Insulin and glucose responses during with isotonic and isometric exercise C. Is. DOLKAS AND J. E. GREENLEAF Biomedical Research Division, NASA-Ames
Research
DOLKAS,~. B., ANDLE. GREENLEAF. InsuLin andglucose responses during bkd rest with isotonic and isometric exercise. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 43(6): 1033-1038, 1977. -The effects of daily intensive isotonic (68% maximum oxygen uptake (vo, max)> and isometric (21% maximum extension force) leg exercise on plasma insulin and glucose responses to an oral glucose tolerance test (0G;TT) during 14-day bed-rest (BR) periods were investigated in seven young healthy men. The OGTT was given during ambulatory control and on day 10 of the no-exercise, isotonic, and isometric exercise BR periods during the 15wk study. The subjects were placed on a controlled diet (mean t SD = 344 t 34 g CHO/day and 3,073 t 155 (SD) kcal/day) starting IO days before each BR period. During BR, basal plasma glucose concentration remained unchanged with no exercise, but increased (P < 0.05) to 87-89 mg/lOO ml with both exercise regimens on day 2, and then fell slightly below control levels on day 13. The fall of glucose content (- 11 to - 15%) during BR was independent of the exercise regimen and was an adjustment for the loss of plasma vol. The intensity of the responses of insulin and glucose to the OG’IT (integrated area under the curves) was inversely proportional to the total daily energy expenditure during BR; i.e., the largest response with no exercise, then isometric, isotonic, and ambulatory exercise. It was estimated that at least 1,020 kcal/day must be provided by supplemental exercise to restore the hyperinsulinemia to control levels.
glucose tolerance
test; plasma volume
Center,
PROCEDURES
bed rest
Moffett Field,
California
94035
AND METHODS
Informed consent was obtained from seven healthy men, from 19 to 22 yr of age (Table l), who participated in a 15-wk study during the summer months. They underwent a 2-wk ambulatory control period, three 2wk periods of bed rest - each separated by 3-wk recovery (control) periods-and finally, 4 days of recovery (Fig. 1). Each recovery period served as the control for the following bed-rest period. The subjects were housed under constant supervision in the Human Research Facility at Ames Research Center for 13 wk; they also spent the 1st wk in each of the recovery periods under supervision at a resort near the ocean to aid recovery. The men remained in the horizontal position throughout bed rest, including their bathing and excretory functions, but they were allowed to rise on one elbow to eat. The diet consisted of 14 different daily menus containing 3,073 * 155 (SD) kcal/day, composed of 121 g (20%) protein, 344 g (56%) carbohydrate, and 144 g (24%) fat by weight, The diet provided a mean t SD daily intake of Na+ of 3.8 t 1.0 g and 1.6 -+ 0.2 g of Ca2+ with an optimal vitamin and mineral content. Water was available ad libitum, but each man was required to drink 225 ml of coffee, tea, and/or milk with each meal. The subjects were placed on the controlled diet 10 days before each bed-rest period. During the ambulatory periods, the subjects exercised daily for 1 h at 50% of their maximal oxygen uptakes 2 max ) in the upright position on a Monark bicycle ergometer (about 565 kcal/day). During two of the three bed-rest periods, the subjects performed daily in the supine position either a) isotonic exercise on a Collins ergometer (6) at 68% of their Vo2 Max (780 kcal/h), or b) isometric exercise at 21% of maximal leg extension force for 1 min followed by 1 min rest (250 kcal/h) for 0.5 h in the morning and 0.5 h in the afternoon. During the isotonic exercise bed-rest period, mean -+ SE heart rates were 138 2 1 beats/min during the morning exercise and 136 * 1 beatslmin with afternoon exercise. During isometric exercise, the mean t SE work/rest heart rates in the morning were 105 t 2/80 t 2 beats/ min and 102 t 2/76 * I beats/min in the afternoon. In spite of the relatively low heart rates, these two exercise regimens performed in the supine position were nearly a maximal effort for the subjects. No supplementary exercise was prescribed during the 3rd bed-rest period (Fig. 1). The VOW maxwas determined with the subjects l
given a standard glucose tolerance test afier 3-7 days of enforced bed rest without supplementary physical exercise, exhibit prolonged hyperinsulinemia and hyperglycemia (1, 4, 5, 8, 11-13, 17). Tissue utilization of glucose is impaired in the presence of high concentrations of immunoreactive insulin (12). Daily isotonic exercise during bed rest reduces the degree of impaired glucose utilization, but does not return it to ambulatory control levels (5, 11). This disturbance in carbohydrate metabolism is no longer detected 2 wk after ambulation (12), but glucose tolerance returns to normal in less than 1 wk when physical conditioning exercises are used during the post-bed-rest period (14). Thus, it seems that glucose intolerance observed during bed rest is diminished with increasing energy expenditure. The purpose of the present study was to compare the effect of intensive isotonic and isometric exercise, performed for 1 h/day, on glucose tolerance and on the insulin response during bed rest. NORMAL
SUBJECTS,
wo
1033
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1034
C. B. DOLKAS
in the supine position. The test started with a 3-min warm-up period at 100 W followed by a progressively increasing work load of 50 W each 3 min until exhaustion (19). Maximal 0, uptake was measured near the end of the bed-rest and control-recovery periods. Submaximal isotonic 0, uptake was measured periodically during daily exercise throughout the study. O2 uptake during bed-rest isometric exercise was estimated from a comparable work/rest protocol on different subjects (18) and was the mean of a number of work/rest cycles. In the present study the volume of expired gas was measured with a Parkinson-Cowan meter. The gas was drawn into ZOO-ml oiled syringes and analyzed with a Beckman E2 oxygen analyzer and a Godart Capnograph CO, analyzer (19). The oral glucose tolerance test (OGTT) was given on day 10 of each bed-rest period (10); the ambulatory control test was done on day 21 of the first recovery period. No exercise was performed on the mornings of the OGTT. The dose of glucose administered was 40 g/ m2 of body surface area (10); the average dose was 82 g, with a range of 68-94 g (Table 1). Basal venous blood samples were taken without stasis, just before and at 1, 2, and 3 h after glucose administration, into syringes coated with EDTA (1 mg/ml blood) and centrifuged at 1,450 x g for 20 min at 5°C. The plasma was removed and frozen immediately for analysis. Plasma insulin concentration was determined by radioimmunoassay (9), and glucose concentration was
Ayo;Ty;LRY
AMBULATORY RECOVERY (CONTROL)
BEDREST-
I
1
0
I
1
RESULTS
Basal plasma volume and glucose. There were no significant differences in basal plasma glucose concentrations in the three control periods, and the values were within the normal range of 83-84 mg/lOO ml (Fig. 2). Compared with control values, plasma glucose concentration increased significantly (P < 0.05) with isometric and isotonic exercise by the second day of bed rest. At the end of bed rest, the glucose concentrations had returned to control levels, but there were increases in glucose above control levels on the 3rd day of recovery, particularly following the no-exercise regimen.
