Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes M. KJkER, C. B. HOLLENBECK, B. FREY-HEWITT, H. GALBO, W. HASKELL, AND G. M. REAVEN Department of Medicine, Stanford University School of Medicine, Geriatric Research, Education and Clinical Center, Veterans Administration Medical Center, Palo Alto, California 94304; and Department of Medical Physiology B, Panum Institute, and Department of Internal Medicine TTA 2001, Rigshospitalet, University of Copenhagen, DK-2200 Copenhagen N, Denmark

KJLER, 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. Appl. Physiol. 68(5): 2067-2074, 1990.-Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on glucoregulation in non-insulin-dependent diabetic subjects (NIDDM). Seven NIDDM and seven healthy control males bicycled 7 min at 60% of their maximal O2 consumption (002 max), 3 min at 100% vo2 max, and 2 min at 110% Vo, max.In both groups, glucose production (R,) increased more with exercise than did glucose uptake (Rd) and, accordingly, plasma glucose increased. However, in NIDDM subjects the increase in R, was hastened and Rd inhibited compared with controls, so the increase in glucose occurred earlier and was greater [147 t 21 to 169 t 19 (30 min postexercise) vs. 90 t 4 to 100 & 5 (SE) mg/dl (10 min postexercise), P < 0.051. Glucose levels remained elevated for ~60 min postexercise in both groups. Glucose clearance increased during exercise but decreased postexercise to or below (NIDDM, P < 0.05) basal levels, despite increased insulin levels (P < 0.05). Plasma epinephrine and glucagon responses to exercise were higher in NIDDM than in control subjects (P < 0.05). By use of the insulin clamp technique at 40 PU l m-2omin-1 of insulin with plasma glucose maintained at basal levels, glucose disposal in NIDDM subjects, but not in controls, was enhanced 24 h after exercise. It is concluded that, because of exaggerated counterregulatory hormonal responses, maximal dynamic exercise results in a 60-min period of postexercise hyperglycemia and hyperinsulinemia in NIDDM. However, this event is followed by a period of increased insulin effect on Rd that is present 24 h after exercise. insulin sensitivity; insulin activity; catecholamines; lactate

clamp; glucose homeostasis; glucagon; free fatty acids;

physical glycerol;

PLASMAGLUCOSECONCENTRATIONS havebeenshownto decrease during exercise of moderate intensity in patients with non-insulin-dependent diabetes mellitus (NIDDM) (20, 23, 30). Moreover, this decrease in plasma glucose persists during the postexercise period, suggesting that moderate dynamic exercise has a beneficial effect on glucoregulation in patients with NIDDM (20, 30). In contrast, we have recently demonstrated that highintensity exercise in normal healthy individuals results 0161-7567/90 $1.50 Copyright

0

in a significant increase in glucose concentration that persists for at least 30 min after the end of exercise (22). The deterioration of glucoregulation in this situation results from a disproportionate increase in hepatic glucose production relative to peripheral glucose uptake and from a postexercise insulin resistance. At the present time, it is not known whether highintensity exercise would increase or decrease plasma glucose concentrations in patients with NIDDM. Because individuals with NIDDM are being encouraged to increase their exercise based on the expectation that this will improve diabetic control, we believed it essential to document the effects of high-intensity exercise on glucoregulation in patients with NIDDM. Thus the present studies were initiated to assess the effects of an acute bout of maximal dynamic exercise on hormonal and metabolic responses during and immediately after exercise in persons with NIDDM. In addition, the effect of short-term acute maximal exercise on insulin-stimulated glucose disposal was studied. MATERIALS AND METHODS Subjects. Seven sedentary males who met the current criteria of the National Diabetes Data Group for the diagnosis of NIDDM (31) and seven healthy age- and weight-matched sedentary males with normal tolerance to 75 g oral glucose participated in these studies. All subjects were normotensive and had normal renal, hepatic, cardiac, and neurological functions as assessed by clinical examination and standard laboratory analyses. Two of the individuals with diabetes were treated with oral sulfonylureas (Glipizide, 12.5 or 10 mg/day), and the remaining five were treated by diet alone. Experiments were performed at least 24 h after intake of sulfonylureas. None of the individuals was taking insulin. All subjects were maintained on self-selected mixed-food diets throughout the study, and none of them engaged in a regular physical exercise program. Judged from individual statements, groups did not differ with respect to physical activity during working hours or leisure time. Pertinent clinical characteristics of the individuals are presented in Table 1. All participants gave informed consent before participating in these studies. Each participant reported to the Stanford University General

