Departments of 1 Radiology, 2 Physiology and Biophysics, and 3 Bioengineering, University of Washington Medical Center, Seattle 98195; and 4 Department of Neurology, Children's Hospital and Regional Medical Center, Seattle, Washington 98105
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ABSTRACT |
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This study asked whether the energetic properties of muscles are changed by insulin-dependent diabetes mellitus (or type 1 diabetes), as occurs in obesity and type 2 diabetes. We used 31P magnetic resonance spectroscopy to measure glycolytic flux, oxidative flux, and contractile cost in the ankle dorsiflexor muscles of 10 men with well-managed type 1 diabetes and 10 age- and activity-matched control subjects. Each subject performed sustained isometric muscle contractions lasting 30 and 120 s while attempting to maintain 70-75% of maximal voluntary contraction force. An altered glycolytic flux in type 1 diabetic subjects relative to control subjects was apparent from significant differences in pH in muscle at rest and at the end of the 120-s bout. Glycolytic flux during exercise began earlier and reached a higher peak rate in diabetic patients than in control subjects. A reduced oxidative capacity in the diabetic patients' muscles was evident from a significantly slower phosphocreatine recovery from a 30-s exercise bout. Our findings represent the first characterization of the energetic properties of muscle from type 1 diabetic patients. The observed changes in glycolytic and oxidative fluxes suggest a diabetes-induced shift in the metabolic profile of muscle, consistent with studies of obesity and type 2 diabetes that point to common muscle adaptations in these diseases.
glycolysis; mitochondrial oxidative phosphorylation; tibialis anterior muscle
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INTRODUCTION |
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SKELETAL MUSCLE IN
OBESE and non-insulin-dependent (type 2) diabetic patients shows
insulin resistance (4, 26) and adaptations in muscle
properties associated with energy metabolism (19). In both
diseases, a reduction in the oxidative enzyme activity and an increase
in the lipid content of all fiber types are found relative to control
subjects (19). This pairing of a reduced oxidative
capacity and an increased lipid content is unusual compared with the
elevation in both factors with chronic physical exercise (15,
21). A trend toward a rise in muscle glycolytic enzyme activity
relative to oxidative enzyme activity is also found in these two
diseases (19, 42). Consistent with these findings in
muscle fibers are reports of reduced maximal O2 consumption (O2 max) and elevated muscle lactate
during exercise in obese and type 2 diabetic patients relative to age-
and activity-matched control subjects (30, 36, 37). These
changes in muscle properties represent a shift in the metabolic profile
of the muscle fibers that has been suggested to be reflective of
diseases involving insulin resistance (19).
Insulin resistance is also found in humans with insulin-dependent (type
1) diabetes (47), but little information is available on
whether energetic properties such as glycolytic flux and oxidative capacity are also affected. Assays of a key glycolytic enzyme, phosphofructokinase, showed no difference between type 1 diabetic patients and control subjects (45). However, measurements
during exercise provide evidence that the lower oxidative and higher glycolytic fluxes found in obesity and type 2 diabetes are also common
to type 1 diabetes; specifically,
O2 max is reduced (34) and
blood lactate levels are elevated (48) in exercising type
1 patients compared with age- and activity-matched control subjects. In
addition, an increased glycolytic flux in a rodent model of
uncontrolled type 1 diabetes was apparent from a greater drop in muscle
pH during stimulation, indicative of increased lactate generation
compared with control muscle (6). Thus the few in vivo
studies of active muscle affected by type 1 diabetes point to an
alteration of energetic properties indicative of a shift in the
metabolic profile of the muscle.
The key energetic and metabolic properties of muscle can be evaluated in vivo with new noninvasive methods that measure chemical fluxes during exercise. The combination of phosphorus magnetic resonance spectroscopy (31P MRS) and exercise protocols that fully recruit muscle fibers permits quantification of the major components of energy metabolism, oxidative and glycolytic ATP supply and contractile ATP demand, in exercising muscle in vivo (2, 7). Validation of these measurements comes from isolated and intact muscle studies that have shown a close agreement between MRS-determined fluxes and direct measurements of O2 consumption and lactate flux during exercise (17, 27). These measurements are sensitive enough to detect individual differences in muscle properties (3), account for declines in muscle function with aging (8, 9), and reveal adaptations of elderly muscle to exercise training (24).
