-30 min) after the final exercise bout and 1, 3, 5, and 7 days after exercise. The incremental area under the plasma glucose curve was markedly higher IPE (355 t ...
Time course for exercise-induced alterations action and glucose tolerance in middle-aged
in insulin people
DOUGLAS S. KING, PHILLIP J. BALDUS, RICK L. SHARP, LYLE D. KESL, TIMOTHY L. FELTMEYER, AND MARK S. RIDDLE Exercise Biochemistry Laboratory, Department of Health and Human Performance, Iowa State University, Ames, Iowa 50011 King, Douglas S., Phillip J. Baldus, Rick L. Sharp, Lyle D. Kesl, Timothy L. Feltmeyer, and Mark S. Riddle. Time course for exercise-induced alterations in insulin action and glucose tolerance in middle-aged people. J. AppZ. Physiol. 78(l): 17-22, 1995.-The purposes of this study were 1) to investigate glucose tolerance and insulin action immediately after exercise and 2) to determine how long the improved glucose homeostatic mechanisms observed 12- 16 h after exercise persist. Nine (seven men, two women) moderately trained middle-aged (51 t 3 yr) subjects performed 45 min of exercise at 73 2 2% of peak Oz uptake for 5 days, followed by 7 days of inactivity. Oral glucose tolerance tests (OGTT; 75 g) were performed immediately postexercise (IPE; -30 min) after the final exercise bout and 1, 3, 5, and 7 days after exercise. The incremental area under the plasma glucose curve was markedly higher IPE (355 t 82 mM min) compared with those on days 1(136 5 57 mM min; P < 0.05) and 3 (173 5 62 mM min; P < 0.05). The glucose area was significantly higher on days 5 (213 t 80 mM min) and 7 (225 t 84 mM min) compared with those on days 1 and 3 (P < 0.05). The incremental insulin area IPE (3,729 ? 1,104 $J~rnll’~ min) was 43% higher compared with that on day 1 (2,603 t 635 PI-J. ml- ’ min; P < 0.05) and 66% higher compared with that on day 3 (2,240 t 517 PU ml-’ min; P < 0.05). The insulin area increased to 3,616 t 617 PU ml-’ min after 5 days of inactivity (P < 0.05). An additional 48 h of inactivity did not result in any further increase in the plasma insulin response. Plasma free fatty acid concentrations were markedly higher before the OGTT performed IPE (0.79 t 0.07 mM) compared with those on day 1 (0.28 t 0.03 mM; P < 0.001) and remained higher (0.07 t 0.02 vs. 0.03 t 0.01 mM; P < 0.001) IPE at the conclusion of the OGTT. These data show an exaggerated insulin response and a marked impairment of insulin action immediately after exercise. This transient insulin resistance, which is associated with elevated plasma free fatty acid concentrations, is replaced within 24 h by enhanced insulin action and a reduced insulin response. The improved insulin action and glucose tolerance after exercise persist for 3 days but not for 5 days. l
l
l
l
l
l
l
l
l
inactivity; insulin fatty acids
sensitivity;
carbohydrate
homeostasis;
l
free
INDIVIDUALS have normal or improved glucose tolerance, despite a markedly reduced insulin response, to a carbohydrate challenge (29, 17). We have previously provided evidence that the lower plasma insulin response appears to be due to a decreased secretion of insulin rather than increased clearance (13- 15). The reduced secretion of insulin is accompanied by an increase in the sensitivity of the glucose disposal system to insulin, that is, a shift in the dose-response curve (15). In two related studies, the increased insulin sensitivity and reduced insulin secretion were abolished when endurance-trained people stopped training for lo- 14 EXERCISE-TRAINED
0161-7567/95
$3.00
Copyright
days (13, 14). These data, as well as those of other investigators(9, 17), suggest that the augmented insulin sensitivity and reduced insulin secretion observed in people who exercise regularly are largely a consequence of th .e acute effects of the last bout of exercise rather than of long-term training adaptation s. Along these lines, we recen tly demonstrate d that 1 wk of intense daily exercise can normalize glucose tolerance in men with non-insulin-dependent diabetes mellitus (NIDDM; Ref. 29). This improvement of glucose tolerance was independent of any change in diet or body fat content and suggests that exercise may be useful as a nonpharmacological intervention for people with NIDDM. The increased insulin sensitivity and reduced insulin secretion associated with exercise have typically been observed when subjects were studied 12-16 h after exercise (2, 9, 13-15, 17). In contrast, the impact of exercise on insulin action during the time period immediately after