Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
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ABSTRACT |
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Skeletal muscle glucose uptake requires delivery of glucose to the sarcolemma, transport across the sarcolemma, and the irreversible phosphorylation of glucose by hexokinase (HK) inside the cell. Here, a novel method was used in the conscious rat to address the roles of these three steps in controlling the rate of glucose uptake in soleus, a muscle comprised of type I fibers, and two muscles comprised of type II fibers. Experiments were performed on conscious rats under basal conditions or during hyperinsulinemic euglycemic clamps. Rats received primed, constant infusions of 3-O-methyl-[3H]glucose (3-O-MG) and [1-14C]mannitol. Total muscle glucose concentration and the steady-state ratio of intracellular to extracellular 3-O-MG concentration, which distributes based on the transsarcolemmal glucose gradient (TSGG), were used to calculate glucose concentrations at the inner and outer sarcolemmal surfaces ([G]im and [G]om, respectively) in muscle. Muscle glucose uptake was much lower in muscle comprised of type II fibers than in soleus under both basal and insulin-stimulated conditions. Under all conditions, the TSGG in type II muscle exceeded that in soleus, indicating that glucose transport plays a more important role to limit glucose uptake in type II muscle. Although hyperinsulinemia increased [G]im in soleus, indicating that phosphorylation was a limiting factor, type II muscle was limited primarily by glucose delivery and glucose transport. In conclusion, the relative importance of glucose delivery, transport, and phosphorylation in controlling the rate of insulin-stimulated muscle glucose uptake varies between muscle fiber types, with glucose delivery and transport being the primary limiting factors in type II muscle.
glucose delivery; glucose phosphorylation; 3-O-methylglucose; 2-deoxyglucose
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INTRODUCTION |
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SKELETAL MUSCLE GLUCOSE UPTAKE requires delivery of glucose to the sarcolemma, transport across the sarcolemma, and the irreversible phosphorylation of glucose by hexokinase (HK) inside the muscle cell. Because these three processes are so tightly coupled, it is difficult to determine the role of each of these steps in controlling the rate of muscle glucose uptake in vivo. Glucose transport is usually asserted to be the rate-determining step for muscle glucose uptake under basal and insulin-stimulated conditions (1, 15, 39). This assertion is based primarily on the fact that calculations of free intracellular glucose from biochemical or nuclear magnetic resonance spectroscopy measurements of total (intra- plus extracellular) muscle glucose typically result in very low or negative values. This approach requires precise knowledge of the amount of glucose in the various extracellular fluid compartments (e.g., arterial and capillary plasma, interstitial fluid) and does not take into account the presence of glucose gradients or the possibility that any intracellular glucose is not equally distributed throughout the intracellular water. An alternative approach is the measurement of the steady-state distribution of a nonmetabolizable glucose analog across the sarcolemma, which allows the calculation of the transsarcolemmal glucose gradient (TSGG) (9, 10, 31). Using this approach, we have previously demonstrated that physiological increments in insulin result in a narrowing of the TSGG in rat soleus muscle, as the increase in sarcolemmal permeability is not accompanied by proportional increases in glucose delivery and/or phosphorylation (31). These data are consistent with glucose transport not being the single rate-determining step of soleus glucose uptake and glucose transport exerting less control over the rate of this process as the insulin concentration increases.
There are reasons to believe that the processes that limit muscle glucose uptake may be fiber type specific. It is well known that slow-twitch, highly oxidative (type I) fibers have a greater capillary density and blood flow (14, 18, 19, 22), express more GLUT-4 protein (11, 36) and have greater HK activity (30) than the fast-twitch, glycolytic type II fibers. These characteristics potentially allow for increased glucose flux at each step of muscle glucose uptake (glucose delivery, sarcolemmal transport, and intracellular metabolism) in type I compared with type II fibers, consistent with the higher insulin sensitivity of type I fibers (9, 14). What is not known is whether the decreased capillary density, GLUT-4, and HK activity of muscle comprised of type II fibers alter the relative importance of each of these processes in controlling the rate of glucose uptake. We have previously demonstrated that decreases in muscle glucose concentration occur in response to increases in plasma insulin concentration in muscles comprised of type II fibers, despite the fact that the rates of glucose uptake are dramatically reduced compared with the soleus. This suggests that muscle glucose delivery may be a greater limitation on muscle glucose uptake in type II fibers (10, 31). The purpose of these experiments, therefore, was to compare the roles of glucose delivery, transport, and phosphorylation in the control of muscle glucose uptake in muscles comprised of type II (gastrocnemius and superficial vastus lateralis) and type I fibers (soleus) under basal and insulin-stimulated conditions.