1990 the American

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Society

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Clinical Research Center (GCRC) on five separate occasions for studies. Test procedures. The first two sessions were used to carefully determine the relationship between work load * and oxygen consumption (VOW). This was done for each individual along with a 12-lead electrocardiogram and auscultatoric blood pressure measurements during graded exercise to exhaustion. Individual maximal Vo2 . NO 2 max ) was defined by the “leveling-off” criterion by use of a bicycle ergometer (Monark, Sweden) and at least five different work loads at a pedal frequency of 60 rpm (Fig. 1). It was assumed that energy output at high work loads accompanied by substantial anaerobic metabolism (100 and 110% VO2 max) could be calculated by linear extrapolation from the part of the relationship between Vo2 and work load obtained at submaximal levels (Fig. I). From these data, work loads requiring an energy output equivalent to 60% (63 t 9 W for NIDDM and 79 t 5 W for controls), 100% (120 t 13 W for NIDDM and 148 t 9 W for controls), and 110% (137 t 12 W for NIDDM and 168 t 10 (SE) W for controls) of the subject’s individual VO 2 maxwere determined. The work load corresponding to 110% v02 max was always higher 1. Subject characteristics

TABLE

Control

NIDDM

54.724.4 53.9t3.7 177t2 179*1 Height, cm 85.0t6.1 92.0t3.3 Weight, kg 21.5t2.9 23.6t1.9 %Body fat 26.7t1.5 28.4t0.8 Body mass index, kg/m2 Body surface area, m2 2.02t0.05 2.11t0.04 3.6 Duration of diagnosed NIDDM, yr (l-10) Resting plasma glucose, 89k4 145t18 (133-270) w/d1 Values are means t SE with range indicated in parentheses. n = 7 subjects in each group. Body mass index is calculated as weight divided by square of height. %Body fat was calculated from body density estimated by hydrostatic weighing and determination of residual lung volume (37). Age, Yr

ygen

NIDDM o-----4 CONTROL

Uptake (co,)

0

d

d

-e--o

0

Work load (%of maximum) I ’

4

20

1

I 40

I

1

60

1

.

80

1

1

100

FIG. 1. Leveling off of vo2 with increasing work intensity in 7 NIDDM and 7 control subjects. Work load is shown relative to individual maximum work load achieved during exercise testing before experiments. Values are means t SE.

