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The Department of Medicine, University of Pittsburgh School of Medicine, and Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania 15261
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES
ABSTRACT 
Colberg, Sheri R., James M. Hagberg, Steve D. McCole, Joseph
M. Zmuda, Paul D. Thompson, and David E. Kelley. Utilization of
glycogen but not plasma glucose is reduced in individuals with NIDDM
during mild-intensity exercise. J. Appl.
Physiol. 81(4): 2027-2033, 1996.
To test the
hypothesis that substrate utilization during mild-intensity exercise
differs in non-insulin-dependent diabetes mellitus (NIDDM) compared
with nondiabetic subjects, seven lean healthy subjects (L), seven obese
healthy subjects (O), and seven individuals with NIDDM were studied
during 40 min of mild-intensity cycling (40% of peak
O2 uptake). Systemic utilization of plasma glucose (Glc Rd) was determined by using isotope dilution methods. Gas exchange was measured to determine rates of carbohydrate (CHO) and lipid oxidation. During exercise, when CHO
oxidation was greater than Glc Rd, the net oxidation of glycogen was
calculated as the difference: CHO oxidation 
Glc Rd. During
mild-intensity cycling, the respiratory exchange ratio was similar
across groups (0.87 ± 0.02, 0.85 ± 0.02, and 0.86 ± 0.01 in
L, O, and NIDDM subjects, respectively), and CHO oxidation accounted
for one-half of total energy expenditure during exercise. Glc Rd
increased during exercise and was greatest in subjects with NIDDM (3.0 ± 0.2, 2.9 ± 0.2, and 4.5 ± 0.4 ml · kg
1 · min1
in L, O, and NIDDM subjects, respectively,
P < 0.05), yet Glc Rd was
less than CHO oxidation during exercise, indicating net oxidation of
glycogen. Glycogen oxidation was greater in L and O than in NIDDM
subjects (3.4 ± 1.0, 2.5 ± 0.9, and 1.7 ± 0.8 ml · kg1 · min1;
P < 0.05). In summary, during
mild-intensity exercise, NIDDM subjects have an increased Glc Rd and a
decreased oxidation of muscle glycogen.
obesity; non-insulin-dependent diabetes mellitus; glucose uptake; muscle glycogen; gas exchange
INTRODUCTION MILD- TO MODERATE-INTENSITY exercise is the form often
recommended and chosen by patients with non-insulin-dependent diabetes mellitus (NIDDM) (9). Although substrate metabolism during exercise has
been extensively investigated in healthy physically trained individuals
(21, 24, 29), less is known about patterns of substrate utilization
during exercise in individuals with NIDDM (12, 16, 19, 22, 29).
Abnormalities of glucose and lipid metabolism are present at rest in
individuals with NIDDM (17, 18) and could affect substrate metabolism
during exercise. Fasting hyperinsulinemia and hyperglycemia in NIDDM
might potentiate glucose utilization (glucose Rd) during exercise,
although insulin resistance of skeletal muscle could have opposing
effects. Patients with NIDDM have reduced uptake and oxidation of free
fatty acids (FFA) by skeletal muscle at rest (18) and therefore could
manifest a similar defect during mild-intensity exercise. Also,
sedentary individuals have greater utilization of carbohydrate relative to fat during exercise than do trained subjects (5, 20, 29).
An indication that greater glucose Rd may occur in NIDDM is the greater
fall in plasma glucose in NIDDM compared with nondiabetic subjects at
moderate-intensity exercise (12, 22, 25). This has been attributed to
an attenuated response of hepatic glucose production in NIDDM (25).
Recent leg balance studies indicate, however, that during
moderate-intensity cycling (60% of maximal O2 uptake) subjects with NIDDM
have higher rates of glucose Rd by skeletal muscle than do healthy
control subject volunteers (19).
The present study was undertaken to examine glucose Rd and FFA during
mild-intensity exercise and to test the hypothesis that, in obesity and
NIDDM, glucose Rd is increased whereas oxidation of fat is diminished.
Substrate utilization was determined at rest, during 40 min of
mild-intensity cycling, and during postexercise recovery. Isotope
dilution methods were used to assess the glucose Rd and FFA Rd, and gas
exchange was measured to examine substrate oxidation.