OGTT
OGTT
I
AMBULATORY RECOVERY (CONTROL)
I ’ 7
I
BEDREST1 12
14
BEDREST-
BEDREST-
BEDREST-
NO EXERCISE
ISOMETRIC
ISOTONIC
B
ISOMETRIC
ISOTONIC
NO EXERCISE
C
ISOMETRIC
ISOTONIC
NO EXERCISE
D
ISOTONIC
NO EXERCISE
ISOMETRtC
E
ISOTONIC
NO EXERCISE
ISOMETRIC
F
ISOTONIC
NO EXERCISE
ISOMETRIC
G
NO EXERCISE
ISOMETRIC
ISOTONFC
1. Individual
Subj
Age, yr
A B c D E
F G Mean &SE SA = surface
m, cm
1, Experimental
anthrupometric SA, m”
design
and sequence
and physiological
Wt Pre, kg
Wt Final,
kg
bwt,
of exercise
I 15
OGTT
OGTT
A
FIG.
TABLE
RE;&!;RY
I
9 WEEKS
SUBJECT
J. E. GREENLEAF
determined with the glucose oxidase method (Glucostat, Worthington Biochemicals Corp.). Plasma volume was measured with Evans blue dye from one lo-min postdye injection blood sample. This technique gave results comparable to the 0-min extrapolation of multiple postdye samples (21). Total plasma glucose content was calculated as the product of fasting glucose concentration and plasma volume. In Fig. 3 the total area under each curve, measured from the zero point on the X axis, was calculated assuming a straight line between sample points. The mean areas are presented in Fig. 4. The results were analyzed with the t-test for correlated data; the null hypothesis was rejected when P < 0.05.
BEDREST-
Jr 4
2
AND
regimens,
data on the subjects %
Leg Force Max, kg
Leg Force Max, kg/ MY&
ire, max, llmin
v$Fg;n!/’
Daily Isometric Load, kg
Daily Isotonic Load, W
Oral Glucase Dose, g
20 19 20 22 19 22 21
166 184 184 177 184 178 188
1.69 2.08 2.20 1.95 2.12 1.94 2.36
62.40 80.50 94,80 78,20 87.40 76.50 103,80
60.95 76,45 89.56 78.76 82.60 75.81. 96.27
-2.3 -5.0 -5.5 +0.7 -5.5 -0.9 -7.3
380 664 673 800 886 691 909
6.1 8.2 7.1 10.2 10.1 9.0 8.8
3.36 3.84 3.76 3.43 4.18 3.46 4.38
54 48 40 44 48 45 42
120 165 168 96 121 130 182
145 180 175 160 180 150 200
68 83 88 78 85 78 94
20 +l
180 rt3
2.05 kO.08
83.37 25.09
80.06 k4.25
-3.7
714 567
8.5 50.6
3.77 20.15
46 -t2
140 *12
170 +7
82 +3
area.
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INSULIN
2
AND
78
GLUCOSE
DURING
BED
1035
REST
I-
2 2 n
3.8
NO EXERCISE ISOMETRIC EXERCtSE ISOTONIC EXERCISE
q 0
5 6 >
3.3
2 2 2
3.1
3.2
FIG.
tration, changes riods.
3.0
2. Mean k SE plasma plasma volume, and during control, bed-rest, *P < 0.05 fromday2.
glucose concenglucose content and recovery pe-
2.8
3.2
4
-3
-2
-1
I
III1
1
2
1 3
4
5
6
6ED
I
REST-
7
II
8
11 9
10
11 11
12
l 13
14
3ECOVERY I I +1
+2
J +3
DAY
Plasma volume decreased (P < 0.05) in all experiments by the 4th day and remained depressed throughout bed rest. The increased glucose concentrations on the 2nd day of bed rest probably reflected the hypovolemia. Plasma glucose content fell progressively during bed rest. At the end of bed rest, the glucose contents for all three exercise regimens were lower (P < 0.05) than their respective ambulatory control values (Fig. 2). The mean loss of glucose content was 434 mg (-15%) with no exercise, 365 mg (-12%) with isometric exercise, and 304 mg (-11%) with isotonic exercise. The losses were not significantly different from each other. The loss of glucose content followed t;he loss of plasma volume, so that by the end of bed rest, glucose concentration had returned to control levels. Oral glucose tolerance test. Prior to ingestion, the Oh glucose concentration in the no-exercise group was elevated (P < 0.05) over the other regimens (Fig. 3).
After ingestion, the glucose concentrations in the noexercise (hour 2) and isometric exercise (hour 3) groups were higher (P < 0.05) than the corresponding ambulatory control values. At hours 2 and 3, the glucose concentrations with isotonic exercise were essentially the same as ambulatory control values (78-85 mg/lOO ml), while isometric and no-exercise values remained elevated in the 90-97 mg/lOO ml range. At hour 3, the glucose level with isotonic exercise was significantly lower (P < 0.05) than with no exercise (Fig. 3). Concomitant plasma insulin concentrations tended to follow the same pattern as the glucose resPonses (Fig* 3). All h our 1 values were higher (P < 0.05) than their respective control values. At hour 2, the three exercise regimen concentrations were significantly higher (P < 0.05) than ambulatory control data, and the isometric and no-exercise values remained elevated at hour 3. Unlike the other three conditions, with
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1036
C. B. DOLKAS
isometric exercise, both the glucose and insulin curves tended to level off in hours 2 and 3, in contrast to the usual peak at hour 1 followed by a decline in hours 2 and3 (Fig. 3). Analysis of the integrated areas under the insulin curves for the four conditions (Fig. 4) indicated that the greatest response occurred with no exercise, followed by progressively attenuated responses with isometric exercise, isotonic exercise, and ambulatory control. The areas under the glucose curves were less variable than insulin, but there was a similar trend of decreasing response with increasing metabolism. The glucose response to the OGTT with isotonic exercise was essentially the same as the ambulatory control value. During bed rest there appears to be an inverse relationship between the level of energy expenditure and the magnitude of the increase in plasma glucose and insulin concentrations following glucose ingestion (Fig. 4), DISCUSSION
The results indicate that heavy isotonic exercise for 1 h/day was more effective than heavy isometric exercise for I h/day in lowering the hyperinsulinemia induced by a standard glucose load during bed rest. This greater effectiveness can be attributed to a factor associated
70
120
100
0
1
I
I /\ [3 0
r
l
I
NO EXERCISE ISOMETRIC EXERCISE ISOTONIC EXERCISE AMBULATORY CONTROL
-
I
I
1
2
I 3
HOUR FIG. 3. Mean -+ SE plasma glucose and plasma insulin concentrations during the 3-h glucose tolerance test. *P < 0.05 from 0 h. C9 P -C 0.05 from ambulatory control value. Open symbols refer to tests during bed rest.
