1 Research Center of Health, Physical Fitness and Sports, Nagoya University, Nagoya 464-8601; 2 Laboratory of Biochemistry of Exercise and Nutrition, Institute of Health and Sport Sciences, University of Tsukuba, Ibaraki 305-8574; 3 Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical School, Tochigi 329-0498; 4 Department of Community Health Science, Saga Medical School, Saga 849-8501; 5 Department of Internal Medicine, School of Medicine, and 6 Laboratory of Exercise Physiology, Faculty of Health and Sports Science, Fukuoka University, Fukuoka, 814-0180 Japan
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ABSTRACT |
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To examine the effects of physical
training on glucose effectiveness (SG), insulin sensitivity
(SI), and endogenous glucose production (EGP) in
middle-aged men, stable-labeled frequently sampled intravenous glucose
tolerance tests (FSIGTT) were performed on 11 exercise-trained
middle-aged men and 12 age-matched sedentary men. The time course of
EGP during the FSIGTT was estimated by nonparametric stochastic
deconvolution. Glucose uptake-specific indexes of glucose effectiveness
(S1 · kg
1,
P < 0.05) and insulin sensitivity
[S
1 · (µU/ml)
1 · kg
1,
P < 0.01], which were analyzed using the
two-compartment minimal model, were significantly greater in the
trained group than in the sedentary group. Plasma clearance rate (PCR)
of glucose was consistently greater in the trained men than in
sedentary men throughout FSIGTT. Compared with sedentary controls, EGP
of trained middle-aged men was higher before glucose load. The EGP of
the two groups was similarly suppressed by ~70% within 10 min,
followed by an additional suppression after insulin infusion. EGP
returned to basal level at ~60 min in the trained men and at 100 min
in the controls, followed by its overshoot, which was significantly greater in the trained men than in the controls. In addition, basal EGP
was positively correlated with
S
glucose effectiveness; insulin sensitivity; endogenous glucose production; stable isotopes
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INTRODUCTION |
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OVERALL GLUCOSE TOLERANCE is determined by three major physiological factors: insulin secretion, insulin sensitivity (SI), and insulin-independent effect, namely glucose effectiveness (SG), which is the combined ability of glucose per se to stimulate its own uptake and suppress its own production (1). In normal individuals, ~50% of the glucose disposal during an oral glucose tolerance test (OGTT) is attributable to SG but not to insulin action, thus suggesting the importance of SG in determining glucose tolerance (1, 3). Using a minimal model, Welch et al. (50) showed that SG as well as SI decreased in type 2 diabetes mellitus. Moreover, our previous reports (11, 42, 43) demonstrated that SG decreased in Japanese type 2 diabetic patients as well as in subjects with impaired glucose tolerance and type 2 diabetic offspring. Furthermore, an epidemiological study reported that a reduced SI and reduced SG are both strong predictors of type 2 diabetes mellitus (26).
Several studies have investigated the effect of exercise training on
SG. Kahn et al. (20) studied healthy elderly
men (aged 60-82 yr) before and 6 mo after intensive exercise
training and found no effects of exercise training on SG.
In addition, no change in SG of middle-aged men after 14 wk
of exercise training was observed by Houmard et al. (17).
In contrast, we (13, 44) previously reported that young
distance runners and strength-trained men have a 76 and 30% higher
SG, respectively, than that of controls. Taken together,
levels of physical training and/or aging might modify the effect of
endurance training on SG. As mentioned above, the
one-compartment minimal model has been widely used to assess both
SG and SI, whereas this classical method could
not single out the estimates of glucose uptake alone from the combined
ability of insulin or glucose per se to stimulate glucose uptake and
suppress its own production. A recently proposed stable-labeled
two-compartment minimal model provides new indexes of glucose
uptake-specific glucose effectiveness
(S
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RESEARCH DESIGN AND METHODS |
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Subjects.
The characteristics of the subjects are presented in Table
1. Eleven exercise-trained middle-aged
men who can run the marathon (42.195 km) within 3.5 h (recent best
marathon record: 3.07 ± 0.09 h) were recruited for this
study. They had trained for an average of 16.0 ± 2.8 yr (range
4-30 yr). They ran an average of 75.6 ± 8.7 km/wk. An
additional 12 age-matched men, who were not engaged in any habitual
exercise for 2 yr and whose body mass index (BMI) was <24
kg/m2 (range 20.7-23.6), were enrolled for comparison
with the exercise-trained men. The sedentary subjects were confirmed to
be normally glucose tolerant. None of the subjects was taking any
medications or supplements. Before this study began, the nature,
purpose, and risks of the study were explained to all subjects, and
informed written consent was obtained. The protocol was approved by the
local ethics committee of Jichi Medical School and was conducted in
accordance with the Helsinki Declaration.