exercise is less clear. Plasma glucose concentrations in response to glucose ingestion have been reported to be elevated when carbohydrate is ingested immediately after endurance exercise (3). In contrast, studies with the hyperinsulinemic-euglycemic clamp procedure performed immediately after exercise have reported unchanged (20) or increased (5, 19) insulin sensitivity. The time course for the reversal of the improved insulin action observed after exercise is also not clear. Some investigators have reported that improved insulin action after exercise is evident at 24 (lo), 48 (19, 24), or 72 h (17). Others have demonstrated that improved insulin action is lost within 38 (23), 60 (5), or 96 h (31) after exercise. Interpretation of these studies is complicated by the diversity of subject characteristics in terms of age, training state, adiposity, and glucose tolerance. To date, only one investigation has studied the time course for the reversal of improved insulin action in a systematic fashion (23). These authors reported that improved insulin sensitivity (measured with the hyperinsulinemic-euglycemic clamp procedure) observed after exercise was lost within 38 h in healthy young people. The duration of the improved insulin action associated with exercise may be an important consideration in exercise prescription, especially for those with impaired glucose tolerance and NIDDM. The purposes of this study were to determine 1) the effect of exercise on glucose tolerance and insulin action during the time period immediately after exercise and 2) how long the improved glucose homeostatic mechanisms typically observed 12-16 h after exercise persist. Most previous studies on the effect of exercise on insulin action utilized the hyperinsulinemic-euglycemic clamp proce-
0 1995 the American
Physiological
Society
17
18
INSULIN
TABLE
ACTION
AND
GLUCOSE
1. Subject characteristics Exercising
Age,Yr
51 5 3
Height, cm Women Men Weight, kg Women Men Body mass index, kg/m2 Body fat, % Women Men Estimated v02 peak l/min ml kg-’ mine1 l
Values 0, uptake.
Inactive
l
are means
171.5 176.1 73.1 64.6 75.5 23.9 21.9 23.7 18.3
+ + t 5 + -+ t + k
0.5 3.1 3.0 0.4 3.4 0.9 3.0 2.3 1.9
73.0
+ 3.2
23.9 22.2
+ 1.0 + 2.5
2.86 + 0.23 39.0 k 2.8
+ SE; n = 2 women
and
7 men.
i702peak,
peak
dure, which breaks the normal feedback loop between insulin and glucose. These results may not reflect what occurs when the normal homeostatic mechanisms of carbohydrate metabolism remain intact. Therefore, carbohydrate tolerance and insulin action were assessedwith oral glucose tolerance tests performed immediately (-30 min) and 1, 3,5, and 7 days after exercise. METHODS Subjects. The time course for reversal of the increased insulin action and improved glucose tolerance after exercise was studied in nine trained subjects (seven men, two women) aged 41-65 yr. Subjects gave their written consent to participate in the study, which was approved by the Iowa State University Human Subjects Committee. Subjects were recruited from participants in the University Exercise Clinic, which is composed primarily of walking, jogging, and cycling programs. Before joining the Exercise Clinic, all participants underwent a physical examination and a graded exercise test with electrocardiographic monitoring. Subjects participating in the study were free of coronary artery disease, had no contraindications to exercise testing or training, and were taking no medication. At the time of study, the subjects were exercising continuously for 30-60 min./session, 3 sessions/ wk, at an exercise intensity of -6O-80% of the maximum heart rate reserve. Six of the subjects were runners, two were cyclists, and one was a walker. All subjects had been exercising regularly for at least 2 yr (range 2- 16 yr). There were no differences in glucose tolerance, body composition, or training status in the subjects performing treadmill exercise and those exercising on a cycle. Subject characteristics are given in Table 1. Study design. For five consecutive days, the subjects performed 45 min of exercise at a work rate designed to elicit 75% of estimated peak O2 uptake (ir~,,,,~). Each exercise session was divided into three 15min exercise bouts separated by 5 min of rest. Heart rate and O2 uptake (VO,) measurements were taken during the final 5 min of each exercise bout for determination of exercise intensity. The runners and walkers exercised on a motorized treadmill, and the cyclists exercised on a stationary cycle ergometer. A similar exercise protocol has been shown to result in marked increases in insulin action (29). Immediately (-30 min) after exercise on the fifth day, subjects underwent an oral glucose tolerance test (OGTT) as described below. OGTTs were also performed 1,3,5, and 7 days after exercise to determine the time course