The goal of this study was to determine whether muscle energetic properties are altered in humans with type 1 diabetes. We assessed the properties of the ankle dorsiflexor muscles of men with well-controlled diabetes and control subjects matched to the diabetic subjects by age and activity level. Our 31P MRS measurements of the three major energetic properties revealed significant alterations of the major pathways of ATP supply in muscle: a higher glycolytic flux and lower oxidative capacity in diabetic subjects relative to control subjects.
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METHODS |
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Subjects.
We selected diabetic patients on the basis of three criteria. The first
was good clinical control, as defined by two criteria set by the
American Diabetes Association (25): 1)
hemoglobin A1c levels of 7% and 2) a lack of
glucose in the urine. The second was an absence of serious medical
conditions such as cardiovascular or musculoskeletal disease. The third
was an age range of mid-20s to mid-40s. It was not possible to recruit
10 inactive subjects with these three recruitment constraints from our
pool of volunteers. Instead, we formed sedentary and active groups of
subjects and matched control subjects to the diabetic patients on the
basis of age and activity levels. The physical characteristics
of our groups are listed in Table 1. The
age range of subjects was 23-45 yr, and the mean age difference
within each patient-control pair was 2.5 ± 0.6 (SE) yr. Our
sedentary group had no habitual physical activity and no job with
physical demands (5 pairs). Our active group had two activity levels:
1) they were recreationally active 1-2 times/wk or had
a job with physical demands (2 pairs), or 2) they were
active 2-9 h/wk (2 pairs) or competitive athletes (1 pair).
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Experimental setup and data acquisition. Our setup was essentially the same as previously described (12), except that six subjects (3 diabetic and 3 control subjects) were studied with a General Electric Signa 1.5 Tesla spectrometer, and the rest were studied with a Bruker 4.7 Tesla spectrometer. Each subject lay supine with his right leg (4.7 T spectrometer) or entire body (1.5 T spectrometer) in the bore of the magnet. The right leg and foot were held in place with a plastic holder to which a strain gauge was attached. The strain gauge measured the force exerted by the ankle dorsiflexor muscles and was linked to a computer running LabView data acquisition software (National Instruments, Austin, TX). A surface coil tuned to the resonating frequency of phosphorus was placed over the anterior compartment of the right leg. 31P MR spectra of the ankle dorsiflexors were then acquired with the surface coil, as previously reported (10). Briefly, a high-resolution control spectrum of the resting muscle was acquired under conditions of fully relaxed nuclear spins (interpulse delay: 16 s). Sequential spectra were then obtained under partially saturating conditions (interpulse delay: 1.5 s) throughout the experimental protocols (see Exercise protocol). The spectrum for each time point consisted of four summed acquisitions taken over 6 s or eight summed acquisitions taken over 12 s.
Analysis of spectra. Free-induction decays were summed, baseline-corrected, line-broadened, and Fourier-transformed into spectra. Areas of phosphorus peaks in the fully relaxed spectra were measured using Omega software (GE Medical Systems, Waukesha, WI). Resting phosphocreatine (PCr)/ATP and Pi/ATP ratios were determined from the relative areas of the appropriate peaks. PCr peaks of partially saturated spectra were analyzed with the "Fit-to-Standard" program (20), and absolute PCr concentrations were then calculated using the PCr/ATP and Pi/ATP ratios of the fully relaxed spectra with the assumption that the muscle [ATP] was 8.2 mM (18). The sum of Pi + phosphomonoesters was assumed to increase stoichiometrically with decreases in PCr, as previously demonstrated (1, 7, 12). The chemical shift of the Pi peak relative to PCr was used to calculate muscle pH (44). Because the Pi peak was often split during exercise, the "MRUI" program was used to fit two peaks to the Pi signal in all spectra, and the average muscle pH was computed as a weighted average of the pH values of the two peaks.