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Physical fitness in exercise-trained middle-aged men.
To measure physical fitness in exercise-trained middle-aged men,
the graded exercise test on a treadmill was performed. The running
speed was initially set at 140 m/min and thereafter was increased every
4 min by 20 m/min. At each undermaximum stage, the heart rate was
measured during the last minute of the stage with a heart rate monitor
(Polar Accurex Plus, Tokyo, Japan). When the heart rate reached 70% of
the heart rate maximum expected for their age, the running speed was
continuously increased every 1 min by 10 m/min until subjective
exhaustion was achieved. Oxygen uptake
(O2) was measured from the mixed expired
gas collected in neoprene bags. The volume of the expired gas was
quantified with a twin-drum type respirometer (Fukuda Irika CR-20,
Tokyo, Japan), and both the O2 and CO2
fractions were analyzed by a mass spectrometer (Perkin-Elmer 1100, Norwalk, CT).
Frequently sampled intravenous glucose tolerance test and OGTT.
On the day when a frequently sampled intravenous glucose tolerance test
(FSIGTT) was performed, in the morning between 0700 and 0900 after
overnight fasting, the subjects were allowed to rest while lying down
for 30 min before blood sampling commenced. Blood samples were
obtained from an antecubital vein in one arm, which was kept in a
radiant warmer at 70°C to provide an arterialized blood source. The
baseline samples for glucose, insulin, and free fatty acid (FFA) were
obtained, and then glucose isotopically labeled with
[6,6-2H2]glucose (Aldrich, Milwaukee, WI) was
administered in the contralateral antecubital vein (300 mg/kg body wt)
within 1 min (27). Regular insulin (Humulin; Shionogi,
Osaka, Japan) was infused (20 mU/kg) into an antecubital vein from 20 to 25 min after the glucose bolus. Blood samples for glucose, insulin,
and FFA were frequently obtained up to 180 min. On the day before
undergoing the FSIGTT, all subjects were provided with an evening meal
consisting of
140 g of carbohydrate,
30 g of fat, and
33 g of
protein. The FSIGTTs on the exercise-trained men were performed 48 h after the last training session.
Biochemical and stable isotope tracer analysis. The plasma glucose levels were measured spectrophotometrically in triplicate using glucose oxidase (Glucose B test; Wako Pure Chemical, Osaka, Japan). The immunoreactive insulin levels were measured in duplicate using a Phadeseph insulin radioimmunoassay kit (Shionogi). The serum FFA levels were assayed using the standard method (41). Deuterated glucose was analyzed as a pentaacetate derivative by use of the method of Wolfe (53), as previously described (27). The measurement error associated with the labeled glucose measurement was assumed to be independent, white, and Gaussian, with a zero mean and a coefficient of variation of 3.0%.
Calculations.
The indexes of glucose effectiveness
(S
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Statistics. All values are shown as means ± SE. To evaluate the differences between the exercise-trained middle-aged men and the control subjects, the data were analyzed by Mann-Whitney's U-test. The significance of the relationship between variables was assessed by the Pearson correlation coefficient. A P value < 0.05 was considered to be statistically significant.
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RESULTS |
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As indicated in Table 1, the trained and sedentary subjects
differed significantly in body weight and BMI. The high-level maximal
O2
(
O2 max) of exercise-trained
middle-aged men in the present study (52.1 ± 1.4 ml · kg
1 · min
1), which
corresponds to the previously reported
O2 max in exercise-trained middle-aged
men (54.4 ± 1.6 ml · kg
1 · min
1)
(17), provided evidence that they were all well trained.
Although the basal glucose levels were similar in both groups, the
basal serum insulin levels were lower in the exercise-trained
middle-aged men than in the sedentary controls (Table
2). KG values were similar in both groups (Table 2 and Fig.
1A). The integrated area of
insulin during the first 20 min after glucose injection in the trained
tended to be lower (P = 0.065) than that of sedentary men (Table 2 and Fig. 1B).
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The volume of the glucose distribution in the first pool
(V1) was identical in untrained and trained subjects
[sedentary vs. trained men: 1.10 ± 0.16 vs. 1.18 ± 0.22 dl/kg, not significant (NS)]. The model-incorporated mixing
parameters, i.e., k21 and k12, between the glucose pools (q1
and q2) were also similar between the two groups
(k21: 0.102 ± 0.012 vs. 0.114 ± 0.018 min1, NS; k12: 0.117 ± 0.013 vs. 0.116 ± 0.013 min
1, NS;
respectively). Two parameters concerning glucose
disposal from the second compartment, kb and
k02, were similar between the sedentary and
trained subjects (kb: 0.124 ± 0.012 vs.
