Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232
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ABSTRACT |
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The aim of this study was to determine
barriers limiting muscle glucose uptake (MGU) during increased glucose
flux created by raising blood glucose in the presence of fixed insulin.
The determinants of the maximal velocity (Vmax)
of MGU in muscles of different fiber types were defined.
Conscious rats were studied during a 4 mU · kg1 · min
1
insulin clamp with plasma glucose at 2.5, 5.5, and 8.5 mM.
[U-14C]mannitol and
3-O-methyl-[3H]glucose ([3H]MG)
were infused to steady-state levels (t =
180 to 0 min). These isotope infusions were continued from 0 to 40 min with the addition of a 2-deoxy-[3H]glucose ([3H]DG)
infusion. Muscles were excised at t = 40 min. Glucose
metabolic index (Rg) was calculated from
muscle-phosphorylated [3H]DG.
[U-14C]mannitol was used to determine extracellular (EC)
H2O. Glucose at the outer ([G]om) and inner
([G]im) sarcolemmal surfaces was determined by the ratio
of [3H]MG in intracellular to EC H2O and
muscle glucose. Rg was comparable at the two higher glucose
concentrations, suggesting that rates of uptake near
Vmax were reached. In summary, by defining the relationship of arterial glucose to [G]om and
[G]im in the presence of fixed hyperinsulinemia, it is
concluded that 1) Vmax for MGU is
limited by extracellular and intracellular barriers in type I fibers,
as the sarcolemma is freely permeable to glucose; 2) Vmax is limited in muscles with predominantly
type IIb fibers by extracellular resistance and transport resistance;
and 3) limits to Rg are determined by resistance
at multiple steps and are better defined by distributed control rather
than by a single rate-limiting step.
extracellular, intracellular water; glucose analogs; rat
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INTRODUCTION |
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MUSCLE GLUCOSE UPTAKE (MGU) requires three serial steps. These steps are delivery of glucose to the muscle, transport of glucose across the sarcolemma, and phosphorylation of glucose intracellularly. Because membrane permeability is low, transport is considered rate limiting for MGU in the basal state. This is not the case under all physiological conditions. Transport is increased during conditions such as hyperinsulinemia (16, 17, 36, 41) and exercise (16, 17, 21) to the point that delivery of glucose to muscle or glucose phosphorylation within muscle becomes a control point of greater significance. The limitations that define the maximal capacity of the muscle to take up glucose during physiological hyperinsulinemia (Vmax) remain to be determined. It is important to understand the factors that determine the Vmax for insulin-stimulated MGU under normal conditions, because a reduction in this variable is a charactistic of insulin-resistant conditions (3).
Because the factors that determine the capacity for MGU involves the integration of many systems, it must be examined in vivo to be fully understood. We learned from our previous studies (18, 19) how barriers to MGU are affected by an increase in insulin. Here, we challenged the pathway for MGU by altering substrate (i.e., blood glucose) in the presence of fixed hyperinsulinemia. These studies utilized an isotopic technique that provides functional indexes of muscle glucose delivery, transport, and phosphorylation in the conscious, unstressed rat. The advantage of the rat model is that some muscles have a predominance of specific fiber types, allowing for effects of fiber type-specific changes to be assessed. The purpose of this study was to determine in vivo the muscle fiber type-specific barriers to insulin-stimulated glucose uptake at Vmax.
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METHODS |
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Animal maintenance and surgical procedures. Male Sprague-Dawley rats were individually housed in cages at 23°C on a 0600-1800 light cycle. The rats were fed chow consisting of 65% carbohydrate, 11% fat, and 24% protein. Rat weight and food consumption were closely monitored, and a food consumption index (FCI: weight gained/food eaten) was calculated. The rats had free access to chow until 6:00 PM the evening before the study.
After reaching a weight of 250-300 g, rats were anesthetized with a intraperitoneal injection of ketamine, rompun, and acepromazine (50:5:1) and underwent surgical placement of polypropylene catheters (0.58 mm ID × 0.97 mm OD) using sterile procedures. A catheter was inserted in the left carotid artery and advanced so that its tip lay at the aortic arch. A second catheter was inserted in the right jugular vein and advanced to the entrance of the right atrium. The free catheter ends were tunneled under the skin and externalized between the scapulae on the back. Catheters were filled with heparinized saline and capped. The rats were administered 40,000 U of penicillin G and 5 ml of saline subcutaneously after surgery. All procedures were in accordance with the guidelines of the National Institutes of Health and the Vanderbilt University Animal Care and Use Committee.Experimental procedures.