METHODS Table 1.
Clinical characteristics
O2 peak), which was
similar across groups, is consistent with a sedentary status and prior
studies of subjects with NIDDM (26). L, O, and NIDDM subjects were
matched for age. The groups had an equivalent gender distribution.
NIDDM subjects were moderately obese, although O nondiabetic subjects
had a higher body mass index
(kg/m2) and fat mass (kg).
Fat-free mass (FFM) also tended to be greatest in O subjects, but the
difference among groups was not significant. NIDDM volunteers had
fasting hyperglycemia (10.7 ± 1.7 mM) and elevated glycosylated
hemoglobin (11.0 ± 1.0%), whereas L and O subjects had normal
values. Volunteers with indications of ischemic heart disease,
peripheral vascular disease, or marked dyslipidemia (triglyceride >3
mmol/l) were excluded. All subjects had normal hematologic, renal, and
hepatic function. NIDDM volunteers who had proteinuria, evidence of
more than mild retinopathy, symptomatic neuropathy, or who were
receiving insulin therapy were excluded. The protocol was approved by
the University of Pittsburgh Institutional Review Board, and informed
consent was obtained from each subject.
Lean (3 M/4 F)
Obese (4 M/3 F)
NIDDM (4 M/3
F)
Age, yr
48 ± 3
50 ± 3
49 ± 2
Weight, kg
71 ± 5
103 ± 4*
85 ± 6*
BMI, kg/m2
23.4 ± 1.0
35.0 ± 1.4*
29.2 ± 2.0*
Fat-free mass, kg
47 ± 5
55 ± 3*
52 ± 2*
Fat
mass, kg
20 ± 2
42 ± 3*
28 ± 4*
Plasma glucose, mmol/l
5.0 ± 0.02
4.9 ± 0.2
12.2 ± 1.7
Triglyceride, mmol/l
0.9 ± 0.2
1.5 ± 0.4
1.5 ± 0.4
O2 peak,
ml · kg1 · min1
25 ± 2
21 ± 2
22 ± 2
Values are means ± SE. M, male; F, female; NIDDM,
non-insulin-dependent diabetes mellitus; BMI, body mass index;
O2 peak, peak
O2 uptake.
*
P < 0.05 vs. lean;
P < 0.05 vs. nondiabetic.
O2 peak
determination.
O2 peak was
determined during a progressive protocol on a cycle ergometer (Bosch
ERG 601, Electra-Med, Flint, MI). Initial work rates were 0 and 20 W
for women and men, respectively. Resistance was increased by 20 W every
2 min until subjects were unable to continue exercise. During this
test, subjects breathed through a two-way non-rebreathing valve (Hans
Rudolph, Kansas City, MO). Expired
O2 and
CO2 fractions were determined by a
Marquette MGA-1100 mass spectrometer (Marquette Electronics, Milwaukee,
WI). Ventilation was determined with an Interface Associates flow
turbine (Interface Associates, Laguna Niguel, CA) connected to a
5-liter mixing chamber (Rayfield RMC-1, Rayfield Equipment, Waitsfield,
VT). O2 uptake (O2) was calculated every
30 s; O2 peak was the
highest O2 achieved during
the test. Regression analysis from this test was used to calculate the
target O2 (40% of
O2 peak)
for the subsequent metabolic studies during mild-intensity exercise.
Heart rate and blood pressure were recorded at the end of every stage
of the O2 peak trial.
Mild-intensity exercise protocol.
Exercise studies were performed at the Preventive Cardiology Applied
Exercise Physiology Laboratory at the University of Pittsburgh. Subjects were instructed to ingest at least 200 g of carbohydrate daily
for the 3 days preceding a study and not to exercise on the day before
a study. NIDDM subjects on sulfonylurea medications stopped this
medication at least 5 days before an exercise study (none of the NIDDM
subjects were treated with metformin). Subjects fasted overnight and
were admitted to the University of Pittsburgh General Clinical Research
Center at 7 A.M. A venous catheter was placed in a forearm vein and a primed (20 µCi) continuous (0.20 µCi/min) infusion of
[3-3H]glucose (New
England Nuclear, Boston, MA) was started, with an allowance of 3 h for
isotope equilibration before basal (resting) measurements of the rates
of glucose appearance (Ra) and Rd. To measure rates of FFA Ra and Rd, a
continuous (0.3 µCi/min) infusion of
[9,10-3H]palmitate was
begun, with 1 h for isotope equilibration (14). A catheter for blood
sampling was placed in the retrograde direction in a vein on the dorsum
of the hand, and a heating pad was used to obtain arterialized samples.