Exercise protocol. Subjects exercised by performing voluntary isometric dorsiflexions against the resistance of the plastic footholder. Subjects attempted to maintain a constant force of 70-75% of their maximal voluntary contraction (MVC) force using visual feedback from a light-emitting diode display. All subjects performed a single sustained contraction lasting 120 s, during which contractile costs and glycolytic flux were quantified. Glycolytic H+ production during this contraction drove muscle pH to levels known to inhibit oxidative phosphorylation (17, 46); therefore, oxidative phosphorylation was quantified during recovery from a shorter (30-s) contraction, during which the muscle pH remained close to 7.0. Fourteen subjects (7 diabetic and 7 control subjects) performed this 30-s contraction in addition to the 120-s one. These subjects performed the 30-s and 120-s contractions on the same day. They were given >12 min of recovery time between exercise bouts.
Calculations. Contractile cost was quantified as the decline in [PCr] during the first 15 s of exercise, during which time there was little PCr resynthesis by glycolysis. We assumed oxidative ATP production during this period to be negligible, because intense continuous contractions occlude blood flow and thus prevent O2 delivery to the muscle (5, 16).
Glycolytic H+ production during exercise was calculated as the observed change in H+ concentration plus the H+ consumed in the breakdown of PCr, as previously described (7)
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(1) |
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(2) |
Statistics. Values reported are means ± SE. Differences between groups were assessed for statistical significance with two-tailed paired t-tests unless otherwise indicated. We tested for the effects of activity level on our group comparisons using a two-factor ANOVA. The time of the significant rise of glycolytic flux above zero was determined using one-tailed t-tests with a sequential Bonferroni correction for multiple comparisons (38). Significance was assigned at the 0.05 level.
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RESULTS |
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Resting muscle.
No differences were seen in resting PCr/ATP ratios for the muscle of
control subjects [4.08 ± 0.12 (CON)] vs. muscle of diabetic patients [4.16 ± 0.11 (DIA)] or in resting Pi/ATP
ratios [0.45 ± 0.05 (CON) vs. 0.40 ± 0.02 (DIA)]. Figure
1A shows spectra of resting
muscle in single subjects from each group. The Pi peak is
expanded in Fig. 1B to show the significant difference in
resting muscle pH between the groups [7.02 ± 0.02 (CON) vs.
6.96 ± 0.01 (DIA)].
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Muscle force, metabolite, and pH changes.
The MVC force was not significantly different between the two groups
[301.2 ± 24.2 N (CON) vs. 334.3 ± 32.4 N (DIA)]. Figure 2, A-C, shows the
isometric force, [PCr], and pH during the 120-s isometric contraction
of individual muscles for a representative matched pair of a control
subject and a diabetic patient. The decline in force below the target
level (70-75% of MVC force) indicates that the two groups
fatigued to a similar extent by the end of exercise [Fig.
2A; 33.6 ± 4.9% of MVC (DIA) vs. 40.6 ± 3.0%
of MVC (CON); P = 0.28]. The [PCr] decline was
similar during exercise for the control and diabetic muscles and
resulted in similar end-exercise values [Fig. 2B; 6.3 ± 1.4 mM (DIA) vs. 6.7 ± 1.2 mM (CON); P = 0.97]. Figure 2C shows that pH dropped more rapidly with
exercise in the DIA compared with CON muscle, with the result that the
end-exercise muscle pH was significantly lower in DIA (6.44 ± 0.07) than in CON (6.64 ± 0.04; P = 0.0164). Figure 1C shows that the Pi peak at the end of
exercise expanded to demonstrate the chemical shift differences that
reflect the disparity in intracellular pH between the control subject
and the diabetic patient. Four DIA and two CON subjects showed a
splitting of the Pi peak, indicative of different pH levels
among distinct populations of fibers. The pH value for these subjects
was the pH of each Pi peak weighted by its respective area.
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Glycolysis.
The accumulated glycolytic flux as a function of time is shown in Fig.