AND

TYPE

2 DIABETES

than the work load that had actually been found to elicit the Vozrnaxe Determination of OO 2 maxwas performed 721 days before the first clamp study. Total body mass was determined before exercise tests, and body density was estimated by hydrostatic weighing and determination of residual lung volume by the nitrogen dilution method. These measurements were carried out in triplicate. Percentage of body fat was calculated from body density according to the equation of Siri (37). Clamp studies. Subjects were studied in the laboratory at 0800 h after a lo- to 12-h fast. All subjects completed two insulin-clamp studies with maintenance of plasma glucose at basal levels. One clamp was performed 3-12 days before and one 24 h after an acute bout of exercise (as defined below). Individuals with NIDDM and control subjects were studied in random order. Clamp studies were performed as previously described (12). Briefly, endogenous insulin was suppressed by infusion of somatostatin at a rate of 250 pg/h, and exogenous insulin was infused at a constant rate of 40 mU rnD2 . min-l. Blood samples were obtained every 10 min from an indwelling catheter placed in a hand vein that was kept in a radiant warmer at 70°C to provide “arterialized” venous blood. Plasma glucose was determined with a glucose analyzer (Beckman Instruments, Fullerton, CA), and a 20% glucose solution was infused at a variable rate to maintain plasma glucose at &lo% of fasting levels. To quantify total glucose turnover, 45 (patients with NIDDM) or 30 &i (controls) of [33H]glucose were injected as an intravenous bolus at the onset of each clamp, followed by a constant infusion of 0.384 &i/min for the duration of the 4-h study. Blood was removed at lo-min intervals and centrifuged, and a protein-free filtrate of plasma was obtained by precipitation with Ba(OH), and ZnS04. The filtrate was then dried, and glucose concentration and radioactivity were measured. Glucose specific activity was determined, and the rates of appearance and disappearance of glucose were calculated, by use of the non-steady-state equations of Steele (38). In individuals with NIDDM, total metabolic glucose disposal was determined by correcting the rate of disappearance of glucose for the rate of urinary glucose loss. To compensate for differences in fasting between individuals with glucose concentrations NIDDM and controls, metabolic clearance rates were calculated by dividing the rate of glucose disposal by fasting glucose concentrations. Units for glucose clearance are milliliters of plasma per square meter of body surface area per minute. Exercise procedure. On the 4th study day, 3-12 days after the first euglycemic clamp study, individuals reported to the GCRC at 0800 h in the fasted state for exercise studies. These studies consisted of measurements of hormone and substrate concentrations before, during, and after a short period (12 min) of graded exercise. In addition, glucose turnover was determined by infusion of [3-3H]glucose throughout the 312 min (120 min of equilibration, 12 min of exercise, and 180 min of recovery) of the study as described above. An outline of the exercise procedure is illustrated on the abscissa of Fig. 2. Individuals rested in a reclining chair for the first

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MAXIMAL M

-

Heart Rate

O-----d

2oom

beats*min”

120-

EXERCISE

NIDDM CONTROL

+

801

88 -----:8 I

f

e 6O%bg1ax

. 100 . 110 7 10 12

40-

b

I, I/

REST

TYPE

2069

2 DIABETES

metric test was used to determine whether significant changes occurred with time. Significant changes were located by the multiple comparison procedure (36). Differences between experiments within the groups were determined by Wilcoxon’s ranking test for paired data, and differences between NIDDM and control subjects were determined by Mann-Whitney’s ranking test for unpaired data (36). A significance level of 0.05 for twotailed testing was chosen a priori. RESULTS