TOLERANCE
AFTER
EXERCISE
for the loss of enhanced insulin action. During the 7 days after the final exercise session, the subjects were instructed to refrain from any vigorous physical activity. Subject compliance during the period of inactivity was verified verbally on a daily basis. Body composition measurements. Skinfold measurements were made before and after 7 days of inactivity. Skinfolds were taken from the triceps, subscapular, pectoral, suprailiac, umbilical, and front thigh sites for the men. For the women, the biceps site was substituted for the pectoral site. Percent body fat was estimated by using the equations of Yuhasz (33). . Estimation of vOzpeak. ir02 peak was estimated during level walking or running on a motorized treadmill for the runners and walker and on a stationary cycle ergometer for the cyclists. A continuous exercise protocol consisting of 5-min stages was performed on both the treadmill and cycle ergometer. Tests were terminated when subjects reached 85% of their estimated heart rate reserve. Heart rate was measured each minute during the exercise test with a Hewlett-Packard three-lead electrocardiogram transmitter and Gould chart recorder. Expired gases were collected for each minute of exercise. Gas volumes were measured with a dry gas meter (Parkinson-Cowan). Concentrations of O2 and CO2 were determined on electrochemical O2 (Applied Electrochemistry S-3A) and infrared CO, (Beckman LB-2) analyzers, respectively. VO 2 peak was predicted from heart rate, and VO, data were extrapolated to age-predicted heart rate (1). OGTTs. Subjects reported to the Exercise Biochemistry Laboratory at 0700 after an overnight fast. A polyethylene catheter was placed into an antecubital vein of one arm for blood sampling and was kept patent by flushing with 0.9% NaCl. Blood samples were obtained before and 30, 60, 120, and 180 min after ingestion of 75 g of glucose. The blood was placed in heparinized tubes that were kept on ice. Plasma was separated by centrifugation at 4°C and stored at -80°C until analysis. Plasma glucose concentrations were measured by the glucose oxidase method with a model 2300GL glucose analyzer (Yellow Springs Instruments, Yellow Springs, OH). Plasma free fatty acid (FFA) concentrations were determined enzymatically with a spectrophotometric method (30). Plasma insulin concentrations were determined in duplicate by radioimmunoassay using commercial kits (Ventrix, Portland, ME). To avoid intra-assay variability, all samples for each subject were run in the same assay. Dietary control. The subjects were asked to maintain a diet containing at least 200 g of carbohydrate for 7 days before the initial OGTT and during the 7 days of inactivity. Adherence to this diet was confirmed by using a 3-day dietary record and subsequent analysis with a commercially available computer program. In an effort to minimize any influence of changes in body composition, subjects were weighed daily and were asked to modify their caloric intake accordingly. CaZcuZations and statistics. Incremental glucose and insulin areas during the OGTTs were calculated by using a computer-based trapezoidal model that summates the area above baseline. To estimate insulin sensitivity, the insulin-glucose (IG) index w as calculated (21). The IG index is the product of the areas under the glucose and insulin curves during the OGTT and is inversely related to insulin sensitivity. The data were analyzed statistically with software for an IBM-compatible microcomputer (Number Cruncher Statistical System, Kaysville, UT). Plasma glucose, insulin, and FFA responses during the OGTTs were analyzed with two-way analysis of variance for repeated-measures designs. Incremental glucose and insulin areas, as well as the IG index, were analyzed with one-way analysis of variance. Where appropriate, significant
INSULIN
ACTION
AND
GLUCOSE
TOLERANCE
2. 24-h Dietary intake before each oral glucose tolerance test TABLE
F
IPE 23 h 70 h 120 h 168 h
‘E -ii 6 E ; 2 aii 0 y
kcal
Values ercise.
Carbohydrate,
1,740 k 167 2,161 1,894 1,930 1,833
+ + + 5
254 319 269 251 230
212 214 219 167
are means
.
k + k k 5
g
Fat,
26 20 30 31 19
g
56+ 7 58 + 13 572 9 68 t 12 65 + 11
t SE; n = 9 subjects.