Rats were used for experiments upon restoration of weight and FCI to
presurgery levels (~7 days postoperative). Rat weights, fasting
plasma insulin, and fasting plasma glucose were within normal ranges
and equivalent in all groups. Experiments consisted of primed infusions
of 3-O-methyl-D-[3H]glucose
([3H]MG; 25 µCi primer and 150 µCi/min infusion) and
[U-14C]mannitol ([14C]MN; 3.5 µCi/min
primer and 60 µCi/min) beginning at t = 180 min
(Fig. 1). At t = 0 min,
an infusion of deoxy-[2-3H]glucose ([3H]DG)
infusion (900 mCi/min) was started. All isotope infusions were
continued until the end of the study (t = 40 min). A
4.0 mU · kg
1 · min
1
intravenous insulin infusion was started at t =
100
min, and arterial plasma glucose was clamped at ~8.5
(n = 8), ~5.5 (n = 7), or ~2.5 mM
(n = 7). The insulin infusion rate used was selected because it results in arterial concentrations in the upper
physiological range. These clamps provided a range of physiological
glucose concentrations (mild hyperglycemia to moderate hypoglycemia). The high-glucose clamp was chosen to create a blood glucose that would
cause near-maximal MGU for a given insulin level so that the site that
limits this process could be identified.
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Analytical procedures. Plasma insulin was assessed via radioimmunoassay (32). Plasma glucose concentrations were measured via a glucose oxidase method with an automated glucose analyzer (Beckman Instruments, Fullerton, CA). Corticosterone levels were determined by competitive binding assay. Norepinephrine and epinephrine levels were measured via high-pressure liquid chromatography (31, 36, 44).
The measurement of the radioactivity of [14C]MN, [3H]MG, and [3H]DG in muscle and plasma was performed as has been described previously (19). Briefly, muscle and plasma samples were incubated with and without yeast hexokinase and treated with Ba(OH)2 and ZnSO4. Yeast hexokinase phosphorylates >99% of [2-3H]DG to [2-3H]DGP, and >98% of the [2-3H]DGP is removed by the addition of Ba(OH)2 and ZnSO4, according to tests done in our laboratory. Tests in our laboratory also revealed that treatment of samples with yeast hexokinase resulted in the phosphorylation of ~25% of the [3H]MG (19). Because both muscle and plasma samples were similarly affected, this does not appreciably change the calculated value of the steady-state ratio of [3H]MG in intracellular to extracellular water; therefore, no correction for this was necessary. Tissue radioactivity and glucose concentrations were measured in neutralized 0.5% perchloric acid extracts. Samples were double-label counted using a Packard Tri-Carb 2900TR liquid scintillation counter. [3H] and [14C] counting windows were defined on the basis of known spectra and correction for isotopic spillover and quenching based on relationships defined in our laboratory for the Packard Tri-Carb. Tissue glucose concentration is expressed as millimoles of muscle water, assuming a muscle water content of 0.75 ml/g (based on measurements performed in our laboratory).Calculations. The fraction of extracellular to total water space in biopsies (Fe) was calculated with [14C]MN as described previously (16). An index of MGU (Rg) was calculated from phosphorylated [3H]DG, the integrated plasma [3H]DG concentration over the infusion period, and the plasma glucose concentration (23).
The steady-state ratio of [3H]MG concentration in intracellular to extracellular water was determined to calculate the glucose concentration at the outer face of the sarcolemma ([G]om) and the glucose concentration at the inner face of the sarcolemma ([G]im), described in detail previously (36) as have been their theoretical bases (8, 11, 16, 19, 29, 34, 36). The ratio of [3H]MG in intracellular and extracellular water (Si/So) is used to derive [G]om and [G]im by the countertransport equation Si/So = (Km + [G]im)/(Km + [G]om), where Km is the Michaelis-Menten constant for glucose transport. A range of 2-5 mM has been reported for the Km of GLUT4 in vitro (15, 37). A Km of 2.6 mM was estimated in previous work using the same methodology as in the present studies (19) and was used. The use of different values for Km in calculations has a quantitative effect on the calculated results but not a qualitative effect (36). The calculation described above defines the mathematical relationship between [G]om and [G]im but not in the actual values. Because of the presence of glucose gradients, it is impossible to directly measure the true glucose concentration at the sarcolemma or anywhere in the interstitial or intracellular space. An approach for calculating limits for the average [G]om based on two theoretical glucose distributions was used (17, 19, 36). In the first calculation of [G]om, [G]im is assumed to be localized to such a small volume of the intracellular water that it contributes only negligibly to the total muscle glucose mass (denoted by ![]() |
RESULTS |
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Arterial plasma glucose and hormone concentrations.