0.094 ± 0.005 min
1, NS; k02:
0.00464 ± 0.00041 vs. 0.00424 ± 0.00027 min
1,
NS), whereas another parameter, ka, was
significantly greater in trained men than that in sedentary men
(0.000157 ± 0.000027 vs. 0.000220 ± 0.000023 ml · µU
1 · min
2,
P < 0.05). The fractional parameters describing the
insulin-independent glucose uptake, i.e., kp,
tended to be greater in trained men than in sedentary men (0.00176 ± 0.00030 vs. 0.00295 ± 0.00044 min
1,
P = 0.065). Tissue-specific glucose effectiveness
(S
The basal EGP in the trained men was significantly greater than that in
the controls (Table 2 and Fig. 1F). A significant positive
correlation between S1 · min
1,
P < 0.01). The serum FFA concentrations during the
FSIGTTs of trained subjects were lower than those of the sedentary
subjects (Table 2 and Fig. 3). As shown
in Fig. 3, FFA in the sedentary men began to recover at 70 min and then
returned to the basal level at 160 min. On the other hand, FFA in the
trained men began to recover at 40 min and rapidly returned to the
basal level at 140 min and thereafter showed a clear overshoot at 180 min.
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A significant correlation between BMI and
S
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DISCUSSION |
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Using the stable-labeled two-compartment minimal model, we found
that glucose uptake-specific glucose effectiveness
(S
An acute rise in plasma glucose concentration has a marked effect of
increasing skeletal muscle non-insulin-dependent glucose uptake in
healthy humans (2). In an animal study, acute
hyperglycemia induced an approximately twofold increase in the skeletal
muscle plasma membrane GLUT4 content independent of insulin, thus
suggesting that glucose per se activates specific glucose transporter
proteins (14). Middle-aged endurance-trained men have a
1.8-fold greater concentration of GLUT4 protein compared with sedentary
controls (16). Likewise, Houmard et al. (17)
reported that only a 14-wk physical training regimen increased the
skeletal muscle GLUT4 protein concentration 1.8-fold in previously
sedentary middle-aged men. On the basis of these reports, it is
possible that a training-induced augmentation in GLUT4 protein
concentration in skeletal muscle might be one of the reasons for the
enhanced SO2 max for 1 mo) was
also reported (31). It is therefore conceivable that GLUT1 may contribute to the greater S
Prolonged increases in FFA availability result in a marked impairment
in the ability of insulin to promote skeletal muscle glucose transport
and/or phosphorylation and also in the accumulation of end products of
the hexosamine biosynthetic pathway (15). In addition, in
the absence of insulin, FFA was able to reduce muscle glucose uptake in
vitro (36). A sharp reduction in FFA levels increased the
muscle non-insulin-mediated glucose uptake by 10%; conversely, an
acute increase diminished the glucose uptake by 26% (32).
These results suggest that FFA could inhibit non-insulin-mediated glucose uptake in human skeletal muscle. In this study, the FFA levels
during FSIGTT in exercise-trained middle-aged men were far lower than
in the sedentary controls (Fig. 3). A lower level of FFA could also
explain the greater S
The basal EGP level correlated with the fasting plasma glucose level and increased substantially in the type 2 diabetic patients who had a fasting plasma glucose >180 mg/dl (18). Surprisingly, the EGP in exercise-trained middle-aged men was also significantly greater compared with that of the untrained controls. Our result as estimated by the two-compartment minimal model was consistent with the results of previous human and animal studies that employed the model-independent method. By using the constant-rate tracer infusion technique, Kjaer at al. (24) showed that the basal EGP tended (P < 0.1) to be higher (15%) in trained than in sedentary men under similar basal glucose concentrations. Turcotte and Brooks (45) also showed that trained animals have a significantly higher basal EGP with the use of [14C]lactate and [3H]glucose. On the other hand, Segal et al. (39) demonstrated an unchanged EGP in both lean and obese men, or even decreased EGP in patients with type 2 diabetes mellitus, after physical training. The response of the basal EGP to exercise training seems to be related to the difference in the basal insulin level, because basal insulin concentration was an independent determinant of EGP in nondiabetic subjects (28). Segal et al. (39) observed an unchanged or decreased EGP level simultaneously with no change in the basal insulin concentration after exercise training. When the insulin levels were maintained at the same levels by insulin infusion, namely at 10 µU/ml, the basal EGP in physically trained subjects was lower than that in the sedentary controls (37). On the basis of these studies, the basal EGP may decrease if the basal insulin levels are maintained at the pretraining levels after training. However, the fasting insulin levels in the exercise-trained middle-aged men who took part in our study were far lower than those of sedentary men (Table 2), thus suggesting that the basal insulin had less of a restraining effect on the basal EGP in trained subjects. Another possible explanation for the greater basal EGP in our trained subjects might be enhanced gluconeogenesis. In rats, gluconeogenesis accounts for 50% of glucose production at basal conditions (38), and the rate of glucose synthesis from the labeled lactate in incubated liver slices declined with age; however, exercise training partially offsets this decline (34). In addition, training has also been reported to significantly increase the activity of some enzymes involved in gluconeogenesis (19). Although in humans the rate of gluconeogenesis that accounts for basal glucose production is lower (~20%) than in rats (40), the increased gluconeogenic capacity as a result of exercise training may, in part, contribute to the enhanced basal EGP in trained men.