240
AND
J. E. GREENLEAF
INSULIN
GLUCOSE
220
180 160
60 40
0
I I $E Q
80
20
t 240
i 140 =3yz120 $ 100 2
I
300
T
200
120-
60
L NOE
0-
IME
1TE
4. Integrated areas during 3-h glucose tolerance exercise (NOE), isometric (ITE) regimens. FIG.
-
AMB
F
NOE
IME
ITE
AMB
under the insulin and glucose curves test for ambulatory (AMB), and noexercise (IME), and isotonic exercise
with the larger metabolic rate with isotonic exercise. Compared with the energy expenditure during normal daily activity, energy expenditure with no exercise during bed rest was reduced approximately 450 kcal/ day; the increased energy cost of the intermittent isometric exercise was about 250 kcal/day, and 780 kcal/ day for isotonic exercise. For comparable energy expenditure with isotonic exercise, the isometric regimen would have to be performed for about 3 h/day. This level of effort may well result in greater attenuation of the hyperinsulinemia, but, from the practical point of view, the more efficient method of increasing energy consumption is with isotonic exercise that utilizes large muscle groups. The plasma insulin and glucose responses to glucose ingestion in the present study agree qualitatively with those of Lipman et al. (11) who utilized combined isotonic-isometric exercise at 70% vu2 lllaX (600 kcal/h) for 1 h/day during bed rest: the smallest response occurred during ambulatory control, an intermediate response with exercise, and the largest response with absolute bed rest. From the results of Lipman et al. and the present study, it is clear that the supplemental energy expenditure must be greater than 780 kcal/day to prevent the “abnormal” insulin and glucose responses. If we assume that the level of hyperinsulinemia is a function of total energy expenditure during bed rest, and that the caloric cost during bed rest with no exercise is 90 kcal/h, it is possible to estimate the total daily energy expenditure required to reduce the insulin response to ambulatory control levels (Fig. 5). The linear regression of the insulin area (from Fig. 4) on the total daily energy output (rest and exercise) for the 3 bed-rest regimens indicates that approximately 3,000 kcal/day are needed; i.e., the normal daily ambulatory level for active men. If 90 kcal/h are utilized for 22 h during bed rest, then about 1,020 kcal/2 h must be obtained from supplemental exercise. This additional energy expenditure could be met by 1 h/day each of the isotonic (780 kcal/h) and isometric (250 kcallh) regimens
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INSULIN
AND
GLUCOSE
DURING
BED
1037
REST
used in the present study. It is clear that it will take a substantial effort to produce the additional 1,020 kcal/ day. It is not certain that elimination of the hyperinsulinemia woul .d return the glucose responses to normal. The increased basal plasma glucose concentrations on the 2nd day of bed rest could be accounted for by the proportionally greater loss of plasma volume than loss of glucose content. The progressive loss of glucose content throughout the three bed-rest periods was independent of ‘the intensi ty or type of exercise. This loss of content was not the result of chronic depleti .on by exercise, since the loss with no exercise was not sign& cantly different from the loss with isotonic exercise. At the end of bed rest, glucose concentrations had returned to normal due to an adjustment between the loss of plasma volume and the- loss of glucose content. The significant increase in glucose concentration on the 3rd day of recovery m ust have been due to a large influx of glucose, because the restoration of plasma volume would have had a tendency to lower glucose concentration. Part of this augmented gl ucose in flux must have been due to assu.mption of the upright position, since the subjects were still confined to the research facility and they had not resumed their normal activity levels. These results suggest that some factor, perhaps related to the gravitational vector but inversely proportional to exercise intensity, is involved in the mechanism of this “abnormal” carbohydrate metabolism during bed rest. Lipman et al. (12j concluded that change in the gravity vector was of minor importance because monkeys, which were confined upright in chairs, still n 0 0
50
INSULIN
I1:oo
AREA = 577.3 - 0.16 {ENERGY) r = 0.99
1800
FIG. 5, Regression curves during glucose for 3 bed-rest regimens.
GLUCOSE
NO EXERCISE ISOMETRIC EXERCISE ISOTONIC E XERClSE
2000
2200 2400 ENERGY EXPENDITURE,
2600 kcaV24
2800
3000
3200
hr
of integrated area under insulin response tolerance tests on 24-h energy expenditures
elicited the “abnormal” glucose response. Furthermore, results from another week-long bed-rest study showed clearly that a full week of ambulatory recovery, without supplemental exercise, did not reduce the hyperinsulinemia to normal levels (unpublished data). Bed-restinduced glucose intolerance returns to normal about 2 wk after resumption of normal, daily activity (12). When intensive physical training was employed, glucose intolerance returned to normal within the first week of recovery (14). The significantly elevated insulin concentrations in the present study indicated that immunoreactive insulin deficiency was not the cause of the amplified glucose responses. Exogenous insulin is no more effective than endogenous insulin in lowering plasma glucose levels (I). Thus, factors other than insulin per se must be involved. The lack of response of the elevated glucose to the large insulin concentrations suggests that the insulin activity is changed by the release of an insulin inhibitor, there is a blockage of the function of a second factor with insulin-like activity, some aspect of cellular membrane function is changed, or perhaps some combination of the above. The evidence discounts the function of the usual insulin antagonists, plasma cortisol (13, 16, ZO), plasma free fatty acids (FFA) (13), the catecholamines (17), and growth hormone (13, 16), because in many cases their concentrations during 2 wk of bed rest were either unchanged or decreased from ambulatory levels. Moderate exercise during bed rest had no effect on basal cortisol concentrations (20), After infusion of 2-deoxy-nglucose, there were no significant differences between ambulatory control and bed-rest responses of plasma glucose, plasma FFA, plasma cortisol, or serum immunoreactive insulin concentrations (13), but the normally marked rise in growth hormone was blunted, in agreement with the results of Pawlson et al. (16). Glucagon has not been evaluated, but it could stimulate insulin secretion and release glucose by hepatic breakdown of glycogen. Thus, it seems that the synthesis or release mechanisms for insulin are functioning normally (Fig. 6, left half). Other evidence suggests that the problem resides in or about the cellular membrane (Fig. 6, right half), and some factor or factors activated by physical exercise, that respond to the quantity of energy expended, are necessary for insulin and possibly glucose to function normally+ Men undergoing intensive physical training (2-5 times/wk) have a more eficient glucose metabolism with very little increase in the plasma insulin concentration, i.e., a higher insulin sensitivity during a resting tolerance test compared to normal,
GROWTH HORMONE
FIG.