Protein,
g
612
7
92 k 11 802 82k 835
IPE, immediately
9 8 9
postex-
cJ
mean differences were located by using the Newman-Keuls multiple-comparison test. All statistical tests were evaluated at the P < 0.05 level. All data are reported as means k SE. RESULTS
Exercise, diet, and body composition. During the 5 days of exercise, subjects exercised for 45 min at an exercise intensity that elicited a VO, of 28.3 ? 1.8 ml kg-’ mix? or 73 ? 3% of estimated v02 peak.This corresponded to 78 t 2% of estimated maximal heart rate. The dietary intake reported by the subjects was similar for the 24 h before each OGTT (Table 2). Seven days of inactivity did not result in any significant changes in body composition (Table I). GZucose tolerance. The plasma glucose response was significantly elevated during the OGTT performed immediately postexercise (IPE) compared with all other days (P < 0.05; Fig. 1). Although the plasma glucose response tended to increase during 7 days of inactivity, no significant differences were observed between days 1,3, 5, and 7. To facilitate presentation and interpretation of the data, the incremental area above fasting plasma glucose concentration was calculated (Fig. 2). The incremental glucose area was significantly elevated IPE compared with those at all other time points (P < 0.05). For example, the glucose area was -2.5fold higher IPE (355 ? 82 mM min) compared with that on day I(136 ? 57 mM min; P < 0.05). No change in the glucose area was observed from day 1 to day 3. After a significant increase in the glucose area on day 5 (213 t 80 mM min; P < 0.05), there was no further increase in the glucose area during the remaining 48 h of inactivity. l
l
l
l
l
AFTER
19
EXERCISE
450 400 350 300 250 20@150IOO50- m
0’
T IPE
I 3 5 Days After Exercise
7
FIG. 2. Area above baseline under plasma glucose response curve during 75-g oral glucose tolerance test. Values are means t SE of 9 subjects. * Significantly different from IPE, P < 0.05. t Significantly different from day 1, P < 0.05.
Ins&in response. The plasma insulin response to oral glucose was significantly higher immediately after exercise compared with those on days 1 and 3 (P < 0.05; Fig. 3). After this blunting of the insulin response, the plasma insulin response increased significantly from day 3 to day 5 (P < 0.05). The overall insulin response on days 5 and 7 did not differ significantly from that IPE. The incremental insulin area IPE (3,729 t 1,104 ml-l min) was significantly higher (P < 0.05) compared with that on day 1 (2,603 t 635 PU ml-’ min) and day 3 (2,240 ? 517 PU ml-’ min) (Fig. 4). After 5 days of inactivity, the insulin area (3,616 t 617 $.J ml-l min) was 61% higher compared with that on day 1. Forty-eight more hours of inactivity did not result in any further increase in the plasma insulin response. InsuZin sensitivity. To provide information regarding the effect of exercise and inactivity on insulin sensitivity, the product of the incremental glucose and insulin areas (IG index) was calculated (Fig. 5). The IG index (PU 9ml-l min x mM min x 1,000) was markedly elevated (P < 0.05) immediately after exercise (1,162 t 373) compared with that on day 1 (362 t 205) and day 3 (378 t 179) but was not different from that on day 5 (843 ? 441) and day 7 (97 1 t 510). After the improved insulin sensitivity was observed on day 3, the IG index increased significantly on day 5 (P < 0.05). pU
l
l
l
l
l
l
l
l
l
‘3 cn 20 c I
ODayl*
l Dav3*
q Dajr5 t IDay t I
1
I
0
30
I
I
60 120 Time (minutes)
I
180
FIG. 1. Plasma glucose response during 75-g oral glucose tolerance test. Values are means of 9 subjects. IPE, immediately postexercise. * Significantly different from IPE, P < 0.05.
0
30
60 120 Time (minutes)
FIG. 3. Plasma insulin response during ance test. Values are means of 9 subjects. from IPE, P < 0.05. 7 Significantly different
180
75-g oral glucose toler* Significantly different from day 3, P < 0.05.
l
20
INSULIN
ACTION
AND
GLUCOSE
TOLERANCE
n
AFTER
1
l
EXERCISE
o-
‘;
. IPE oDay7
*
-
i n IPE
1 3 5 Days After Exercise
7
;;I:
;;*
o- I-1 0
: I 30
60 Time
I 120 (minutes)
I 180
FI(;. 4. Area above baseline under plasma insulin response curve during 75-g oral glucose tolerance test. Values are means + SE of 9 subjects. ‘!’ Significantly different from days 1 and 3, P < 0.05.