The question arises as to whether or not EGP is geared to match glucose
utilization. Eighty percent of the basal glucose disappearance is
noninsulin mediated in healthy men (2), and
insulin-independent glucose removal under basal conditions is assumed
to be three times greater than insulin-dependent removal in the model
that we used. As expected, we found a very strong positive correlation between S
Another interesting finding of the present study is the significantly
greater EGP overshoot observed in trained middle-aged men. The
difference in the EGP overshoot between trained men and sedentary
subjects may reflect the difference in the plasma glucose concentration. The nadir of glucose levels during the FSIGTTs was
deeper (trained men: 25.4 ± 2.8 mg/dl; controls:
20.8 ± 3.0 mg/dl compared with the basal glucose level) and was
earlier (trained men: 68.2 ± 4.2 min; controls: 94.2 ± 10.3 min after glucose ingestion) in the trained men. Kjaer et al.
(24) demonstrated that, during insulin-induced
hypoglycemia, despite identical plasma glucose concentrations,
epinephrine and growth hormone reached higher levels (98 and 52%,
respectively) in the trained men than in the untrained controls. In
this study, a deeper decline in the plasma glucose concentration may
therefore elicit a greater counterregulatory hormonal response in
trained middle-aged men. In addition, FFA in the sedentary men slowly
returned to the basal level at the end of the FSIGTT, whereas FFA in
the trained men rapidly returned to the basal level, and a clear
overshoot was also observed at 180 min (Fig. 3). These results also
imply a higher counterregulatory hormonal response in the trained men.
In this study, the endogenous insulin area above the basal insulin
(0-20 min) in trained men tended to be smaller (P < 0.1) than that in sedentary men (Table 2). On the other hand, the exogenous insulin areas above insulin levels at 19 min (20-40 min)
were similar between the two groups (sedentary vs. trained: 608 ± 53 vs. 561 ± 50 µU · ml1 · (µU/ml)
1 · min
1,
P = 0.44, NS). We thus speculate that slightly reduced
insulin area in response to glucose challenge in exercise-trained men was primarily due to changes in insulin secretion, consistent with
previous reports (22, 23). It has generally been observed that insulin-sensitive subjects secrete less insulin in response to
glucose challenge (21). However, the detailed mechanisms for such an adaptation remain to be elucidated. At least one group of
investigators (51, 52) has suggested that endurance
training results in an enhanced clearance of insulin from plasma that
accounts in part for the lower insulin area to glucose administration. Because we could not assess insulin clearance in the studied subjects directly, such a possibility cannot be fully ruled out.
In conclusion, using the two-compartment labeled minimal model
and deconvolution, we found that exercise-trained middle-aged had a
significantly greater S
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ACKNOWLEDGEMENTS |
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We thank all the subjects who participated in this study. In addition, we thank the Department of Pharmacy in Jichi Medical School for compounding the sterile-labeled glucose solutions.
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FOOTNOTES |
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This work was partially supported by grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (10770574, 11480005, 12671123), the Central Research Institute of Fukuoka University, the Japan Diabetes Foundation, the Institute for Adult Disease Asahi Life Foundation, and a Jichi Medical School Young Investigator Award.
Address for reprint requests and other correspondence: H. Tanaka, Laboratory of Exercise Physiology, Faculty of Health and Sports Science, Fukuoka University, 8-19-1 Nanakuma Jonan-Ku, Fukuoka 814-0180, Japan (E-mail: htanaka{at}fukuoka-u.ac.jp).
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.
June 25, 2002;10.1152/ajpendo.00237.2001
Received 31 May 2001; accepted in final form 13 June 2002.
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