Metabolic measurements were started 30 min before exercise. With
subjects sitting, blood samples were obtained for determination of
plasma glucose and glucose radioactivity, FFA and palmitate
radioactivity, whole blood lactate and glycerol, and plasma levels of
insulin and norepinephrine. Samples were obtained at 20-,
10-, and 0-min time points. Resting gas exchange was determined
by collecting expired air while subjects breathed through a
low-resistance breathing valve (Daniels, Cortland, NY) connected by
spiral tubing to neoprene meteorological balloons. Expired air was
analyzed for O2 and
CO2 content with a Marquette MGA-1100 mass spectrometer, and volumes were determined with a chain-compensated Tissot spirometer. Expired air was collected for a
total of 12 min during seated rest on the cycle. At the start of
exercise, resistance on the cycle ergometer was set so that subjects
would work at 40% of their predetermined
O2 peak while
pedaling at 60 revolutions/min.
O2 was checked and the workload adjusted as necessary during the first 10 min of exercise in
order for subjects to achieve their target level of exertion. At the
start of cycling, infusion rates of both isotopes were doubled to
maintain stable specific activities (8, 15) and were later reduced to
basal rates at completion of exercise and throughout the 40 min of
postexercise recovery. During exercise, blood and expired air were
sampled every 10 min (10, 20, 30, and 40 min), with sampling continuing
during postexercise recovery (50, 60, 70, and 80 min). Heart rate was
recorded every 10 min.
Analyses.
Plasma glucose was measured with a glucose oxidase system (YSI glucose
analyzer, Yellow Springs Instruments, Yellow Springs, OH). Blood for
lactate, alanine, and glycerol analyses was mixed with chilled 7%
perchloric acid, and, after centrifugation, supernatant was kept at
70°C until analysis (6). Plasma FFA was determined by using
an enzymatic method (NEFAC kit; Wako Chemicals, Dallas, TX). Plasma
insulin was measured by radioimmunoassay. Plasma norepinephrine was
measured by a high-performance liquid chromatography method with
electrochemical detection. For determination of
[3-3H]glucose
radioactivity, plasma was deproteinized with barium sulfate and zinc
hydroxide, supernatant was dried under vacuum, residue was
reconstituted in 0.5 ml of distilled water, and radioactivity was
measured with liquid scintillation spectrometry. Organic extraction of
plasma was performed to obtain palmitate radioactivity, with separation
and collection of the palmitate fraction by isocratic reverse-phase
high-performance liquid chromatography; this fraction was counted with
liquid scintillation spectrometry, as previously described (18). As
previously demonstrated, aqueous and organic extraction of plasma
quantitatively separates tritiated palmitate and glucose (18).
Calculations.
Plasma glucose and palmitate Ra and Rd were calculated by using
non-steady-state equations (8, 14); in NIDDM subjects, glucose Rd was
adjusted for urinary loss of glucose. Rates of carbohydrate (CHO)
oxidation and lipid oxidation were calculated by using the equations of
Frayn (10), with protein oxidation estimated on the basis of
measurement of urinary nitrogen loss. During exercise, when rates of
CHO oxidation exceeded simultaneous rates of glucose Rd, the net
oxidation of glycogen was estimated as the difference between CHO
oxidation and glucose Rd, as previously described in well-trained
healthy L subjects (24).
Statistics.
Data are expressed as means ± SE. Time (rest, exercise, and
recovery) and group (L, O, and NIDDM) comparisons were made by using
analyses of variance. A value of P 
0.05 was considered statistically significant.