FIG. 6. Plasma free fatty acid oral glucose tolerance test. Values < 0.001, IPE vs. 23 h (day 1).
Plasma FFA. One possible mechanism for the impaired insulin action observed IPE is the increased concentrations of FFA in the plasma associated with endurance exercise that may inhibit glucose uptake (25). Therefore, plasma FFA concentrations were measured on samples obtained at 0, 30, and 180 min during the OGTT performed IPE and 1 day after exercise (Fig. 6). The plasma FFA concentration before the OGTT performed immediately after exercise was three times higher (0.79 + _ 0 .07 mM) compared with that on day I (0.28 5 0.03 mM; P < 0.001). Although the plasma FFA concentration decreased markedly during each OGTT, values remained significantly elevated IPE, reaching nadir values of 0.07 t 0.02 and 0.03 t 0.01 mM for IPE and day 1, respectively (P < 0.001).
served that intense (>lOO% of maximal vo2) exercise in NIDDM subjects resulted in a marked decrease in whole body glucose clearance despite markedly elevated plasma insulin concentrations. It has been appreciated for some time that fatty acids inhibit glucose uptake by isolated muscle (25). In the present study, plasma concentrations of FFA were twoto threefold higher during the OGTT performed immediately after exercise compared with that on day 1 after exercise. It is possible, then, that the impaired glucose tolerance observed immediately after exercise was related to inhibition of glucose uptake and/or metabolism by high circulating FFA levels. In contrast to the marked insulin resistance noted immediately after exercise, acute exercise has been reported to either increase (5, 19) or have no effect (20) on insulin sensitivity measured with the hyperinsulinemic-euglycemic clamp procedure. In the study of Mikines and co-workers (19), plasma FFA levels were significantly higher before the clamp procedure performed immediately after exercise. The differences in the plasma FFA were abolished during sustained insulin infusion. Thus, any effect of FFA levels on suppressing glucose uptake would have been masked in these earlier studies. The hormonal milieu during the period immediately after exercise would be expected to result in impaired insulin action in both splanchnic and skeletal muscle tissues. Plasma catecholamine levels, which have been reported to remain elevated for at least 30 min postexercise (16), may produce insulin resistance at the liver by increasing both glycogenolysis and gluconeogenesis. The elevated plasma catecholamine levels would also be expected to suppress insulin-mediated glucose disposal in skeletal muscle (11). Other hormonal factors may also have contributed to the insulin resistance observed immediately after exercise. Elevations in growth hormone may decrease glucose tolerance by reducing both the suppression of hepatic glucose production by insulin and the insulin-mediated glucose uptake by muscle (22). Elevations in plasma cortisol (10) and glucagon (16) as a consequence of exercise may also play a role in the transient insulin resistance. The relative importance of hepatic and peripheral tissues in mediating the insulin resistance and im-
DISCUSSION
The striking findings of this study were the insulin resistance and impaired glucose tolerance observed immediately after exercise. These results agree with earlier work demonstrating that the ingestion of glucose immediately after exhaustive endurance exercise produces an exaggerated glucose response compared with that in the rested condition (3). Kjaer et al. (16) ob1,800 1,600 1,400 g 1,200 E 1,000 3 800 600 400 200 O-
* 1 IPE
5 7 1 3 Days After Exercise ,Tr(\ * I I 1 1or I-’insulin1’ ana 1glucose 1 I lw inaex 1proauct
FIG. 5. Insulin-glucose areas (PU ml ’ . min x mM min x 1,000) above baseline] during 75-g oral glucose tolerance test. Values are means t SE of 9 subjects. ‘!: Significantly different from days 1 and 3, P < 0.05. l
l
(FFA) concentrations during 75-g are means + SE of 9 subjects. * P
INSULIN
ACTION
AND
GLUCOSE
paired glucose tolerance observed IPE is not clear. Felig et al. (6) observed that the splanchnic bed was responsible for removing 60% of an oral glucose load. In contrast, others (12) reported that 75% of an oral glucose load escapes the splanchnic bed and is taken up by peripheral tissues, presumably skeletal muscle. Maehlum et al. (18) observed a large @O-300%) increase in splanchnic glucose output when glucose was ingested after exercise. Thus it is possible that the impaired glucose tolerance observed after exercise is related, at least in part, to either a greater proportion of the oral glucose load escaping hepatic retention or a reduced suppression of hepatic glucose production. A second aim of this study was to provide information regarding the time course for the reversal of the enhanced insulin action observed after exercise. The plasma glucose response, insulin response, and IG index increased during the period between days 1 and 5 after exercise and did not change during an additional 48 h of inactivity. Therefore, the improved insulin sensitivity associated with exercise appears to last 3, but not 5, days. Previous investigators, using a single determination of insulin action after exercise, have observed that the enhanced insulin sensitivity seen after exercise is lost within 