3. The difference in muscle pH dynamics
with exercise is due in part to an earlier onset of glycolytic flux
during exercise in DIA relative to CON. A significant rise in
glycolytic H+ production was observed at 15 s of
exercise for DIA and at 27 s of exercise for CON.
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Contractile costs. The similar PCr dynamics shown in Fig. 2B resulted in contractile costs for CON (0.71 ± 0.12 mM ATP/s) and DIA (0.98 ± 0.08 mM/s) that were not significantly different.
Oxidative properties.
A second experiment, involving a shorter muscle contraction and a
subset of subjects (n = 7), was used to deplete PCr
without significantly changing pH. The end-exercise pH for both groups [7.04 ± 0.02 (CON) and 6.96 ± 0.05 (DIA)] was well above
the pH (i.e., 6.8) at which PCr recovery rate is affected (33,
46). Figure 5 shows the oxidative
PCr recoveries following this 30-s contraction for individual muscles
from a representative matched CON and DIA pair. Each individual's
recovery was fit to a monoexponential curve from which the oxidative
recovery rate constant (kPCr) was derived as
previously described (9). Figure
6 shows the mean and individual values
for low- vs. high-activity subjects in each group. The
kPCr was significantly higher for CON
(0.025 ± 0.003 s1) vs. DIA (0.017 ± 0.002 s
1) in a paired comparison (P < 0.05).
This disparity in oxidative properties was also reflected in the
oxidative capacity of the muscles [0.80 ± 0.07 mM/s (CON) and
0.61 ± 0.09 mM/s (DIA)].
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DISCUSSION |
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The key findings of this paper are significant differences in energetic fluxes during exercise in muscle of type 1 diabetic patients vs. control subjects. Altered glycolytic metabolism was evident both at rest and during exercise. A significantly lower pH at rest and at the end of exercise indicated a greater reliance on glycolytic metabolism in the muscles of the diabetic patients. In addition, oxidative recovery was slower after exercise, indicating a lower oxidative capacity in the diabetes-affected muscles. These alterations in metabolic flux are the first reported differences in muscle energetic properties in type 1 diabetes vs. control subjects, but they are consistent with the increased ratio of glycolytic to oxidative enzyme activity reported in obesity and type 2 diabetes. Thus muscle from type 1 diabetic patients under good clinical control shows significant alteration in energetic properties with changes in common with obesity and type 2 diabetes.
Subjects.
Our diabetic patients were screened for well-managed disease and an age
range that avoided subjects with a high risk of cardiovascular complications. These criteria prevented us from recruiting 10 sedentary
patients from our volunteer population. Instead, we matched our
patients to control subjects to reduce the effects of two factors known
to affect muscle properties: age and activity. Prior studies of
diabetic muscle properties have typically selected patients without
carefully screening for activity (23, 42) or included
active patients with "no more than two exercise sessions weekly on a
regular basis" (19). We chose to closely match patients to control subjects to eliminate any bias due to activity and used a
sample size similar to that in other studies of muscle properties in
types 1 and 2 patients (42, 45, 47). This matching
permitted us to take into account the role of chronic activity level in
the variation in the energetic properties of a muscle. The variation in
properties apparent in Figs. 4 and 6 is somewhat greater than the
nearly twofold range for contractile costs and oxidative recovery rates
that we have found among normal individuals (3) and
reflects the range of chronic activity levels in this study. The fact
that we could distinguish muscle properties between the two groups with
a sample size of 10 subjects emphasizes the effectiveness of matching
to activity level to reduce this contribution to the individual
variation in muscle properties. We avoided additional screening factors
such as body mass, which is not known to affect muscle properties
[except in obesity, and our patients' average body mass index
(BMI = 28) was well below the threshold for this malady (i.e., BMI
>30)]. We also did not match subjects by
O2 max to avoid obscuring the
diabetes-induced differences in the muscle oxidative properties that we
sought to study.
Methodology.