=e-+ -----

01

AND

There were no significant differences in fat-free body mass between individuals with diabetes and controls (Table 1). Both resting and maximal heart rates were identical in the two groups (Fig. 2). On the other hand, . vo 2 max was significantly lower in individuals with NIDDM (25.2 t 2.4 ml. min-’ . kg-‘) than in controls (32.2 t 2.1 mlmin-’ kg-‘, P < 0.05), and it is evident from Fig. 1 that the leveling-off criterion for obtaining I702 maxwas met for both groups. Responses to graded exercise. On the day of the exercise study, resting heart rates were identical in the two groups. During the 12 min of graded exercise, mean heart rates increased at the same rate in both groups. During the 2 h of preexercise equilibration, hepatic glucose production (Ra) and peripheral glucose uptake (RJ were similar in the two groups (Fig. 3), but glucose clearance was higher in controls (1.89 t 0.18 ml. min-’ kg-‘) than in NIDDM subjects (1.27 t 0.16, P < 0.05). Ra always increased with exercise, but the increase was more rapid in NIDDM than in controls (time to peak value 12.9 t 0.1 vs. 15.9 t 0.7 min, P < 0.05). Furthermore, in NIDDM, Ra increased more than Rd (P < 0.05), whereas this was not the case in controls (P > 0.05, Fig. 3). Accordingly, during exercise, plasma glucose concentrations increased in NIDDM subjects [145 t 18 (rest) VS. 155 t 27 mg/dl (110% iT02 max), P < 0.051 but did not change significantly in the controls (Fig. 4). In the first few minutes of the recovery period, Ra always exceeded Rd, and plasma glucose concentrations increased in both groups, reaching peak levels after 10 min in control subjects (100 t 5 mg/dl) and after 30 min in patients with NIDDM (169 t 19 mg/dl, significantly different from the lo-min postexercise value). In patients with NIDDM, this level was maintained until 60 min after the end of exercise, and then plasma glucose concentrations decreased over the remainder of the recovery period. In control subjects, glucose concentrations 60 min postexercise did not differ significantly from preexercise levels. Glucose clearance peaked immediately after exercise [2.75 t 0.72 (NIDDM) and 6.93 t 1.45 ml. min-’ . kg-’ (controls)] and at 20 min postexercise decreased to [ 1.86 t 0.29 ml min-’ . kg-‘, P > 0.05 (controls)] or below [0.72 2 0.23 ml .min-‘. kg-‘, P < 0.05 (NIDDM)] basal levels. Fasting plasma insulin concentrations were significantly higher in patients with NIDDM compared with control subjects (P c 0.05). At the end of exercise, plasma insulin concentrations in control subjects had decreased below basal levels (P < 0.05). In patients with NIDDM, no significant change from preexercise levels was obl

min

EXERCISE

2. Heart rate at rest and during a graded bicycle exercise experiment in 7 NIDDM and 7 control subjects. Maximum heart rates (HR,,,) obtained in preliminary tests are shown at upper left. Values are means t SE. FIG.

105 min of the study. They then moved to a stationary bicycle, where they rested for the remaining 15 min of the 120-min preexercise equilibration period. After the equilibration period, individuals bicycled at 60 rpm for 7 min at an energy output ~60% of individual VOW mBx.The work load was then increased to give an energy output =lOO% Vo 2 m8Xfor 3 min, and it finally was increased to 110% VO2 max for the final 2 min of the 12-min graded exercise period. After exercise the subjects rested on the bicycle for 2 min and then in a reclining chair for the remaining 178 min of the 3-h postexercise period. Blood samples were obtained from a heated hand vein every 10 min during the preexercise period, at the end of each stage of exercise, and at defined intervals during the postexercise period (see Figs. 3-6). Analysis of hormones and metabolites. Blood for catecholamine analysis was collected in chilled glass tubes ethylene glycol-bis(P-aminoethyl ether)containing N,N,N’,N’-tetraacetic acid and reduced glutathione and placed on ice. Samples were promptly centrifuged at 4”C, and plasma was stored at -8OOC. Catecholamine concentrations were determined by a single-isotope radioenzymatic method (3). The concentrations of insulin (8), pancreatic glucagon (15), growth hormone (GH) (16), adrenocorticotropic hormone (ACTH) (13)) and cortisol (16) were determined with previously described radioimmunoassays. Plasma glucose was determined spectrophotometritally by the hexokinase method. Free fatty acid (FFA), glycerol, and lactate concentrations in plasma were determined by enzymatic fluorometric methods. Hematocrit was measured by the microhematocrit method, and electrocardiogram was registered with precordial electrodes. Statistical evaluation. Data are presented as means t SE. For repeated measurements, Friedman’s nonpara-

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l

2070

MAXIMAL

Glucose

production mg- min+ kg-I r

(Ra)

l

a---o

l

8

EXERCISE l

AND TYPE

NIDDM CONTROL

210

2 DIABETES

GLUCOSE

-

NIDDM

mg-dl”

190 170 150 4

10

Glucose utikation mg- mid.