48-96 h after exercise (5, 24). Only one previous study has investigated the time course for the reversal of improved insulin action in a systematic fashion (23). Interestingly, these authors reported that the increased glucose disposal observed in young well-trained subjects during a hyperinsulinemic-euglycemic clamp procedure was lost in onehalf the time (within 38 h after exercise) of the reversal observed in the present study. The reason for the more persistent improvement in insulin action observed in our subjects is not readily apparent. Both dietary carbohydrate intake and the exercise stimulus were similar in the two studies. One potential explanation relates to the possibility that exercise promotes insulin sensitivity in both skeletal muscle (7, 26) and the liver (28) and that these two tissues may have different time courses for the reversal of improved insulin sensitivity. Because plasma insulin concentrations during the glucose clamp technique used by Oshida et al. (23) would be expected to completely suppress hepatic glucose production in subjects with normal insulin sensitivity (27), any change in hepatic sensitivity to insulin associated with exercise would have been obscured. Because of the lower plasma insulin concentrations observed during the OGTT in the present study, it is possible that hepatic production was only partially suppressed and that some of the improved insulin action observed after exercise was due to increased suppression of hepatic glucose production. These data are therefore compatible with the possibility that exercise-induced alterations in hepatic insulin sensitivity are more long lasting than the improved insulin sensitivity of skeletal muscle. In addition, the subjects studied by Oshida et al. (23) were younger, more fit, and leaner than the subjects in the present investigation. Therefore, it is possible that one or more of these factors are important in determining the time course for loss of improved insulin action after exercise. The changes occurring between 3 and 5 days that
TOLERANCE
AFTER
EXERCISE
21
mediate the reversal of the enhanced insulin action after exercise are unknown. This is not surprising, because the mechanism(s) responsible for the improved insulin sensitivity after exercise is poorly understood. One possible mechanism for the increased glucose disposal after exercise is an increased number and/or intrinsic activity of glucose transporters in the plasma membrane. Recently, Goodyear et al. (8) found that the reversal of the increased glucose uptake observed after exercise in perfused rat hindquarters was well correlated with a reversal of the increased transporter number and activity in the plasma membrane. The rate of whole body glucose disposal has been reported by some to be inversely related to the muscle glycogen content and glycogen synthase activity (4, 7, 26). More recently, however, it has been shown that the reversal for the exercise-induced increase in glucose uptake observed in rat skeletal muscle is independent of glycogen synthesis (32) and that the increased whole body glucose disposal observed during a hyperinsulinemic-euglycemic clamp procedure after exercise is also independent of glycogen storage capacity (20). In support of these findings, the subjects in the present study were probably not markedly glycogen depleted after the moderate exercise bout. Any significant glycogen depletion on day 1 would also have been minimized by the relatively high carbohydrate intake (319 g) taken during this time period. One factor that may influence the duration of the improved insulin action and secretion after exercise is the diet during the period of inactivity. LeBlanc et al. (17) noted that the reduced insulin response observed in trained subjects during a carbohydrate challenge persisted for 3 days after exercise if caloric intake was reduced from 3,291 to 2,076 kcal/day. In the present study, in which the improved insulin sensitivity and reduced insulin secretion also persisted for 3 days, caloric intake was not restricted but was maintained at relatively low levels (-1,900 kcal/day) during the period of inactivity. It is important to note that the subjects in the present study had normal glucose tolerance in the nonexercised state. Because NIDDM patients and people with impaired glucose tolerance may be of differing age, training status, and body composition and may therefore have a different time course for the reversal of improved insulin action, caution should be used when applying these data to those populations. In summary, the initial effect of endurance exercise in moderately trained middle-aged people is a marked resistance to the effects of insulin. This insulin resistance is accompanied by an elevation in plasma FFA concentrations but may also be related to increased plasma concentrations of the counterregulatory hormones. This insulin resistance is transient and i s replaced with improved insulin action within 24 h after exercise. The increased insulin sensitivity observed after exercise in moderately trained middle-aged people with normal glucose tolerance lasted for 3, butnot for 5, days after exercise. These data suggest that the frequency of exercise needed to maintain the exerciseinduced improvement in glucose tolerance is once every 3 days.