GROWTH HORMON
6. Major
in .tolerance
EPINEPHRINE +
during
components bed rest,
of insulin
and
glucose
INSULIN EFFECTIVENESS
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1038 untrained men (3, 15). Baile et al. (2) have hypothesized that increased blood lactate with exercise induces the release of a factor that increases the rate of glucose metabolism. Lactate itself might alter the cell membrane to promote increased influx of glucose (7). Clinical observations indicate that the longer the period of inactivity during bed rest, the greater Le frequency and amplitude of abnormal glucose tolerance curves (5, 8). There appears to be an inverse linear relationship between energy expenditures and the level of hyperinsulinemia and glucose intolerance during bed rest. In addition to the resting energy level of 2,160 kcal/day during bed rest, an additional energy expendi-
C. B. DOLKAS
AND
J.
E. GREENLEAF
ture of at least 1,020 kcal/day would be necessary to eliminate the ‘cabnormal” glucose tolerance. High-intensity intermittent isometric leg exercise provides some remedial effect, but the most efficient and practical method of increasing enerm production is with isotonic exercise that utilizes the large muscle groups of the legs. The authors thank Dr. assistance with the chemical preparation, and the subjects Received
for publication
R. Grindeland and L. T. Juhos for analyses, C. Greenleaf for manuscript for their cooperation.
3 February
1977.
REFERENCES 1. ALTMAN, D. F,, S. D. BAKER, M. MCCALLY, AND T. E. PIEMME. Carbohydrate and lipid metabolism in man during prolonged bed rest. CZin.. Res. 17: 543, 1969. 2. BAILE, C, A., W. ZINN, AND Cm MCLAUGHLIN. Exercise, blood lactate and food intake. Eqerientia 26: 1227-1229, 1970. 3. BJ~RNTORP, P., M. FAHLAN, G. GRXMBY, A. GUSTAFSON, J. HOLM, P. RENSTR~M, AND T. SCHERSTEN. Carbohydrate and lipid metabolism in middle-aged, physically well-trained men. Metabolism 21: 1037-1044, 1972. 4. BLOTNER, H. Effect of prolonged physical inactivity in tolerance of sugar. Arch. Intern. Med. 75: 39-44, 1945. 5. BOHR, P. A. On the influence of prolonged bodily inactivity in the blood sugar curves after oral glucose loading. HeLu. Med. Actu 30: 156-175, 1963. 6. CLARKE, J. H., AND J, E. GREENLEAF. Electronic bicycle ergometer: a simple calibration procedure. J. Appl. Physiol. 30: 440442, 1971. 7. COCHRAN, B., JR., E. P. MARBACH, R. POWCHER, T. STEINBERG, AND G. GWINUP. Effect of acute muscular exercise on serum immunoreactive insulin concentration, Diabetes 15: 838-841, 1966. 8. GUNTHER, O., AND R. FRENZEL. Uber den Einfluss Langer andauernder kiirperlicher 1naktivitti.t auf die Kohlendydrattoleranz. Zeit. Ges. Inn. Med. Ihre Grenzg. 24: 814-817, 1969. 9. HALES, C. N., AND P, J. RANDLE. Immunoassay of insulin with insulin antibody precipitate. Biochem. J. 88: 137-146, 1963. 10. KLIMT, C. R., T. E. PROUT, R. F. BRADLEY, H. DOLGER, G. FISHER, C. F. GASTINEAU, H. MARKS, C. L. MEINERT, AND 0. P. SCHUMACHER. Standardization of the oral glucose tolerance test. Diabetes 18: 299-307, 1969. 11. LIPMAN, R. L., P. RA~KIN, T, LOVE, J. TRIEBWASSER, F. R. LECOCQ, AND J. J. SCHNURE. Glucose intolerance during decreased physical activity in man. Dtibefes 21: 101-107, 1972. 12. LIPMAN, R. L., J. J. SCHNURE, E. M. BRADLEY, AND F. R. LECOCQ. Impairment of peripheral glucose utilization in normal
13.
14. 15. 16.
17.
18.
19,
20.
21.
subjects by prolonged bed rest. J. Lab. Chin. Med. 76: 221-230, 1970. LIPMAN, R. L., F. ULVEDAL, J. 3, SCHNURE, E. M. BRADLEY, AND F. R. LECOCQ. Gluco-regulatory hormone response to 2deoxy-d-glucose infusion in normal subjects at bed rest. Metabolism 19: 980-987, 1970. LUTWAK, L., AND G. D. WHEDON, The effect of physical conditioning on glucose tolerance, Clin. Res. 7: 143-144, 1959. NAUGHTON, J., AND J. WULFF. Effect of physical activity on carbohydrate metabolism. J. Lab. C&z. Med. 70: 996, 1967. PAWLSON, L. G., J. B. FIELD, M. MCCALLY, P, G. SCHMID, J. J. BENSY, AND T. E. PXEMME. Effect of two weeks of bed rest on glucose, insulin and human growth hormone levels in response to glucose and arginine stimulation. Aerospace Med. Assoc. Preprints, 1968, p+ 105-106a PIEMME, T. E, Effects of two weeks of bed rest on carbohydrate metabolism. In: Hypogruvic and Hypodynumic Environments, edited by R. H. Murray and M. McCally. 1971, NASA Spec. Publ. 269, p. 281-287. REESE, R. D. Physiological Responses to Static and Phasic Exercise in the Supine Position: the Development of a Prescriptive ProtocoZ for Supine Exercise (doctoral dissertation). Palo Alto, California: Stanford University, 1972. STREMEL, R. W., V. A. CONVERTINO, E. M. BERNAUER, AND J. E. GREENLEAF. Cardiorespiratory deconditioning with static and dynamic leg exercise during bed rest. J. Appl. Physiol. 41: 905-909, 1976. VERNIKOS-DANELLIS, J., C. M. WINGET, C. S, LEACH, AND P. C. RAMBAUT. Circadian, endocrine, and metabolic effects of prolonged bed rest: two 56-day studies. NASA Tech. Mem. X-3051, 1974. YOUNG, H. L., L. JUHOS, B. L. CASTLE, J. YUSKEN, AND J. E. GREENLEAF. Body water compartments during bed rest: evaluation of analytical methods. NASA Tech. Rept. 406, 1973.