INSULIN

40

(Rd)

pU* rnP

kg-’

30 *i

20 10 0 0J 110 t

t 9 GO-110% 120 0 5I 10 . 15 . 20 -

REST ‘UEF&l%

120

.

min 160

RECOVERY &efdse

301

l

45t min

RECOVERY

FIG. 3. Glucose kinetics during and after bicycling in 7 NIDDM and 7 control subjects. Values are means & SE. In patients with NIDDM, loss of glucose in urine was subtracted from tracer-determined disappearance of glucose from plasma to obtain Rd.

served during exercise. After exercise, plasma insulin concentrations increased significantly (P < 0.05) above preexercise levels in both groups and returned to baseline levels by 120 min postexercise (Fig. 4). Plasma norepinephrine concentrations tended to be elevated in patients with NIDDM compared with controls before exercise (P c 0.01, Fig. 5). Norepinephrine levels increased with increasing exercise intensity; peak values occurred 1 min postexercise in both groups. Although norepinephrine concentrations throughout exercise generally were higher in patients with NIDDM than in controls, significance was reached only at the lowest intensity of exercise (60% Vo2 max). Epinephrine concentrations did not differ between the two groups in the basal state but reached significantly higher levels at every intensity of exercise in patients with NIDDM than in the control subjects (P < 0.05, Fig. 5). Maximal concentrations of epinephrine in NIDDM subjects (4.80 t 2.13 nmol/l) were more than twice as high as those observed in controls (1.75 t 0.49 nmol/l).

FIG. 4. Effect of graded bicycling on glucose and insulin concentrations in plasma of 7 NIDDM and 7 control subjects. Values are means t SE.

Plasma glucagon levels did not differ significantly between groups before exercise (Fig. 5). However, during exercise, plasma glucagon concentrations declined in the control subjects only and became significantly lower than in individuals with NIDDM (P < 0.05). During the postexercise period, plasma glucagon levels increased in both groups (Fig. 5). However, it should be noted that in the control group this increase represented a return to preexercise levels (P > 0.05), whereas the increase in patients with NIDDM represented an increase above preexercise levels 5 and 10 min postexercise (P < 0.05). GH, ACTH, and cortisol increased in response to exercise and reached peak values 15, 15, and 30 min postexercise, respectively. No differences existed between NIDDM subjects and controls (P > 0.05, Table 2) ‘During the preexercise period, plasma levels of lactate, glycerol, and FFA did not differ between patients with NIDDM and controls (Fig. 6). During exercise, plasma lactate concentrations increased to the same extent in both groups. Maximum concentrations were reached 510 min postexercise. Plasma glycerol concentrations also increased with exercise, reaching maximum concentra-

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MAXIMAL

EXERCISE

TYPE

2071

2 DIABETES

2. Concentrations and control subjects

of hormones

TABLE

Norepinephrine

(nmol x 1-l)

AND

30 f 1

in NIDDM

Basal

Exercise

0 min

12 min

27 min

Recovery 42 min

1.3k0.8 1.1t0.5

3.0t1.9* 1.8t0.7*

5.0*1.3* 4.5*1.6*

3.2*0.8* 2.9*1.2*

GH, mu/l NIDDM

Control ACTH, pmol/l NIDDM

Control Cortisol, nmol/l

15.6t3.4*

9.0t2.4

19.7t3.8”

28.2*4.9* 44.5&11.1*

NIDDM 318233 409&40” 762*67* 793t77* Control 319k77 393t95* 666t83* 700&83* Values are means t SE. GH, growth hormone; ACTH, adrenocorticotropic hormone. Seven non-insulin-dependent diabetic subjects (NIDDM) and 7 healthy control males performed 12 min of graded intense bicycle exercise (60-110% VO 2 mBx).Blood was sampled from a heated hand vein. Times were measured from onset of exercise. * P < 0.05 vs. basal value.

Epinephrine

(nmol

9.0t0.8

LACTATE m mol. I”

l

Glucagon

-----o

NIDDM CONTROL

(pm01 x I-1) 30.

20.

10.