22
INSULIN
ACTION
AND
GLUCOSE
The authors would like to express their gratitude to the subjects for willingness to stop training during this study. The helpful comments of Drs. W. Franke and L. Panton and of M. Ray are appreciated. This work was supported by the National Institutes of Health Biomedical Research Support Grant 2SO7-RR-07034-25. Address for reprint requests: D. S. King, Dept. of Health and Human Performance, 247 PEB, Iowa State Univ., Ames, IA 50011. Received
21 March
1994;
accepted
in final
form
27 August
1994.
REFERENCES 1. American College of Sports Medicine. Guidelines for Exercise Testing and Prescription (4th ed.). Philadelphia, PA: Lea & Febiger, 1991. P., M. Fahlen, G. Grimby, A. Gustafson, J. 2. Bjorntorp, Holm, P. Renstrom, and R. Schersten. Carbohydrate and lipid metabolism in middle aged physically well trained men. Metabolism 21: 1037- 1044, 1972. 3. Blom, P. C. S., A. T. Hostmark, 0. Flaten, and L. Hermansen. Modification by exercise of the plasma gastric inhibitory polypeptide response to glucose ingestion in young men. Acta Physiol. &and. 123: 367-368, 1985. 4. Bogardus, C., 0. Thuillez, E. Ravussin, B. Vasquez, M. Narimica, and S. Azhar. Effect of muscle glycogen depletion on in vivo insulin action in man. J. CZin. Inuest. 72: 1605-1610, 1983. 5. Burstein, R., Y. Epstein, Y. Shapiro, I. Charuzi, and E. Karnieli. Effect of an acute bout of exercise on glucose disposal in human obesity. J. AppZ. Physiol. 69: 299-304, 1990. 6. Felig, P., J. Wahren, and R. Hendler. Influence of oral glucose ingestion on splanchnic glucose and gluconeogenic substrates metabolism in man. Diabetes 24: 468-475, 1975. 7. Fell, R. D., S. E. Terblanche, J. L. Ivy, J. C. Young, and J. 0. Holloszy. Effect of muscle glycogen content on glucose uptake following exercise. J. AppZ. PhysioZ. 52: 434-437, 1982. 8. Goodyear, L. J., M. F. Hirshman, P. A. King, E. D. Horton, C. M. Thompson, and E. S. Horton. Skeletal muscle plasma membrane glucose transport and glucose transporters after exercise. J. AppZ. Physiol. 68: 193-198, 1990. 9. Heath, G. W., J. R. Gavin III, J. M. Hinderliter, J. M. Hagberg, S. A. Bloomfield, and J. 0. Holloszy. Effects of exercise and lack of exercise on glucose tolerance and insulin sensitivity. J. Appl. Physiol. 55: 628-634, 1983. 10. Holm, G., P. Bjorntorp, and R. Jagenburg. Carbohydrate, lipid, and amino acid metabolism following physical exercise in man. J. AppZ. Physiol. 45: 128- 131, 1978. D. E., K. M. Burleigh, and E. W. Kraegen. In vivo 11. James, glucose metabolism in individual tissues of the rat. Interaction between epinephrine and insulin. J. BioZ. Chem. 261: 63666374, 1986. 12. Katz, L., M. G. Glickman, S. Rapoport, E. Ferrannini, and R. A. Defronzo. Splanchnic and peripheral disposal of oral glucose in man. Diabetes 32: 675-679, 1983. W. E. Clutter, D. A. Young, M. A. 13. King, D. S., G. P. Dalsky, Staten, P. E. Cryer, and J. 0. Holloszy. Effects of lack of exercise on insulin secretion and action in trained subjects. Am. J. Physiol. 254 (Endocrinol. Metab. 17): E537-E542, 1988. 14. 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. AppZ. Physiol. 64: 1942-1946, 1988. 15. King, D. S., G. P. Dalsky, M. A. Staten, W. E. Clutter, D. R. Van Houten, and J. 0. Holloszy. Insulin action and secretion in endurance-trained and untrained humans. J. AppZ. Physiol. 63: 2247-2252, 1988.