RESULTS
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O2 peak, and these
values are consistent with an untrained status (Table 3). The
O2 during exercise was
similar across groups. Expressed as a percentage of
O2 peak, the value
during exercise was 42 ± 2%, which was the target intensity of
exercise and was similar across groups. Rates of energy expenditure
during exercise were fourfold higher than during basal conditions
(P < 0.01). During basal conditions,
the respiratory exchange ratio (RER), CHO oxidation, and lipid
oxidation were equivalent in L, O, and NIDDM subjects. At rest, lipid
oxidation accounted for approximately two-thirds of energy production
in all groups. During mild-intensity exercise, rates of lipid oxidation
were double the resting rates, but the increase in CHO oxidation was
substantially greater, increasing 10-fold above resting rates. This
pattern of lipid and glucose oxidation was similar in L, O, and NIDDM
subjects. In L, O, and NIDDM subjects, respectively, lipid oxidation
accounted for 37 ± 6, 47 ± 5, and 44 ± 3% of energy
expenditure during exercise (nonsignificant across groups). The
relative contribution of lipid oxidation to energy expenditure during
exercise was less than during basal conditions
(P < 0.05), as reflected in an
increase of RER during exercise to 0.86 ± 0.02 (P < 0.01 vs. basal). RER was
similar across subject groups during exercise. During recovery after
exercise, these parameters of gas exchange returned to basal values.
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1 · min1
in L, O, and NIDDM, respectively). During exercise, glucose Ra increased by ~50% and remained higher in NIDDM subjects (2.95 ± 0.17, 2.90 ± 0.17, and 4.15 ± 0.45 mg · kg1 · min1,
in L, O, and NIDDM, respectively). Rates of Rd for plasma glucose were
nearly identical to rates of glucose Ra, as would be anticipated from
the stability of plasma glucose concentrations during exercise. Plasma
glucose Rd during exercise was greater in NIDDM subjects (P < 0.05) than in L and O subjects
(3.03 ± 0.17, 2.91 ± 0.21, and 4.28 ± 0.44 mg · kg1 · min1
in L, O, and NIDDM, respectively).
Across all groups, rates of plasma glucose Rd were lower than rates of
carbohydrate oxidation, as shown in Fig 1. These findings that glucose Rd was less than corresponding rates of CHO
oxidation indicate oxidation of glycogen during exercise. Rates of
glycogen oxidation, whether expressed per weight of FFM (Fig. 1) or as a percentage of overall energy expenditure (Fig.
2), were lowest in NIDDM subjects
(P < 0.05 vs. L or O),
whereas differences between L and O subjects did not achieve
significance (P = 0.10). Thus, at
similar rates of CHO oxidation during mild-intensity exercise, subjects
with NIDDM oxidized a greater amount of plasma glucose and a lesser
amount of glycogen than did nondiabetic individuals.
During recovery after exercise, glucose Ra decreased to values that were slightly and significantly lower than had been present during baseline conditions (P < 0.05 for all groups). The disparity between glucose Ra in NIDDM and nondiabetic subjects was also less during recovery than at baseline (1.52 ± 0.09, 1.50 ± 0.11, and 1.95 ± 0.18 mg · kg
1 · min1
in L, O, and NIDDM). During this time, rates of glucose Rd exceeded rates of overall carbohydrate oxidation (0.54 ± 0.14, 0.66 ± 0.20, and 0.78 ± 0.15 mg · kg1 · min1
in L, O, and NIDDM, respectively).
During basal conditions, rates of palmitate utilization were similar in
L, O, and NIDDM subjects (1.91 ± 0.53, 2.46 ± 0.69, and 2.14 ± 0.23 µmol · kg
FFM1 · min1,
respectively). These rates increased during mild-intensity exercise (P < 0.01) but remained similar
across groups (2.44 ± 0.81, 3.35 ± 0.60, and 2.67 ± 0.40 µmol · kg
FFM1 · min1
for L, O, and NIDDM, respectively). During recovery after exercise, rates of palmitate utilization decreased in all groups
(P < 0.05) but were lower in L
subjects (1.04 ± 0.21, 2.49 ± 0.59, and 1.74 ± 0.41 µmol · kg
FFM1 · min1
in L, O, and NIDDM subjects, respectively;
P < 0.05).