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MATERIALS AND METHODS |
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Animal maintenance and surgical procedures.
Male Sprague-Dawley rats (Sasco, Omaha, NE) were individually housed at
23°C on a 0600-1800 light cycle and allowed free access to water
and Purina Rodent Chow. Rats were housed under these conditions for
~1 wk, by which time their weights had reached 250-300 g.
Catheters were inserted under anesthesia in the left common carotid
artery and the right jugular vein (10). After surgery,
animal weights and food intake were monitored daily, and only animals
in which presurgery weight was restored were used for experiments (5
days). All procedures were preapproved by the Vanderbilt University
Animal Care and Use Subcommittee and followed National Institutes of
Health guidelines for the care and use of laboratory animals.
Experimental procedures.
Food was removed from rats ~2 h before the beginning of a study. Rats
were studied either under basal conditions or during a hyperinsulinemic
euglycemic clamp. Experiments were performed as described previously
(10), except that the length of isotope infusions was
increased from 140 to 340 min to ensure steady-state conditions in the
muscles comprised of fast-twitch fibers. At t = 300
min, primed infusions of [1-14C]mannitol
([14C]MN) and
3-0-methyl-[3H]glucose (3-0-MG)
were initiated. 3-0-MG is a substrate for glucose transport but is not further metabolized in skeletal muscle, whereas [14C]MN is restricted to the extracellular space and thus
can be used to measure this space. At t =
100 min, an
infusion of insulin (1.0 mU · kg
1 · min
1) was begun
in the rats studied under hyperinsulinemic conditions. From
t = 0-40 min, a constant rate infusion of
2-deoxy-[1,2-3H]glucose (2-DG) was given to allow for the
calculation of a glucose uptake index (17). All
radioisotopes were obtained from New England Nuclear (Boston, MA).
Arterial blood samples for tracer and/or insulin analyses were taken at
t =
300,
240,
180,
120,
70,
40,
10, 1, 2.5, 5, 7.5, 10, 15, 20, 25, 30, and 40 min. Washed erythrocytes from
the experimental animal and whole blood from a donor rat were used to
maintain hematocrit, but neither was infused after t =
10 min. At t = 40 min, the animal was rapidly anesthetized with intravenous pentobarbital sodium (~25 mg/kg), and
the soleus (comprised of type I, or slow-twitch oxidative, fibers),
gastrocnemius (comprised of types IIa and IIb, or fast-twitch oxidative
and fast-twitch glycolytic, fibers, respectively), and superficial
vastus lateralis (superficial vastus; comprised of type IIb fibers)
muscles were excised and frozen in liquid nitrogen within 10 s
of removal from the animal. Rats were then administered a lethal
dose of pentobarbital sodium intravenously (~125 mg/kg).
Processing of blood and muscle samples. Plasma glucose concentrations were measured by the glucose oxidase method by means of an automated glucose analyzer (Beckman Instruments, Fullerton, CA), and immunoreactive insulin was measured using a double-antibody method (24). A HK method was used to distinguish radioactivity from [14C]MN, 3-O-MG, and 2-DG in muscle and plasma, as has been described previously (9). Tests in our laboratory revealed that treatment of samples with yeast HK resulted in the phosphorylation of ~25% of the 3-O-MG. Because both muscle and plasma samples were similarly affected, this did not appreciably change the calculated value of the steady-state ratio of 3-O-MG in intracellular to extracellular water (Si/So); therefore, no correction for this was necessary. Tissue radioactivity and glucose concentrations were measured in neutralized 0.5% perchloric acid extracts. Tissue glucose concentration is expressed as millimoles per liter of muscle water, assuming a muscle water content of 0.75 ml/g (based on previous measurements performed in our laboratory; data not shown).
Calculations. The fraction of extracellular to total water space in biopsies (Fe) was calculated with [14C]MN as described previously (10). An index of muscle glucose uptake (Rg) (17) was calculated from phosphorylated 2-DG species within muscle, the integrated plasma 2-DG concentration over the infusion period, and the plasma glucose concentration. Rg may underestimate the actual rate of glucose uptake, because phosphorylation by HK may favor glucose over 2-DG (4, 23); however, Rg is still useful as an index of muscle glucose uptake.
In these experiments, Si/So is determined to calculate the glucose concentration at the outer face of the sarcolemma ([G]om), the glucose concentration at the inner face of the sarcolemma ([G]im), and the TSGG. Si is the arterial plasma 3-O-MG concentration (in dpm/µl), and So is the intracellular water 3-O-MG concentration (in dpm/µl). Si/So can be calculated as
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Statistical analyses.
