within the normal
range.
The hyperglycemic clamp procedure was performed
according to DeFronzo et al. (9). A priming dose of
glucose was given over 15 min to raise the arterialized
plasma glucose concentration to 180 mg/dl. Plasma glucose was then maintained at this level for an additional
l
IN THE TRAINED
STATE
165 min by determining the plasma glucose concentration at 5-min periods and adjusting the rate of glucose
infusion. Samples taken at 2,4, 6,8, 10, and 15 min and
every 15 min thereafter were placed in chilled tubes
containing 1,000 kallikrein units of aprotinin and 6.0 mg
ethylenediaminetetraacetic
acid (EDTA),
centrifuged
and stored at -2OOC for determination
of plasma insulin
concentration by radioimmunoassay
(12). After 180 min,
a urine sample was obtained for determination
of urinary
glucose concentration.
At the conclusion of the hyperglycemic and euglycemic
clamp procedures, subjects were fed lunch. During recovery the glucose infusion was continued as needed to
maintain the plasma glucose concentration near the fasting value. Subjects were released after their plasma glucose concentration
had remained stable for 1 h without
infusion of glucose.
Calculations and statistics. Data were managed and
analyzed using the CLINFO
Data-Analysis
System of
the Washington University Clinical Research Center and
BMDP (Biomedical Computer Program, 1983, Los Angeles, CA) software system. Rates of glucose disposal (M)
during hyperglycemic and euglycemic clamp procedures
were calculated for each 30-min period by correcting the
mean infusion rate for loss of glucose in the urine and
for glucose that was added to or removed from the glucose
space (9) M values are expressed as milligrams of glucose
infused per kilogram of fat-free mass (FFM) per minute.
The M values during the final 30 min of the 40- and 400.
mu. mm2 min-l insulin infusions were used for data
analysis
Incremental
areas for early (O-10 min) and late (lo180 min) plasma insulin responses during the hyperglycemic clamp procedure were calculated with a computer
program using a trapezoidal model that sums the area
above base line (28). Plasma insulin concentrations in
the trained and untrained subjects were compared using
a two-way analysis of variance for repeated measures
Significant differences were located using the NewmanKeuls multiple-comparison
test. Unpaired t tests were
used to compare subject characteristics,
insulin areas,
and M values.
RESULTS
Subjects. Although the untrained subjects tended to be
heavier than the trained group, the differences in body
weight and percent body fat did not reach statistical
significance (Table 1). VOW
maxwas ~30% higher in the
trained subjects (P < 0.005).
Fasting glucose and insulin concentrations. The fasting
arterialized plasma glucose concentration
was lower in
the trained (90 t 1 mg/dl) compared with the untrained
subjects (97 t 1 mg/dl) before the euglycemic clamp
procedure (P < 0.001). Plasma insulin was also lower in
the trained subjects (7 t 1 vs. 12 & 2 pU/ml; P c 0.005).
Fasting plasma glucose (90 & 1 vs. 93 t 2 mg/dl; P <
0.05) and insulin (6 -CI 1 vs. 12 t 2 pU/ml; P < 0.005)
concentrations
were also lower in the trained subjects
before the hyperglycemic clamp procedure.
Insulin infusion. The plasma glucose concentration
was the same in the trained (89 & 1 mg/dl) and untrained
INSULIN
ACTION
AND SECRETION
IN THE TRAINED
STATE
2249
(90 $I 1 mg/dl) groups during the final 30 min of the 40- untrained groups, respectively.
mU rnw2 min-l insulin infusion. The stability of the
The plasma insulin concentration was markedly lower
plasma glucose concentration during this period is indiin the trained subjects during both early (O-10 min) and
cated by coefficients of variation of 3.9 t 0.5 and 3.3 & late (lo-180 min) responses (Fig. 2). Peak values for the
0.4% in the trained and untrained groups, respectively.
early response, reached at 4 min, were 39 $- 4 hU/ml for
Although the plasma insulin concentration
was some- the trained subjects compared with 57 & 5 pU/ml for the
what higher in the untrained (95 t 7 yU/ml) than in the untrained (P < 0.001) group, whereas the 1800min values
trained (79 t 5 pU/ml) subjects, this difference was not were 43 t 7 and 89 & 14 pU/ml (P < O.OOl), respectively.
statistically
significant.
M values were significantly
The incremental areas for insulin during the early (O-10
higher in the trained subjects throughout the 40.mU a
min) and late (lo-180 min) responses were -50% lower
mm2 min-1 infusion. M during the final 30 min of the 40- in the trained subjects (Table 2).
mU rnM2. min-l infusion was 28% greater in the trained
Mean M values during the hyperglycemic clamp pro(10.2 t 0.5 mg* kg FFM-’ . min-l) than in the untrained
cedure were not significantly different in the two groups.
(8 0 t 0.6 mg kg FFM-1 min-l) subjects (Fig. 1; P < For the 150. to 180.min infillsion period, M was 13.1 t
0.01).