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Research
DOLKAS,~. B., ANDLE. GREENLEAF. InsuLin andglucose responses during bkd rest with isotonic and isometric exercise. J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 43(6): 1033-1038, 1977. -The effects of daily intensive isotonic (68% maximum oxygen uptake (vo, max)> and isometric (21% maximum extension force) leg exercise on plasma insulin and glucose responses to an oral glucose tolerance test (0G;TT) during 14-day bed-rest (BR) periods were investigated in seven young healthy men. The OGTT was given during ambulatory control and on day 10 of the no-exercise, isotonic, and isometric exercise BR periods during the 15wk study. The subjects were placed on a controlled diet (mean t SD = 344 t 34 g CHO/day and 3,073 t 155 (SD) kcal/day) starting IO days before each BR period. During BR, basal plasma glucose concentration remained unchanged with no exercise, but increased (P < 0.05) to 87-89 mg/lOO ml with both exercise regimens on day 2, and then fell slightly below control levels on day 13. The fall of glucose content (- 11 to - 15%) during BR was independent of the exercise regimen and was an adjustment for the loss of plasma vol. The intensity of the responses of insulin and glucose to the OG’IT (integrated area under the curves) was inversely proportional to the total daily energy expenditure during BR; i.e., the largest response with no exercise, then isometric, isotonic, and ambulatory exercise. It was estimated that at least 1,020 kcal/day must be provided by supplemental exercise to restore the hyperinsulinemia to control levels.
glucose tolerance
test; plasma volume
Center,
PROCEDURES
bed rest
Moffett Field,
California
94035
AND METHODS
Informed consent was obtained from seven healthy men, from 19 to 22 yr of age (Table l), who participated in a 15-wk study during the summer months. They underwent a 2-wk ambulatory control period, three 2wk periods of bed rest - each separated by 3-wk recovery (control) periods-and finally, 4 days of recovery (Fig. 1). Each recovery period served as the control for the following bed-rest period. The subjects were housed under constant supervision in the Human Research Facility at Ames Research Center for 13 wk; they also spent the 1st wk in each of the recovery periods under supervision at a resort near the ocean to aid recovery. The men remained in the horizontal position throughout bed rest, including their bathing and excretory functions, but they were allowed to rise on one elbow to eat. The diet consisted of 14 different daily menus containing 3,073 * 155 (SD) kcal/day, composed of 121 g (20%) protein, 344 g (56%) carbohydrate, and 144 g (24%) fat by weight, The diet provided a mean t SD daily intake of Na+ of 3.8 t 1.0 g and 1.6 -+ 0.2 g of Ca2+ with an optimal vitamin and mineral content. Water was available ad libitum, but each man was required to drink 225 ml of coffee, tea, and/or milk with each meal. The subjects were placed on the controlled diet 10 days before each bed-rest period. During the ambulatory periods, the subjects exercised daily for 1 h at 50% of their maximal oxygen uptakes 2 max ) in the upright position on a Monark bicycle ergometer (about 565 kcal/day). During two of the three bed-rest periods, the subjects performed daily in the supine position either a) isotonic exercise on a Collins ergometer (6) at 68% of their Vo2 Max (780 kcal/h), or b) isometric exercise at 21% of maximal leg extension force for 1 min followed by 1 min rest (250 kcal/h) for 0.5 h in the morning and 0.5 h in the afternoon. During the isotonic exercise bed-rest period, mean -+ SE heart rates were 138 2 1 beats/min during the morning exercise and 136 * 1 beatslmin with afternoon exercise. During isometric exercise, the mean t SE work/rest heart rates in the morning were 105 t 2/80 t 2 beats/ min and 102 t 2/76 * I beats/min in the afternoon. In spite of the relatively low heart rates, these two exercise regimens performed in the supine position were nearly a maximal effort for the subjects. No supplementary exercise was prescribed during the 3rd bed-rest period (Fig. 1). The VOW maxwas determined with the subjects l
given a standard glucose tolerance test afier 3-7 days of enforced bed rest without supplementary physical exercise, exhibit prolonged hyperinsulinemia and hyperglycemia (1, 4, 5, 8, 11-13, 17). Tissue utilization of glucose is impaired in the presence of high concentrations of immunoreactive insulin (12). Daily isotonic exercise during bed rest reduces the degree of impaired glucose utilization, but does not return it to ambulatory control levels (5, 11). This disturbance in carbohydrate metabolism is no longer detected 2 wk after ambulation (12), but glucose tolerance returns to normal in less than 1 wk when physical conditioning exercises are used during the post-bed-rest period (14). Thus, it seems that glucose intolerance observed during bed rest is diminished with increasing energy expenditure. The purpose of the present study was to compare the effect of intensive isotonic and isometric exercise, performed for 1 h/day, on glucose tolerance and on the insulin response during bed rest. NORMAL
SUBJECTS,
wo
1033
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1034
C. B. DOLKAS
in the supine position. The test started with a 3-min warm-up period at 100 W followed by a progressively increasing work load of 50 W each 3 min until exhaustion (19). Maximal 0, uptake was measured near the end of the bed-rest and control-recovery periods. Submaximal isotonic 0, uptake was measured periodically during daily exercise throughout the study. O2 uptake during bed-rest isometric exercise was estimated from a comparable work/rest protocol on different subjects (18) and was the mean of a number of work/rest cycles. In the present study the volume of expired gas was measured with a Parkinson-Cowan meter. The gas was drawn into ZOO-ml oiled syringes and analyzed with a Beckman E2 oxygen analyzer and a Godart Capnograph CO, analyzer (19). The oral glucose tolerance test (OGTT) was given on day 10 of each bed-rest period (10); the ambulatory control test was done on day 21 of the first recovery period. No exercise was performed on the mornings of the OGTT. The dose of glucose administered was 40 g/ m2 of body surface area (10); the average dose was 82 g, with a range of 68-94 g (Table 1). Basal venous blood samples were taken without stasis, just before and at 1, 2, and 3 h after glucose administration, into syringes coated with EDTA (1 mg/ml blood) and centrifuged at 1,450 x g for 20 min at 5°C. The plasma was removed and frozen immediately for analysis. Plasma insulin concentration was determined by radioimmunoassay (9), and glucose concentration was
Ayo;Ty;LRY
AMBULATORY RECOVERY (CONTROL)
BEDREST-
I
1
0
I
1
RESULTS
Basal plasma volume and glucose. There were no significant differences in basal plasma glucose concentrations in the three control periods, and the values were within the normal range of 83-84 mg/lOO ml (Fig. 2). Compared with control values, plasma glucose concentration increased significantly (P < 0.05) with isometric and isotonic exercise by the second day of bed rest. At the end of bed rest, the glucose concentrations had returned to control levels, but there were increases in glucose above control levels on the 3rd day of recovery, particularly following the no-exercise regimen.