Statistical significance for single comparisons was determined using
Student's t-test (differences between basal and
insulin-stimulated values) or one-factor ANOVA (differences between
muscles), using Fisher's protected least significant difference test
as a post hoc test. For comparison of ranges defined by - and
-boundaries ([G]im, [G]om, and TSGG),
one-factor ANOVA was used to compare data sets consisting of both
-
and
-values for each group. Differences were considered
statistically significant at P < 0.05. Data are expressed as means ± SE.
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RESULTS |
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Animal characteristics and glucose clamps.
Rats used for the basal and hyperinsulinemic clamp experiments weighed
~300 g. Arterial plasma glucose concentration over the final 40 min
of the experiments was 7.1 ± 0.4 mM in the basal experiments and
7.8 ± 0.3 mM in hyperinsulinemic experiments. During infusion of
insulin, 15.9 ± 2.2 mg · kg1 · min
1 of glucose
were required to maintain euglycemia.
Muscle glucose, Rg, and
Si/So.
Total glucose concentration did not differ between the
homogenates of different muscles under basal conditions (Table
1). Hyperinsulinemic euglycemia
resulted in a significant fall in muscle glucose concentration in both
the soleus and gastrocnemius muscles (P < 0.05).
Muscle glucose concentration tended to decrease in response to
hyperinsulinemia in superficial vastus, but this did not reach
statistical significance (P = 0.059). When muscle glucose concentrations were expressed relative to arterial plasma glucose, however, all three muscles displayed a significant decrease in
glucose concentration in response to hyperinsulinemia (data not shown).
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Effect of Km value on calculated regional glucose
concentrations.
Shown in Fig. 1 are values of
[G]
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Ranges for [G]om and
[G]im.
Shown in Fig. 2 are the ranges for
[G]om and [G]im, with the bars being
limited by the means of the calculations performed using the -
and
-assumptions. Because these represent the minimal and maximal
possible mean values, the true values for [G]om and [G]im fall somewhere within the bars. As can be seen in
Fig. 2, top, the range for [G]om under both
basal and insulin-stimulated conditions is greater in gastrocnemius and
superficial vastus, the two muscles comprised of type II fibers. This
is the case even though the total glucose masses are similar in the
three muscles due to the lower Fe in the gastrocnemius and
superficial vastus (Table 1). Also evident from Fig. 2, top,
is that the range for [G]om is decreased by insulin in
all three muscles, with a greater fall in the poorly perfused type II
muscles.
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Range for the TSGG.
The TSGG is the difference between the glucose concentrations at the
outer and inner surfaces of the sarcolemma. A greater value for the
TSGG means that transport of glucose across the sarcolemma is playing
an important role in controlling the rate of muscle glucose uptake.
Shown in Fig. 3 are the ranges for the TSGG bounded by the mean values calculated using the - and
-assumptions. In response to the hyperinsulinemic clamp, the TSGG is
significantly decreased in all three of the muscles studied, which is
consistent with the greater degree of membrane permeability due to
translocation of GLUT-4 to the sarcolemma. In contrast to soleus, where
the TSGG is essentially zero under hyperinsulinemic conditions, the TSGG is still ~2-3 mM in the gastrocnemius and superficial
vastus with insulin. Therefore, glucose transport is still an important barrier to glucose uptake in these muscles comprised of type II fibers.
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DISCUSSION |
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The purpose of these experiments was to determine the muscle fiber type-specific roles of glucose delivery, transport, and phosphorylation in controlling the rate of muscle glucose uptake under basal and insulin-stimulated conditions in vivo. It has previously been demonstrated that pre- and posttransport steps are important determinants of the rate of glucose uptake in the soleus, a muscle comprised of type I fibers, especially under insulin-stimulated conditions (9, 10, 31). In the experiments presented here, a 5-h 40-min equilibration period [~3-fold greater than in previous studies (6, 9, 10, 31)], which is approximately five half-lives for the plasma 3-O-MG pool (38), was used to ensure a steady state in all muscle fiber types. The data from the present experiments show that, in muscles comprised of type II fibers, glucose transport is the primary rate-determining step of glucose uptake under basal conditions. Under hyperinsulinemic euglycemic clamp conditions, glucose delivery to the sarcolemma of type II fibers becomes a second important factor in limiting uptake. In contrast to the data from soleus, glucose phosphorylation does not seem to play a major role in determining the rate of uptake in the gastrocnemius and superficial vastus.