1.4 mg kg FFM-’ . min-1 in the trained and 11.4 t 0.9
During the final 30 min of the 400-mU mm20mir?
mg* kg FFM-’ l 11nin-l in the untrained group. These rates
infusion, plasma glucose concentrations were 90 t 1 and of glucose disposal were associated with mean plasma
91 t 1 mg/dl for the trained and untrained subjects, with
insulin concentrations
of 42 t 7 pU/ml in the trained
coefficients of variation of 5 6 t 0.8 and 4.0 t 0.5%, and 89 & 13 &J/ml in the untrained group. The similar
respectively. The plasma insulin concentration averaged
glucose disposal rate, despite a lower plasma insulin
2,214 t 167 &/ml
for the trained and 2,329 t 296 &J/
concentration observed in the trained subJects, indicates
ml for the untrained group. During the 400-mu. rnD2. a greater insulin-stimulated
M in these subjects.
min” insulin clamp procedure, M was not significantly
different in the trained and untrained subjects at any DISCUSSION
time point During the final 30 min of the 400-mU*m-2*
Several groups of investigators, using the euglycemic
min.* infusion, M was 17.7 t 0.6 mg kg FFM-l. mine1
in the trained and 16.7 & 0.7 mg* kg FFM-l. min-’ in the clamp technique, have found insulin action to be increased in endurance-trained
subjects (7, 15, 27, 30). In
untrained subjects.
Hyperglycemic clamp. Arterialized plaema glucose con- these studies, a single submaximal insulin concentration
was used to evaluate insulin action. With this approach,
centrations during the hyperglycemic
clamp procedure
were similar in the two groups, averaging 179 t 1 and it is possible to study insulin action at comparable
steady-state plasma insulin concentrations;
however, it
178 & 1 mg/dl during the 165 min of sustained hyperglydoes not distinguish between increases in insulin sensicemia in the trained and untrained groups, respectively.
The plasma glucose concentration during this period was tivity and insulin responsiveness.
The greater M in trained subjects during the 40=mU*
quite stable, as indicated by the coefficients of variation,
which were 4.7 t 0.4 and 3.1 t 0 2% for trained and m 2. min-1 insulin infusion and the lack of a significant
difference in M during the 400.mu. rnm2. min-l insulin
infusion provide evidence that the enhanced insulin acm
Pained
tion associated with endurance training is due to an
increase in sensitivity to insulin. In support of this
Untrained
conclusion, the percent of maximal response reached
during the 400mu. rnB2. mine1 infusion (i.e., Mm&
M210-2& was higher (58 k 3 vs. 48 t 3%) for the trained
subjects (P c 0.05).
To construct dose-response curves for in vivo insulinstimulated glucose disposal, the metabolic clearance rate
(MCR) of glucose (in ml kg-l .min-‘; MCR = M/mean
plasma glucose concentration) was calculated for the 90.
to 12O-min interval of the 4O- and 400-mU~m-20min-1
infusions and for the same time period during the hyperglycemic clamp procedure. In Fig. 3 the glucose MCR
(expressed as percent of maximal
MCR) is plotted
against the logarithm of the mean plasma insulin concentration.
Figure 3 provides clear evidence that the
major effect of endurance training is a leftward shift of
the insulin dose-response curve (i.e., a change in insulin
sensitivity) rather than an increase in responsiveness to
insulin.
40 mU/m2/min
400mU/rn2/min
The mechanism that mediates the increaied insulin
FIG. 1. Glucose disposal rates during final 30 min of 40- and 400sensitivity in trained individuals is not known. It has
mUgm-2 .min” insulin infusions. Values are means 2 SE of 11 trained
been reported that insulin-stimulated
glucose disposal is
and 11 untrained subjects. * Significantly different from trained (P <
0.01). FFM, fat-free mass.
inversely related to percent body fat (4, 30). In the
l
l
l
l
l
l
l
l
.
L
2250
INSULIN
ACTION
AND SECRETION
IN THE TRAINED
Z 60
T?
1cn
STATE
FIG. 2. Plasma insulin response during lWmg/dl
hyperglycemic clamp procedure. Values are means *
SE of 15 trained and 12 untrained subjects. Trained
significantly different from untrained: * P < 0.01; f P
< 0.001.
Trained
Untrained
O0
w
04
I
I
I
I
I
I
30
60
90
120
150
180
m
TIME (minutes)
2. Incremental insulin areas during
hyperglycemic clamp procedure
TABLE
Time min
O-10
lo-180
Trained
140*18
4,582+689
Untrained
223223’
8,895,+1,316*
Values are means =~tSE for 15 trained and 12 untrained subjects.
Units for area above base line are &J.ml-‘*min.
* Trained vs. untrain& P < 0.01.