OGTT
OGTT
I
AMBULATORY RECOVERY (CONTROL)
I ’ 7
I
BEDREST1 12
14
BEDREST-
BEDREST-
BEDREST-
NO EXERCISE
ISOMETRIC
ISOTONIC
B
ISOMETRIC
ISOTONIC
NO EXERCISE
C
ISOMETRIC
ISOTONIC
NO EXERCISE
D
ISOTONIC
NO EXERCISE
ISOMETRtC
E
ISOTONIC
NO EXERCISE
ISOMETRIC
F
ISOTONIC
NO EXERCISE
ISOMETRIC
G
NO EXERCISE
ISOMETRIC
ISOTONFC
1. Individual
Subj
Age, yr
A B c D E
F G Mean &SE SA = surface
m, cm
1, Experimental
anthrupometric SA, m”
design
and sequence
and physiological
Wt Pre, kg
Wt Final,
kg
bwt,
of exercise
I 15
OGTT
OGTT
A
FIG.
TABLE
RE;&!;RY
I
9 WEEKS
SUBJECT
J. E. GREENLEAF
determined with the glucose oxidase method (Glucostat, Worthington Biochemicals Corp.). Plasma volume was measured with Evans blue dye from one lo-min postdye injection blood sample. This technique gave results comparable to the 0-min extrapolation of multiple postdye samples (21). Total plasma glucose content was calculated as the product of fasting glucose concentration and plasma volume. In Fig. 3 the total area under each curve, measured from the zero point on the X axis, was calculated assuming a straight line between sample points. The mean areas are presented in Fig. 4. The results were analyzed with the t-test for correlated data; the null hypothesis was rejected when P < 0.05.
BEDREST-
Jr 4
2
AND
regimens,
data on the subjects %
Leg Force Max, kg
Leg Force Max, kg/ MY&
ire, max, llmin
v$Fg;n!/’
Daily Isometric Load, kg
Daily Isotonic Load, W
Oral Glucase Dose, g
20 19 20 22 19 22 21
166 184 184 177 184 178 188
1.69 2.08 2.20 1.95 2.12 1.94 2.36
62.40 80.50 94,80 78,20 87.40 76.50 103,80
60.95 76,45 89.56 78.76 82.60 75.81. 96.27
-2.3 -5.0 -5.5 +0.7 -5.5 -0.9 -7.3
380 664 673 800 886 691 909
6.1 8.2 7.1 10.2 10.1 9.0 8.8
3.36 3.84 3.76 3.43 4.18 3.46 4.38
54 48 40 44 48 45 42
120 165 168 96 121 130 182
145 180 175 160 180 150 200
68 83 88 78 85 78 94
20 +l
180 rt3
2.05 kO.08
83.37 25.09
80.06 k4.25
-3.7
714 567
8.5 50.6
3.77 20.15
46 -t2
140 *12
170 +7
82 +3
area.
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INSULIN
2
AND
78
GLUCOSE
DURING
BED
1035
REST
I-
2 2 n
3.8
NO EXERCISE ISOMETRIC EXERCtSE ISOTONIC EXERCISE
q 0
5 6 >
3.3
2 2 2
3.1
3.2
FIG.
tration, changes riods.
3.0
2. Mean k SE plasma plasma volume, and during control, bed-rest, *P < 0.05 fromday2.
glucose concenglucose content and recovery pe-
2.8
3.2
4
-3
-2
-1
I
III1
1
2
1 3
4
5
6
6ED
I
REST-
7
II
8
11 9
10
11 11
12
l 13
14
3ECOVERY I I +1
+2
J +3
DAY
Plasma volume decreased (P < 0.05) in all experiments by the 4th day and remained depressed throughout bed rest. The increased glucose concentrations on the 2nd day of bed rest probably reflected the hypovolemia. Plasma glucose content fell progressively during bed rest. At the end of bed rest, the glucose contents for all three exercise regimens were lower (P < 0.05) than their respective ambulatory control values (Fig. 2). The mean loss of glucose content was 434 mg (-15%) with no exercise, 365 mg (-12%) with isometric exercise, and 304 mg (-11%) with isotonic exercise. The losses were not significantly different from each other. The loss of glucose content followed t;he loss of plasma volume, so that by the end of bed rest, glucose concentration had returned to control levels. Oral glucose tolerance test. Prior to ingestion, the Oh glucose concentration in the no-exercise group was elevated (P < 0.05) over the other regimens (Fig. 3).
After ingestion, the glucose concentrations in the noexercise (hour 2) and isometric exercise (hour 3) groups were higher (P < 0.05) than the corresponding ambulatory control values. At hours 2 and 3, the glucose concentrations with isotonic exercise were essentially the same as ambulatory control values (78-85 mg/lOO ml), while isometric and no-exercise values remained elevated in the 90-97 mg/lOO ml range. At hour 3, the glucose level with isotonic exercise was significantly lower (P < 0.05) than with no exercise (Fig. 3). Concomitant plasma insulin concentrations tended to follow the same pattern as the glucose resPonses (Fig* 3). All h our 1 values were higher (P < 0.05) than their respective control values. At hour 2, the three exercise regimen concentrations were significantly higher (P < 0.05) than ambulatory control data, and the isometric and no-exercise values remained elevated at hour 3. Unlike the other three conditions, with
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1036
C. B. DOLKAS
isometric exercise, both the glucose and insulin curves tended to level off in hours 2 and 3, in contrast to the usual peak at hour 1 followed by a decline in hours 2 and3 (Fig. 3). Analysis of the integrated areas under the insulin curves for the four conditions (Fig. 4) indicated that the greatest response occurred with no exercise, followed by progressively attenuated responses with isometric exercise, isotonic exercise, and ambulatory control. The areas under the glucose curves were less variable than insulin, but there was a similar trend of decreasing response with increasing metabolism. The glucose response to the OGTT with isotonic exercise was essentially the same as the ambulatory control value. During bed rest there appears to be an inverse relationship between the level of energy expenditure and the magnitude of the increase in plasma glucose and insulin concentrations following glucose ingestion (Fig. 4), DISCUSSION
The results indicate that heavy isotonic exercise for 1 h/day was more effective than heavy isometric exercise for I h/day in lowering the hyperinsulinemia induced by a standard glucose load during bed rest. This greater effectiveness can be attributed to a factor associated
70
120
100
0
1
I
I /\ [3 0
r
l
I
NO EXERCISE ISOMETRIC EXERCISE ISOTONIC EXERCISE AMBULATORY CONTROL
-
I
I
1
2
I 3
HOUR FIG. 3. Mean -+ SE plasma glucose and plasma insulin concentrations during the 3-h glucose tolerance test. *P < 0.05 from 0 h. C9 P -C 0.05 from ambulatory control value. Open symbols refer to tests during bed rest.