I

GLYCEROL

0. 0

12 Exercise

22

32

42

72 min

Recovery

FIG. 5. Plasma concentrations of catecholamines and glucagon in 7 NIDDM and 7 control subjects who exercised for 12 min according to protocol in Fig. 2. Recovery period started at end of exercise (time 0 in Figs. 3, 4, and 6). Values are means k SE. * P < 0.05 and (*) P < 0.1 between groups.

tions in both groups at 5-10 min postexercise. However, at the end of the exercise period, plasma glycerol concentrations were significantly higher in the control group than in individuals with NIDDM (P < 0.05). In both groups plasma FFA concentrations decreased with increasing intensity of exercise and returned to basal values within 5 min after exercise (Fig. 6). Finally, hematocrits were similar in the two groups before exercise [44.8 t 1.4 (NIDDM) and 45.6 t 1.2% (controls)], increased slightly with exercise [to 47.8 t 1.2 (NIDDM) and 47.1 t 1.2 (controls), P < 0.051, and decreased to near-preexercise levels [46.2 t 1.4 (NIDDM) and 46.4 t 1.2 (controls)] by 10 min after exercise. Clamp studies. In the basal state immediately before the clamp studies, plasma glucose and insulin concentrations did not differ between the exercise studv and the

0

12 olo2030 EXERCISE

60

120

180

RECOVERY

FIG. 6. Plasma concentrations of metabolites in 7 NIDDM and 7 control subiects. Values are means +: SE. * P c 0.05 between groups.

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2072

MAXIMAL

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AND

TYPE

24-h postexercise study (Table 3). During the clamp procedure, plasma glucose concentrations were constant and, close to basal levels both before [coefficient of variation (CV) 6.3 t 0.4%] and 24 h after exercise (CV 8.1 t 0.8%). In the steady-state period (180-240 min), plasma glucose concentration was 153 t 18 ml/d1 (mean t SE of 7 values, each value a mean value of 12 determinations in 1 subject) in NIDDM subjects and 88 t 4 mg/dl in controls before the exercise bout and 151 t 16 mg/dl in NIDDM subjects and 90 t 2 mg/dl in controls 24 h after the exercise bout. Plasma insulin concentrations were constant during the last 30 min of the clamp studies, and no significant differences were seen in plasma insulin between the two groups (Fig. 7). However, plasma insulin concentrations tended to be lower during the clamp studies performed 24 h after exercise than during clamp studies performed before exercise, despite the fact that insulin infusion rates were identical (Fig. 7, P < 0.05 for 14 values). R, was always totally suppressed during clamp studies. Insulin-stimulated disposal and clearance of glucose were always higher in controls than in NIDDM subjects (P c 0.05, Fig. 7). Comparison of clamp studies before and 24 h after exercise shows that a single bout of acute high-intensity exercise resulted in significant increases in insulin-stimulated glucose disposal and clearance in the patients with NIDDM (P C 0.05). In contrast, insulin-stimulated glucose disposal rate was not significantly changed by exercise in the control subjects.

2 DIABETES

Insulin N/ml 100

1)

Baseline

r?!j

Post

Exercise

80604020O-

NIDDM

Control

Glucose Disposal mg/m * /min

300,

200.

(Rd)

I

100.

0.

NIDDM

Contr

01

Contr

01

Glucose Clearance ml /m * /min

OMCR)

DISCUSSION

In sedentary NIDDM subjects with elevated basal glucose levels, the glucoregulation response to high-intensity exercise is very different from that to mild exercise. Instead of lessening the plasma glucose concentration, short-term high-intensity exercise increases glucose levels during and for >l h after work. Exaggerated responses of counterregulatory hormones are elicited that are similar to those seen in exercising poorly controlled insulin-dependent diabetics, in whom exercise worsens the diabetic state (4, 18, 39). In healthy subjects, a decrease in plasma insulin concentrations is a prerequisite of the essentially constant plasma glucose concentration during exercise of mild to moderate intensity (14). The decrease in insulin level is due to an cu-adrenergic nervous inhibition of the pan3. Effect of prior exercise on basal glucose and insulin levels

TABLE

Before Exercise

Plasma glucose, NIDDM Control Insulin, pU/ml NIDDM Control

After Exercise, 24 h

mg/dl 161t24 90t2

166k22 91t3

19t5 9t2

1924 9_t2

Values are means k SE. Arterialized hand-vein blood was drawn in the resting state in 7 overnight-fasted NIDDM and 7 overnight-fasted control subjects. Data were obtained before start of a hyperinsulinemic clamp 3-12 days before and 24 h after a bout of short intense bicycle exercise (60-110% VOW ,,,).