Our exercise protocol was designed to achieve a high rate of muscle
energy use, to eliminate blood flow without the possible complications
of a tourniquet, and to minimize any effect of blood-borne substrates
or hormones. A continuous contraction resulted in a high contractile
ATP use above the oxidative capacity (see Muscle glycolytic
properties) and ensured cessation of O2 delivery,
since blood flow ceases at force levels as low as 30% of MVC force
(5, 16). This high exercise flux has been shown to rely
nearly entirely on intracellular and not blood-borne substrates
(11). For example, indirect calorimetry studies of control
and diabetic subjects at 70% of
O2 max show that muscle glycogen
and lipid comprise >80% of the fuel for contraction
(35). This intracellular substrate use and the lack of
blood flow mean a negligible contribution of blood-borne substrates and
hormone effects on substrate flux in our protocol.
Muscle glycolytic properties.
A difference in glycolytic metabolism in the diabetic vs. control
muscle is apparent both at rest and in exercise. At rest, muscle pH was
significantly lower by a small amount (pH = 0.06) in the
diabetic muscle (Fig. 1). A similar, small disparity was reported in
resting diabetic rodent muscle (6) and in vitro cells
deprived of insulin (32). Moore (32) suggests
that this disparity seen in cells in vitro reflects the role of insulin in ion transport in cells. Such a role of insulin in muscle is also
plausible given recent findings that glycolysis is linked to ion
pumping in isolated skeletal muscle (23).
Oxidative capacity.
We performed a short (30-s) exercise bout with a subset of our subjects
(n = 7/group) to follow the recovery of PCr after exercise as a measure of the muscle oxidative capacity (Fig. 5). The
short exercise bout of this experiment avoided the large pH drop known
to inhibit PCr recovery (33, 46) that occurred in our
longer exercise protocol. The PCr recovery rate constant in our control
subjects' muscles (0.025 s1) was similar to that
obtained by Kent-Braun and Ng (28) in male control
subjects with no chronic activity and of similar age [0.027
s
1 (converted to kPCr from
half-time)]. However, these kPCr are well below the values reported in the tibialis anterior of collegiate athletes specializing in sprint (0.032 s
1) and distance
running (0.050 s
1) (13). Thus the
kPCr in our type 1 diabetic subjects (0.017 s
1) is low compared with age- and activity-matched
control subjects, and well below athletic subjects, indicating a
reduced oxidative capacity as a result of the diabetes (Fig. 6).
Metabolic profile.
The higher glycolytic flux and lower oxidative capacity reported here
are consistent with the greater lactate generation and reduced
O2 max seen in age- and
activity-matched type 1 diabetic patients (34, 48). These
results suggest a shift in muscle metabolic profile of muscle in type 1 diabetics patients similar to the increased glycolytic-to-oxidative
enzyme activity ratio seen in muscle fibers of obese and type 2 diabetic individuals (19). This shift in metabolic profile
is consistent with a greater predominance of the fast-twitch,
glycolytic fiber type, but several studies indicate metabolic
properties are more plastic than the fiber type. The increased lipid
content and reduced oxidative enzyme activity found in obese and type 2 diabetic muscle was found in all fiber types (19).
Similarly, an increase in oxidative capacity in all fiber types has
been reported with endurance training (22). Thus
alteration of the metabolic profile found here does not require changes
in muscle fiber type.
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ACKNOWLEDGEMENTS |
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We thank E. G. Shankland for assistance with MRS data acquisition and D. J. Koerker for editorial comments.
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FOOTNOTES |
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This research was supported by National Institute of Arthritis and Musculoskeletal and Skin Diseases Grants AR-41928 and AR-45184 and by the Diabetes Endocrinology Research Center Grant no. 5-P30-DK-17047. G. J. Crowther was supported in part by a National Science Foundation predoctoral fellowship.
Address for reprint requests and other correspondence: K. E. Conley, Dept. of Radiology, Box 357115, Univ. of Washington Medical Center, Seattle, WA 98195-7115 (E-mail: kconley{at}u.washington.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00343.2002
Received 1 August 2002; accepted in final form 18 December 2002.
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