240
AND
J. E. GREENLEAF
INSULIN
GLUCOSE
220
180 160
60 40
0
I I $E Q
80
20
t 240
i 140 =3yz120 $ 100 2
I
300
T
200
120-
60
L NOE
0-
IME
1TE
4. Integrated areas during 3-h glucose tolerance exercise (NOE), isometric (ITE) regimens. FIG.
-
AMB
F
NOE
IME
ITE
AMB
under the insulin and glucose curves test for ambulatory (AMB), and noexercise (IME), and isotonic exercise
with the larger metabolic rate with isotonic exercise. Compared with the energy expenditure during normal daily activity, energy expenditure with no exercise during bed rest was reduced approximately 450 kcal/ day; the increased energy cost of the intermittent isometric exercise was about 250 kcal/day, and 780 kcal/ day for isotonic exercise. For comparable energy expenditure with isotonic exercise, the isometric regimen would have to be performed for about 3 h/day. This level of effort may well result in greater attenuation of the hyperinsulinemia, but, from the practical point of view, the more efficient method of increasing energy consumption is with isotonic exercise that utilizes large muscle groups. The plasma insulin and glucose responses to glucose ingestion in the present study agree qualitatively with those of Lipman et al. (11) who utilized combined isotonic-isometric exercise at 70% vu2 lllaX (600 kcal/h) for 1 h/day during bed rest: the smallest response occurred during ambulatory control, an intermediate response with exercise, and the largest response with absolute bed rest. From the results of Lipman et al. and the present study, it is clear that the supplemental energy expenditure must be greater than 780 kcal/day to prevent the “abnormal” insulin and glucose responses. If we assume that the level of hyperinsulinemia is a function of total energy expenditure during bed rest, and that the caloric cost during bed rest with no exercise is 90 kcal/h, it is possible to estimate the total daily energy expenditure required to reduce the insulin response to ambulatory control levels (Fig. 5). The linear regression of the insulin area (from Fig. 4) on the total daily energy output (rest and exercise) for the 3 bed-rest regimens indicates that approximately 3,000 kcal/day are needed; i.e., the normal daily ambulatory level for active men. If 90 kcal/h are utilized for 22 h during bed rest, then about 1,020 kcal/2 h must be obtained from supplemental exercise. This additional energy expenditure could be met by 1 h/day each of the isotonic (780 kcal/h) and isometric (250 kcallh) regimens
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INSULIN
AND
GLUCOSE
DURING
BED
1037
REST
used in the present study. It is clear that it will take a substantial effort to produce the additional 1,020 kcal/ day. It is not certain that elimination of the hyperinsulinemia woul .d return the glucose responses to normal. The increased basal plasma glucose concentrations on the 2nd day of bed rest could be accounted for by the proportionally greater loss of plasma volume than loss of glucose content. The progressive loss of glucose content throughout the three bed-rest periods was independent of ‘the intensi ty or type of exercise. This loss of content was not the result of chronic depleti .on by exercise, since the loss with no exercise was not sign& cantly different from the loss with isotonic exercise. At the end of bed rest, glucose concentrations had returned to normal due to an adjustment between the loss of plasma volume and the- loss of glucose content. The significant increase in glucose concentration on the 3rd day of recovery m ust have been due to a large influx of glucose, because the restoration of plasma volume would have had a tendency to lower glucose concentration. Part of this augmented gl ucose in flux must have been due to assu.mption of the upright position, since the subjects were still confined to the research facility and they had not resumed their normal activity levels. These results suggest that some factor, perhaps related to the gravitational vector but inversely proportional to exercise intensity, is involved in the mechanism of this “abnormal” carbohydrate metabolism during bed rest. Lipman et al. (12j concluded that change in the gravity vector was of minor importance because monkeys, which were confined upright in chairs, still n 0 0
50
INSULIN
I1:oo
AREA = 577.3 - 0.16 {ENERGY) r = 0.99
1800
FIG. 5, Regression curves during glucose for 3 bed-rest regimens.
GLUCOSE
NO EXERCISE ISOMETRIC EXERCISE ISOTONIC E XERClSE
2000
2200 2400 ENERGY EXPENDITURE,
2600 kcaV24
2800
3000
3200
hr
of integrated area under insulin response tolerance tests on 24-h energy expenditures
elicited the “abnormal” glucose response. Furthermore, results from another week-long bed-rest study showed clearly that a full week of ambulatory recovery, without supplemental exercise, did not reduce the hyperinsulinemia to normal levels (unpublished data). Bed-restinduced glucose intolerance returns to normal about 2 wk after resumption of normal, daily activity (12). When intensive physical training was employed, glucose intolerance returned to normal within the first week of recovery (14). The significantly elevated insulin concentrations in the present study indicated that immunoreactive insulin deficiency was not the cause of the amplified glucose responses. Exogenous insulin is no more effective than endogenous insulin in lowering plasma glucose levels (I). Thus, factors other than insulin per se must be involved. The lack of response of the elevated glucose to the large insulin concentrations suggests that the insulin activity is changed by the release of an insulin inhibitor, there is a blockage of the function of a second factor with insulin-like activity, some aspect of cellular membrane function is changed, or perhaps some combination of the above. The evidence discounts the function of the usual insulin antagonists, plasma cortisol (13, 16, ZO), plasma free fatty acids (FFA) (13), the catecholamines (17), and growth hormone (13, 16), because in many cases their concentrations during 2 wk of bed rest were either unchanged or decreased from ambulatory levels. Moderate exercise during bed rest had no effect on basal cortisol concentrations (20), After infusion of 2-deoxy-nglucose, there were no significant differences between ambulatory control and bed-rest responses of plasma glucose, plasma FFA, plasma cortisol, or serum immunoreactive insulin concentrations (13), but the normally marked rise in growth hormone was blunted, in agreement with the results of Pawlson et al. (16). Glucagon has not been evaluated, but it could stimulate insulin secretion and release glucose by hepatic breakdown of glycogen. Thus, it seems that the synthesis or release mechanisms for insulin are functioning normally (Fig. 6, left half). Other evidence suggests that the problem resides in or about the cellular membrane (Fig. 6, right half), and some factor or factors activated by physical exercise, that respond to the quantity of energy expended, are necessary for insulin and possibly glucose to function normally+ Men undergoing intensive physical training (2-5 times/wk) have a more eficient glucose metabolism with very little increase in the plasma insulin concentration, i.e., a higher insulin sensitivity during a resting tolerance test compared to normal,
GROWTH HORMONE
FIG.