DISCUSSION
Regular exercise is regarded as one of the cornerstones in the management of patients with NIDDM. In part, this recommendation for exercise in patients with NIDDM is aimed at improving insulin sensitivity (2, 3, 7). The effect of exercise to improve insulin sensitivity is largely attributable to short-lived (i.e., 1-2 days) effects of each session rather than long-term effects of training per se (21), especially if there are not concomitant changes in weight (27). From the perspective, therefore, of potential short-term effects of exercise, it is important to determine patterns of substrate utilization during an exercise session. For example, a single bout of strenuous (glycogen-depleting) exercise can improve insulin sensitivity and lower hepatic glucose production in NIDDM (7). Recently, our group has reported that rates of glucose utilization during moderate-intensity exercise are similar in previously sedentary NIDDM and O nondiabetic subjects (16). This is consistent with an earlier report by Minuk et al. (22), who noted a greater decline of plasma glucose in NIDDM than in nondiabetic subjects during moderate-intensity exercise and attributed this to an attenuated stimulation of hepatic glucose production. Increased glucose utilization during exercise in NIDDM compared with nondiabetic subjects could also be a factor in the more pronounced change in plasma glucose during exercise in NIDDM. Martin et al. (19) examined glucose Rd by skeletal muscle during moderate-intensity exercise (60% of maximal O2 uptake) by measuring arteriovenous balance across the leg and found higher rates in NIDDM compared with nondiabetic subjects. Thus, despite the insulin resistance that characterizes skeletal muscle glucose metabolism during resting conditions in NIDDM, prior studies indicate that exercise-induced glucose utilization is either not reduced or even increased in NIDDM. The current study was undertaken to examine the effects of NIDDM on substrate utilization during mild-intensity exercise. Although mild-intensity exercise is the form most commonly chosen by patients with NIDDM (9), there have not been published data regarding patterns of substrate utilization in patients with NIDDM during mild-intensity exercise. Braun et al. (3) have recently reported that low-intensity exercise is effective in improving insulin sensitivity in NIDDM, complementing other studies that have indicated that moderate- to high-intensity exercise improves insulin sensitivity in NIDDM (2, 7).
In the present study, subjects with NIDDM were found to have higher rates for glucose Rd during mild-intensity exercise than comparably sedentary L and O glucose-tolerant subjects. Thus our results are concordant with those of Martin et al. (19). In the present study, rates of CHO oxidation and lipid oxidation during exercise were, however, similar in NIDDM and nondiabetic subjects. Also, rates of CHO oxidation exceeded simultaneous rates for the glucose Rd during mild-intensity exercise. Because glucose Rd during mild-intensity exercise was less than CHO oxidation, this indicates net oxidation of glycogen as an additional contribution to CHO oxidation. The net oxidation of muscle glycogen can be estimated as the difference between CHO oxidation determined by indirect calorimetry and the glucose Rd determined by isotope dilution methods (24). Using this approach, we found that subjects with NIDDM, at equivalent rates of energy expenditure and CHO oxidation, oxidized a lesser amount of glycogen and had a proportionately greater glucose Rd during mild-intensity exercise than did nondiabetic subjects. We cannot discern with this approach whether there were group differences in rates of glycogenesis and glycogenolysis during exercise but only that the results indicate less net oxidation of glycogen in NIDDM. Whether the lower net use of glycogen in NIDDM was solely compensatory to greater uptake of plasma glucose or whether these were additional effects related to altered metabolism of muscle glycogen in NIDDM also cannot be addressed with the present study.
Hyperglycemia is probably of primary importance in accounting for increased uptake of plasma glucose during exercise in NIDDM. At rest, hyperglycemia in NIDDM partially compensates for insulin resistance (17). If contraction-induced translocation of the glucose transporter isoform GLUT-4 and glucose transport are normal in insulin-resistant human skeletal muscle, as has been found in a rodent model of insulin resistance (4), then mass action effects of hyperglycemia may be accentuated during exercise. Of note, insulin-resistant human skeletal muscle has normal glucose transport in response to hypoxia (1), which connotes that impairment of glucose transport in NIDDM may be selective for insulin stimulation. The clinical physiology described by the present study, as well as the findings of Martin et al. (19), suggests that, during exercise, glucose transport in NIDDM is not impeded and, in fact, may even be enhanced by concomitant hyperglycemia. The present study was undertaken as a single session of exercise in untrained subjects. Because exercise training can increase the expression of GLUT-4 in skeletal muscle (11), it would be of interest to determine what impact training-induced increases of GLUT-4 might have on glucose utilization during exercise in individuals with NIDDM.