300,

200

100

0

NIDDM

7. Plasma insulin concentration, total metabolic glucose disposal, and glucose clearance (MCR = R&oncentration of plasma glucose) as determined during minutes 160-240 of hyperinsulinemic clamp before (base line) and 24 h after a single exercise bout (postexercise) in 7 NIDDM and 7 control subjects. In patients with NIDDM, loss of glucose in urine was subtracted from total glucose disappearance from plasma to obtain metabolic glucose disposal. Values are means + SE. * P < 0.05 between values before and after exercise. Glucose disposal and clearance always differed significantly between the 2 groups (P < 0.05). FIG.

creatic ,&cells (14,16). Previous studies of NIDDM have indicated that sympathetic control of insulin secretion is impaired during mild to moderate exercise, probably because of the prevailing hyperglycemia. Thus insulin and C-peptide levels did not decrease at these exercise intensities in NIDDM subjects (24, 30). This explains the fact that during mild to moderate exercise R, is inhibited and Rd enhanced compared with findings in nondiabetic subjects, and the imbalance results in a decrease in the plasma glucose concentration (20,23,30, 35) I&en during severe exercise with very high adrenergic

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MAXIMAL

EXERCISE

activity, the plasma insulin concentration does not decrease significantly in NIDDM subjects (Fig. 4). However, in contrast to findings at mild exercise (2O), during heavy exercise, concentrations of epinephrine and glucagon were markedly higher in NIDDM than in control subjects (Fig. 5). Concentrations of GH, ACTH, and cortisol did not differ between groups, but these hormones are not considered to be important for acute glucose counterregulation (7). The exaggerated counterregulatory hormonal response during heavy exercise in NIDDM subjects probably accounts for the fact that, in contrast to findings in control subjects, R, exceeded Rd and plasma glucose concentration increased (Fig. 3). In the early postexercise period, R, exceeded Rd in both groups. Accordingly, the plasma glucose concentration increased immediately after exercise in our 55yr-old sedentary control subjects as was found previously in 23yr-old healthy untrained subjects (22). Interestingly, although the exercise protocol and norepinephrine responses were identical, increases in glucose concentration, R,, and epinephrine concentration were twice as high in the young (22) as in the middle-aged men. These findings are compatible with the view that the capacity to secrete epinephrine decreases with age and physical fitness (22). We used the hyperinsulinemic clamp technique to demonstrate that the rates of insulin-stimulated disposal and clearance of glucose were markedly lower in NIDDM than in control subjects. In agreement with previous findings (33, 34), VO 2 maxalso was lower in the NIDDM subjects (Fig. 2), even though their reported level of physical activity was similar to that of the controls. Previous studies of 60- to ‘IO-yr-old healthy subjects have shown a positive correlation between insulin sensitivity and VOW max (19). However, this correlation could not account for the lower insulin sensitivity in NIDDM than in control subjects. Accordingly, the impaired insulinmediated glucose metabolism in NIDDM seems to be due to specific metabolic defects that are not related to aerobic capacity. However, no differences in insulin binding, receptor kinase, maximal glucose transport, or glucose-metabolizing enzymes have yet been demonstrated between muscle from NIDDM subjects and muscle from healthy subjects of comparable fitness and adiposity (1, 6, 9, 11, 26, 33). During the postexercise recovery period in both NIDDM and control subjects, glucose disappearance decreased to and glucose clearance decreased below basal levels in the face of increased plasma insulin concentrations. Glucose levels remained elevated for >60 min (Fig. 4). This contrasts with what is usually emphasized, i.e., after exercise, glucose clearance in the absence of insulin and insulin sensitivity are increased (17, 27, 32). However, findings similar to those of the present study have previously been obtained in healthy young subjects, in whom the apparent insulin resistance was ascribed to inhibition of muscle hexokinase by an accumulation of glucose 6-phosphate resulting from enhanced glycogenolysis and fat combustion (21, 22). In accordance with this explanation, plasma lactate and glycerol levels were increased in the recovery period in both studies (Fig. 6)