1
1
\
1000
100
PLASMA INSULIN (~Uvnl”)
FIG. 3. Dose-response curves for insulin-stimulated
glucose disposal
in trained and untrained subjects. Metabolic clearance rates (MCR)
were calculated by dividing mean glucose disposal rate by mean plasma
glucose concentration during 90- to 120-min period of 40- and 4000
mUo rn’O* min” insulin infusions and during same time period of MOmg/dl hy@rglycemic clamp procedure. Data are expressed as percent
of MCR obtained during 4000mU rna2. min” insulin infusion.
l
present study, the untrained subjects tended to be heavier and fatter than the trained subjects; however, the
difference was not significant. None of the untrained
subjects was overweight, and it is unlikely thrrt the difference in insulin sensitivity can be explained solely on
the basis of differences in body composition.
Skeletal muscle is the primary site of disposal of intravenously administered glucose (8) and appears to be the
site of the enhanced insulin sensitivity associated with
endurance training (1,19). Exercise has persistent effects
on muscle cell permeability
to glucose (10,16). Changes
in insulin sensitivity are usually ascribed to changes in
binding of insulin to its receptor (21). Although the
influence of exercise on insulin binding to muscle is not
clear (5, 6, 30), exercise has been shown to increase
insulin binding to monocytes and erythrocytes (7, 13,
22)
There is also evidence, both in rats (10, 26) and in
humans (3,17), that exercise-induced depletion of muscle
glycogen may play a role in the enhanced insulin action
observed after exercise. However, it seems unlikely that
glycogen depletion played a major role in our trained
subjects, because they ate a carbohydrate-containing
meal 2-3 h after their last exercise bout before the glucose
clamp study.
The decreased insulin response to oral or intravenous
glucose administration
has been interpreted as indicating
that exercise training results rn a reduced secretion of
insulin. This conclusion is complicated by the finding of
a lower plasma glucose response to a glucose challenge
in trained individuals
observed by Borne, but not all,
investigators (2,20,23,24,28).
This problem was avoided
in the present study by the use of the hyperglycemic
clamp technique, which provides an identical glucose
stimulus to the ,&cell. Cur results show that the blunted
insulin response to a carbohydrate challenge m trained
individuals cannot be attributed to a reduced stimulus to
the pancreas.
The smaller increase in the plasma insulin concentra-
INSULIN
ACTION
AND SECRETION
tion in response to an identical glucose stimulus could
be due to I) a decreased sensitivity of the ,&cell to
increases in plasma glucose, 2) a reduced maximal secretory capacity of the /%cell, 3) a combination
of reduced
sensitivity and maximal
secretory capacity, or 4) an
increase in the rate of insulin clearance. In rats, exercise
training results in a decreased release of insulin from
isolated pancreatic islets in response to physiological
increments in the glucose stimulus, whereas insulin release in response to maximal glucose concentrations
is
unaffected by training (11, 32). This suggests that the
blunted insulin secretion observed is related to a change
in @-cell sensitivity to glucose. Clearly this question
requires further detailed studies in humans.
Previous studies have provided evidence that the enhanced insulin action and blunted insulin response observed in well-trained individuals
is lost quickly after
cessation of training (7, 13, 23). We have also observed
that a short period (7 days) of intense exercise training
can improve insulin action in insulin-resistant
patients
(M. A. Rogers et al., unpublished observations) without
producing a measurable change in vo2maxDIt is likely
that a large proportion of the increased insulin sensitivity
and reduced insulin secretion observed in trained humans (15, 23, 27) is due to persistent effects of the last
bout(s) of exercise, as opposed to more long-term adaptations to training. Relative to this hypothesis, Bogardus
et al. (3) observed that a single bout of exercise resulted
in an increased insulin-stimulated
M at both submaximal
(-100 pU/ml) and maximal (-2,000 pU/ml) insulin concentrations. Further studies are necessary to determine
the relative importance of the effects of long-term exercise training and of persistent effects of the last bouts of
exercise in bringing about the increase in insulin sensitivity and the decrease in insulin secretion.
In coticlusion, our data suggest that the improved
insulin action observed in endurance-trained
individuals
is due to an increased sensitivity to insulin. Endurance
training does not appear to result in a significant change
in responsiveness to insulin in young, healthy humans.
Associated with the increased insulin sensitivity,
the
plasma insulin response to a given plasma stimulus is
markedly attenuated.
We thank Dr. Dariush Elahi for his helpful advice in the performance of euglycemic and hyperglycemic clamp procedures. We also
gratefully acknowledge the technical assistance of the Section of Applied Physiology staff and the nursing staff of the General Clinical
Research Center at Washington University School of Medicine and
Daniel Weidman, CLINFO System Manager, for his help in data
analysis.
This research was supported in part by Program Project Grant AG005562, Diabetes Research and Trai&ng Center Grant AM-20579, and
Grant 5-MOlRR-00036 from the General Clinical Research Center
Branch, Division of Research Facilities and Resources, National Institutes of Health. D. S. King was supported by Institutional National
Research Service Award AG-00078 from the National Institutes of
Health.
Received 20 April 1987; accepted in final form 7 July 1987.
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