In healthy, physically trained L individuals, utilization of plasma FFA can account for the majority of energy production during sustained mild-intensity exercise (24). This is not the case in sedentary subjects, who seem to rely less on fat oxidation (20, 29). In the present study, we hypothesized that untrained individuals with NIDDM would have still lower rates of fat oxidation during mild-intensity exercise than comparably sedentary L and O nondiabetic subjects. This hypothesis was based on lower rates of FFA utilization by skeletal muscle during resting conditions in NIDDM (18). However, rates of fat oxidation during mild-intensity exercise were similar in NIDDM and nondiabetic subjects. Rates of systemic palmitate utilization were also similar across groups. Thus, with regard to utilization of lipid in NIDDM, the abnormalities found at rest do not appear to be manifest during exercise. In comparing L women, O women with upper body fat distribution and O women with lower body fat distribution, among whom there are differences in resting rates of lipolysis (14) and FFA utilization by skeletal muscle (6), Kanaley et al. (15) found similar rates of palmitate utilization and overall lipid oxidation during mild-intensity exercise, which is consistent with the present findings. Several caveats temper complete rejection of hypotheses concerning impaired FFA utilization by skeletal muscle during exercise in NIDDM. One caveat is that we did not directly assess skeletal muscle uptake of palmitate, which would have required limb balance methodology. Also, the metabolic rate of FFA taken up by muscle cannot be ascertained with the isotope methods used, and, on the basis of systemic gas exchange, we cannot distinguish between the oxidation of plasma FFA vs. that of muscle triglyceride.
The low fractional contribution of fat oxidation (less than one-half of overall energy expenditure during mild-intensity exercise) was similar across groups and is consistent with the closely matched sedentary status of the subjects. Factors limiting fat oxidation during exercise in sedentary individuals may include lower oxidative capacity of skeletal muscle (28) and reduced skeletal muscle capillary density. The capacity of untrained individuals to utilize plasma FFA during exercise can be improved by exercise training (20, 29). Among nondiabetic subjects, just 10 days of daily exercise improve lipid oxidation in previously sedentary subjects (23). It is uncertain whether subjects with NIDDM would respond to training in a similar manner. This is a question of clinical importance given the adverse impact of adiposity and elevated plasma FFA and lipoproteins in NIDDM. Bogardus et al. (2) found that, after weight loss and exercise training, subjects with NIDDM did increase their rates of resting lipid oxidation. However, on the basis of the present findings that glucose uptake is increased in NIDDM during exercise and recognizing that hyperglycemia is not usually rectified by exercise training in NIDDM, we postulate that subjects with NIDDM might not be able to as effectively augment lipid utilization during exercise training as can nondiabetic individuals.
In summary, during mild-intensity exercise, oxidation of CHO and lipid is similar in L and O sedentary nondiabetic subjects and O individuals with NIDDM. Rates of glucose Rd are increased during exercise in NIDDM, although still less than rates of CHO oxidation during exercise. This indicates that the contribution to energy expenditure from the net oxidation of muscle glycogen is reduced in NIDDM compared with nondiabetic individuals. The findings of increased glucose Rd during exercise in NIDDM suggest that contraction-mediated glucose transport and oxidation are not impaired in NIDDM despite the severe insulin resistance that characterizes glucose homeostasis during resting conditions.
ACKNOWLEDGEMENTS
This project was supported by a Department of Veterans Affairs Merit Award and by the University of Pittsburgh General Clinical Research Center (5MO1RR00056).
FOOTNOTES
Address for reprint requests: D. E. Kelley, Division of Endocrinology and Metabolism, E-1140 Biomedical Science Tower, Univ. of Pittsburgh, Pittsburgh, PA 15261.
Received 15 December 1995; accepted in final form 7 May 1996.
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