TOLERANCE
AFTER
EXERCISE
16. Kjaer, M., C. B. Hollenbeck, B. Frey-Hewitt, H. Galbo, W. Haskell, and G. M. Reaven. Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes. J. AppZ. Physiol. 68: 2067-2074, 1990. 17. LeBlanc, J., A. Nadeau, R. Richard, and A. Tremblay. Studies on the sparing effect of exercise on insulin requirements in human subjects. Metabolism 30: 1119- 1124, 1981. 18. Maehlum, S., P. Felig, and J. Wahren. Splanchnic glucose and muscle glycogen metabolism after glucose feeding during postexercise recovery. Am. J. Physiol. 235 (EndocrinoZ. Metab. Gastrointest. PhysioZ. 4): E255-E260, 1978. 19. Mikines, K. J., B. Sonne, P. A. Farrell, B. Tronier, and H. Galbo. Effect of physical exercise on sensitivity and responsiveness to insuliq in humans. Am. J. PhysioZ. 254 (EndocrinoZ. Metab. 17): E248-E259, 1988. 20. Mikines, K. J., B. Sonne, B. Tronier, and H. Galbo. Effects of acute exercise and detraining on insulin action in trained men. J. AppZ. Physiol. 66: 704-711, 1989. 21. Mondon, C. E., C. B. Dolkas, and G. M. Reaven. Effect of confinement in small space flight size cages on insulin sensitivity of exercise-trained rats. Auiat. Space Environ. Med. 54: 919922, 1983. 22. Ng, S. F., L. H. Storlien, E. W. Kraegen, M. C. Stuart, G. E. Chapman, and L. Lazarus. Effect of biosynthetic human growth hormone on insulin action in individual tissues of the rat in vivo. MetaboZism 39: 264-268, 1990. 23. Oshida, Y., K. Yamanouchi, S. Hayamizu, J. Nagasawa, I. Ohsawa, and Y. Sato. Effects of training and training cessation on insulin action. Int. J. Sports Med. 12: 484-486, 1991. 24. Oshida, Y., K. Yamanouchi, S. Hayamizu, and Y. Sato. Long-term mild jogging increases insulin action despite no influence on body mass index or VOW I,laX. J. AppZ. PhysioZ. 66: 22062210, 1989. 25. Randle, P. J., P. B. Garland, C. N. Hales, and E. A. Newsholme. The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1: 785-789, 1963. 26. Richter, E. A., L. P. Garetto, M. N. Goodman, and N. B. Ruderman. Muscle glucose metabolism following exercise in the rat. J. Clin. Invest. 69: 785-793, 1982. 27. Rizza, R. A., L. J. Mandarino, and J. E. Gerich. Dose-response characteristics for effects of insulin on production and utilization of glucose in man. Am. J. PhysioZ. 240 (EndocrinoZ. Metab. 3): E630-E639, 1981. 28. Rodnick, K. J., W. L. Haskell, A. L. M. Swislocki, J. F. Foley, and G. M. Reaven. Improved insulin action in muscle, liver, and adipose tissue in physically trained human subjects. Am. J. Physiol. 253 (EndocrinoZ. Metab. 16): E489-E495, 1987. 29. Rogers, M. A., C. Yamamoto, D. S. King, J. M. Hagberg, A. A. Ehsani, and J. 0. Holloszy. Improvement in glucose tolerance after 1 wk of exercise in patients with mild NIDDM. Diabetes Care 11: 613-618, 1988. 30. Shimizu, S., K. Inoue, Y. Tani, and H. Yamada. Enzymatic microdetermination of serum free fatty acids. Anal. Biochem. 107: 193- 198, 1978. 31. Tonino, R. P. Effect of physical training on the insulin resistance of aging. Am. J. Physiol. 256 (EndocrinoZ. Metab. 19): E352-E356, 1989. 32. Young, D. A., H. Wallberg-Henriksson, M. D. Sleeper, and J. 0. Holloszy. Reversal of the exercise-induced increase in muscle permeability to glucose. Am. J. PhysioZ. 253 (EndocrinoZ. Metab. 16): E331-E335, 1987. 33. Yuhasz, M. S. The Effects of Sports Training on Body Fat in Man With Prediction of Optimal Body Weight (PhD Thesis). Urbana, IL: Univ. of Illinois, 1962.