GROWTH HORMON
6. Major
in .tolerance
EPINEPHRINE +
during
components bed rest,
of insulin
and
glucose
INSULIN EFFECTIVENESS
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1038 untrained men (3, 15). Baile et al. (2) have hypothesized that increased blood lactate with exercise induces the release of a factor that increases the rate of glucose metabolism. Lactate itself might alter the cell membrane to promote increased influx of glucose (7). Clinical observations indicate that the longer the period of inactivity during bed rest, the greater Le frequency and amplitude of abnormal glucose tolerance curves (5, 8). There appears to be an inverse linear relationship between energy expenditures and the level of hyperinsulinemia and glucose intolerance during bed rest. In addition to the resting energy level of 2,160 kcal/day during bed rest, an additional energy expendi-
C. B. DOLKAS
AND
J.
E. GREENLEAF
ture of at least 1,020 kcal/day would be necessary to eliminate the ‘cabnormal” glucose tolerance. High-intensity intermittent isometric leg exercise provides some remedial effect, but the most efficient and practical method of increasing enerm production is with isotonic exercise that utilizes the large muscle groups of the legs. The authors thank Dr. assistance with the chemical preparation, and the subjects Received
for publication
R. Grindeland and L. T. Juhos for analyses, C. Greenleaf for manuscript for their cooperation.
3 February
1977.
REFERENCES 1. ALTMAN, D. F,, S. D. BAKER, M. MCCALLY, AND T. E. PIEMME. Carbohydrate and lipid metabolism in man during prolonged bed rest. CZin.. Res. 17: 543, 1969. 2. BAILE, C, A., W. ZINN, AND Cm MCLAUGHLIN. Exercise, blood lactate and food intake. Eqerientia 26: 1227-1229, 1970. 3. BJ~RNTORP, P., M. FAHLAN, G. GRXMBY, A. GUSTAFSON, J. HOLM, P. RENSTR~M, AND T. SCHERSTEN. Carbohydrate and lipid metabolism in middle-aged, physically well-trained men. Metabolism 21: 1037-1044, 1972. 4. BLOTNER, H. Effect of prolonged physical inactivity in tolerance of sugar. Arch. Intern. Med. 75: 39-44, 1945. 5. BOHR, P. A. On the influence of prolonged bodily inactivity in the blood sugar curves after oral glucose loading. HeLu. Med. Actu 30: 156-175, 1963. 6. CLARKE, J. H., AND J, E. GREENLEAF. Electronic bicycle ergometer: a simple calibration procedure. J. Appl. Physiol. 30: 440442, 1971. 7. COCHRAN, B., JR., E. P. MARBACH, R. POWCHER, T. STEINBERG, AND G. GWINUP. Effect of acute muscular exercise on serum immunoreactive insulin concentration, Diabetes 15: 838-841, 1966. 8. GUNTHER, O., AND R. FRENZEL. Uber den Einfluss Langer andauernder kiirperlicher 1naktivitti.t auf die Kohlendydrattoleranz. Zeit. Ges. Inn. Med. Ihre Grenzg. 24: 814-817, 1969. 9. HALES, C. N., AND P, J. RANDLE. Immunoassay of insulin with insulin antibody precipitate. Biochem. J. 88: 137-146, 1963. 10. KLIMT, C. R., T. E. PROUT, R. F. BRADLEY, H. DOLGER, G. FISHER, C. F. GASTINEAU, H. MARKS, C. L. MEINERT, AND 0. P. SCHUMACHER. Standardization of the oral glucose tolerance test. Diabetes 18: 299-307, 1969. 11. LIPMAN, R. L., P. RA~KIN, T, LOVE, J. TRIEBWASSER, F. R. LECOCQ, AND J. J. SCHNURE. Glucose intolerance during decreased physical activity in man. Dtibefes 21: 101-107, 1972. 12. LIPMAN, R. L., J. J. SCHNURE, E. M. BRADLEY, AND F. R. LECOCQ. Impairment of peripheral glucose utilization in normal
13.
14. 15. 16.
17.
18.
19,
20.
21.
subjects by prolonged bed rest. J. Lab. Chin. Med. 76: 221-230, 1970. LIPMAN, R. L., F. ULVEDAL, J. 3, SCHNURE, E. M. BRADLEY, AND F. R. LECOCQ. Gluco-regulatory hormone response to 2deoxy-d-glucose infusion in normal subjects at bed rest. Metabolism 19: 980-987, 1970. LUTWAK, L., AND G. D. WHEDON, The effect of physical conditioning on glucose tolerance, Clin. Res. 7: 143-144, 1959. NAUGHTON, J., AND J. WULFF. Effect of physical activity on carbohydrate metabolism. J. Lab. C&z. Med. 70: 996, 1967. PAWLSON, L. G., J. B. FIELD, M. MCCALLY, P, G. SCHMID, J. J. BENSY, AND T. E. PXEMME. Effect of two weeks of bed rest on glucose, insulin and human growth hormone levels in response to glucose and arginine stimulation. Aerospace Med. Assoc. Preprints, 1968, p+ 105-106a PIEMME, T. E, Effects of two weeks of bed rest on carbohydrate metabolism. In: Hypogruvic and Hypodynumic Environments, edited by R. H. Murray and M. McCally. 1971, NASA Spec. Publ. 269, p. 281-287. REESE, R. D. Physiological Responses to Static and Phasic Exercise in the Supine Position: the Development of a Prescriptive ProtocoZ for Supine Exercise (doctoral dissertation). Palo Alto, California: Stanford University, 1972. STREMEL, R. W., V. A. CONVERTINO, E. M. BERNAUER, AND J. E. GREENLEAF. Cardiorespiratory deconditioning with static and dynamic leg exercise during bed rest. J. Appl. Physiol. 41: 905-909, 1976. VERNIKOS-DANELLIS, J., C. M. WINGET, C. S, LEACH, AND P. C. RAMBAUT. Circadian, endocrine, and metabolic effects of prolonged bed rest: two 56-day studies. NASA Tech. Mem. X-3051, 1974. YOUNG, H. L., L. JUHOS, B. L. CASTLE, J. YUSKEN, AND J. E. GREENLEAF. Body water compartments during bed rest: evaluation of analytical methods. NASA Tech. Rept. 406, 1973.
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