Two findings contributed to the conclusion that glucose delivery is a limiting factor for muscle glucose uptake under hyperinsulinemic euglycemic clamp conditions: a modest fall in total muscle glucose relative to the arterial plasma glucose concentration (which is independent of the isotope method) and a decrease in the calculated values for [G]om. For either muscle glucose or [G]om to fall in response to an increase in insulin, the rate of metabolism of glucose by the muscle (i.e., removal of glucose from the interstitial water and its subsequent phosphorylation) must exceed the rate at which the interstitial glucose is replenished. Direct measurements of the interstitial glucose concentration by microdialysis have shown significantly larger gradients between arterial plasma glucose and interstitial glucose concentrations in response to euglycemic hyperinsulinemia in rat (12) and human (13, 26) skeletal muscle as well. This is not surprising, because it is well established that insulin increases the fractional extraction of glucose by muscle in vivo (34). What has not been appreciated is that decreases in the extracellular glucose concentration may have an impact on the rate of insulin-stimulated glucose uptake, as the calculated values for [G]om (or those measured with microdialysis) are close to those for the Km of GLUT-4 for glucose (8, 29).
On the basis of the fall in [G]om shown in the present study, glucose delivery is a limiting factor for muscle glucose uptake in both type I and type II fibers. Total muscle blood flow per gram of tissue, measured in conscious animals with the use of radioactive microspheres, is approximately threefold greater in soleus than in gastrocnemius and superficial vastus (14). In addition, the capillary density is known to be much higher in the soleus than in muscle comprised of type II fibers, with capillary density being inversely proportional to the distance a molecule of glucose must travel from the capillary to reach the sarcolemma. For example, rat soleus muscle contains approximately five capillaries per fiber, whereas the plantaris muscle (which is similar in fiber type to the mixed gastrocnemius) contains only two capillaries per fiber (35). It should be noted that the hyperinsulinemic euglycemic clamp differs from the normal physiological state, in which hyperinsulinemia is coupled with hyperglycemia. Therefore, after feeding, the increase in plasma glucose may offset the fall in interstitial glucose observed under clamp conditions.
As shown in Fig. 3, the TSGG is higher under both basal and insulin-stimulated conditions in muscle comprised of type II fibers than it is in the soleus, highlighting the importance of glucose transport in controlling the rate of muscle glucose uptake. The high value for TSGG under basal conditions in type II fibers is consistent with the fact that the primary glucose transporter expressed in muscle, GLUT-4, is present in the sarcolemma only in very low concentrations under basal conditions (8), resulting in a membrane with low permeability to glucose under these conditions. This is in contrast to the soleus, where greater [G]im at any given value of Km (Fig. 1) and decreased basal TSGG (Fig. 3) indicate that glucose transport plays a lesser role in determining the rate of uptake under basal conditions. The TSGG was decreased by hyperinsulinemia in all muscles studied, consistent with the increased glucose permeability of the sarcolemma as GLUT-4 translocation increased. The fact that the TSGG does not approach zero in type II muscles may relate to the lower expression of GLUT-4 in these muscles (11).
It is important to understand how glucose uptake is regulated in muscles comprised of different fiber types. One reason for this is the correlation between muscle fiber type and the insulin-resistant state. It has been demonstrated that insulin resistance is associated with a muscle comprised of higher percentage of type II fibers as well as decreased capillary density in muscle (19, 20). The rat model is advantageous in that certain muscles are relatively homogeneous in fiber composition, which allows for the type of mechanistic studies of the steps that limit glucose uptake that we have performed in these experiments. The data we have collected in the rat suggest that delivery of glucose to the sarcolemma may therefore be an important functional limitation to glucose uptake in insulin-resistant individuals; further experiments in humans will be important to further define the functional implications of the increased percentage of type II fibers.
In muscles comprised of type II fibers, glucose delivery and glucose transport both serve to limit the rate of insulin-stimulated muscle glucose uptake. This is unlike the soleus, in which relatively moderate hyperinsulinemia increases the permeability of the sarcolemma to the degree that pre- and posttransport steps are the determinants of the rate of glucose uptake. These data support the hypothesis that interventions that are designed to increase the rate of glucose uptake in insulin-resistant muscle but focus solely on the transport step may not yield maximal benefit.
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ACKNOWLEDGEMENTS |
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This work was supported by grants from the Juvenile Diabetes Foundation International and by National Institutes of Health Grant RO1 DK-54902.
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Halseth, Pharmacia Corp., 800 N. Lindbergh Blvd., Mail Zone T1G, St. Louis, MO 63167 (E-mail: amy.e.halseth{at}pharmacia.com).
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.
Received 24 October 2000; accepted in final form 5 February 2001.
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