AND TYPE

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(22). Inhibition of glucose transporters caused by increased epinephrine levels may also be involved in the insulin resistance early after exercise (2). In NIDDM subjects, 24 h after exercise, at which time glucose 6-phosphate and epinephrine probably were at basal levels, insulin-mediated glucose disposal was 30% higher than it was before exercise (Fig. 7). A similar increase has recently been found 14 h after short-term high-intensity exercise in both NIDDM and insulinresistant obese subjects (9, 10). The magnitude of the increase is comparable to reported training-induced improvements in insulin-mediated glucose disposal in NIDDM subjects (25,40). However, in these studies (25, 40) insulin action was measured 2-4 days after the last training session, which makes it difficult to conclude whether regular physical exercise enhances the effect of insulin more than a single bout of exercise, as has been demonstrated in young healthy subjects (28,29). Of note, however, is the fact that the increase in insulin sensitivity seen 24 h after acute exercise in the present study was not accompanied by any decrease in basal glucose or insulin levels in plasma (Table 3). A possible explanation for this apparent discrepancy is that after exercise an increase in insulin sensitivity is outbalanced by an increase in food intake. In accordance with this, we recently found that, during the day, trained healthy subjects with increased insulin sensitivity have mean plasma glucose concentrations identical to those of untrained subjects. However, the trained subjects eat more than the untrained (unpublished observations). In conclusion, the present study shows that in NIDDM, high-intensity exercise elicits exaggerated responses of epinephrine and glucagon and worsens glucoregulation during and for ~60 min after work. Furthermore the insulin resistance seen early after such exercise is followed by increased insulin-mediated glucose disposal. The increase in insulin sensitivity lasts at least until 24 h after exercise but is at that time not accompanied by decreased postabsorptive glucose or insulin levels. It appears that in NIDDM, high-intensity exercise may have less therapeutic value than low- or moderate-intensity exercise. The staff at Stanford General Clinical Research Center is greatly acknowledged for assistance. Rita Christiansen is acknowledged for typing the manuscript. This study was supported by Danish Medical Research Council Grants Jr. 12-6852 and 12-7797, the NOVO Foundation, the Nordic Insulin Foundation, and Farmitalia, Carlo Erba. Address for reprint requests: M. KjEr, Dept. of Medical Physiology, Panum Institute, Blegdamsvej 3-C, DK-2200 Copenhagen N, Denmark. Received 13 March 1989; accepted in final form 18 December 1989. REFERENCES P., T. POLLARE, H. LITHELL, AND J. N. LIVINGSTON. Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 30: 437-440, 1987. BALY, D. L., AND R. HORUK. The biology and biochemistry of the glucose transporter. Biochim. Biophys. Acta 947: 571-590, 1988. BEN JONATHAN, N., AND J. C. PORTER. A sensitive radioenzymatic assay for dopamine, norepinephrine and epinephrine in plasma and tissue. Endocrinology 98: 1497-1507, 1976. BERGER, M., P. BERCHTOLD, H. J. COPPERS, H. DROST, H. K. ARNER,

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Glucoregulation and hormonal responses to maximal exercise in non-insulin-dependent diabetes.

Maximal dynamic exercise results in a postexercise hyperglycemia in healthy young subjects. We investigated the influence of maximal exercise on gluco...
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