The average steady-state plasma glucose concentrations were not
significantly different from the target glucose concentrations of 2.5, 5.5, and 8.5 mM (Fig. 2). Insulin levels
were in the upper physiological range (~120 µU/ml) during all
clamps, with no significant differences between groups (Fig. 2). Table
1 shows that the epinephrine, norepinephrine, and corticosterone levels were significantly increased during the 2.5 mM glucose clamp experiment compared with the 8.5 mM
glucose clamp experiment (P < 0.05).
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Glucose infusion rate.
The glucose infusion rates (Fig. 3)
increased significantly with glucose clamp concentrations. The increase
was most sensitive between 2.5 and 5.5 mM glucose clamp concentrations
(increment of 126 µmol · kg1 · min
1).
The increment in glucose infusion rate was only 38 µmol · kg
1 · min
1
between 5.5 and 8.5 mM glucose clamps, indicating that whole body
glucose kinetics were approaching Vmax.
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Skeletal muscle Rg.
Rg (Fig. 3) was 6.0 ± 0.6, 30.2 ± 3.8, and
26.7 ± 2.6 µmol · kg1 · min
1
in soleus; 5.6 ± 1.7, 10.3 ± 0.8, and 12.3 ± 1.4 µmol · 100 g
1 · min
1 in
gastrocnemius; and 3.2 ± 0.6, 10.7 ± 1.3, and 11.4 ± 2.1 µmol · 100 g
1 · min
1 in SVL at
2.5, 5.5, and 8.5 mM glucose clamps, respectively. Rg was
consistently two- to threefold higher in soleus compared with
gastrocnemius and SVL at all glucose clamp levels. There was no
significant difference between Rg at the two highest
glucose clamp concentrations. The plateau seen at the two higher
glucose clamps suggest that Vmax for MGU had
been obtained or was approached in each muscle.
Skeletal muscle glucose concentrations, extracellular water space,
and Si/So.
The total glucose concentration in soleus homogenates rose
significantly with increasing glucose clamp levels (Table
2). The total glucose concentration in
gastrocnemius was significantly higher at the 8.5 mM glucose clamp
compared with the 2.5 mM glucose clamp. There were no significant
differences in SVL glucose concentration between different glucose
clamp experiments. Soleus glucose concentrations were approximately
twofold higher than that in the other two muscles at the 8.5 mM glucose
clamp level.
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Muscle [G]om and [G]im.
Because it is based on the premise that intracellular glucose is
localized to such a small space that it contributes only negligibly to
the total muscle glucose mass, the -distribution gives
[G]om and [G]im values that are greater
than those of the
-distribution, which assumes that glucose is
distributed evenly throughout the intracellular water.
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DISCUSSION |
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Barriers to insulin-stimulated MGU were defined in the present
study by relating increments in arterial glucose to changes in the
"intermediates" of the glucose uptake pathway (i.e.,
[G]om and [G]im) at a fixed
hyperinsulinemia. The highest arterial glucose clamp level was
sufficient to elicit an MGU that was at or near the
Vmax of this process. The premise is that the
greatest barrier to MGU will have the steepest glucose gradient across
it. The drop in glucose concentration from artery to muscle surface
(arterial glucose [G]om) is a reflection of the
capillary bed/extracellular diffusion barrier to glucose uptake,
whereas the drop in concentration across the sarcolemma
([G]om
[G]im) is a reflection of
the transport barrier to glucose uptake. Because [G]im is
the substrate for the irreversible, intracellular metabolism of
glucose, its value alone is an index of the importance of the
phosphorylation barrier to glucose uptake. This approach assumes that
glucose fluxes through the steps that comprise MGU are similar in a
steady state. The effect of increasing substrate availability on
limitations to MGU is evident from the relationships of
[G]om and [G]im to arterial glucose (Figs.
4-6). Changes in [G]om were significantly dampened in relation to a given change in arterial glucose, clearly
demonstrating vascular/extracellular resistance to MGU in all fiber
types. Changes in [G]im in relation to changes in
arterial glucose were the same as those for [G]om in type
I muscle fibers, indicating that membrane transport does not create an
added barrier to MGU under the conditions of the present study. In
muscles with a high percentage of type IIb fibers, [G]im
did not increase, as did [G]om, with increasing arterial glucose. This indicates that, in contrast to type I fibers, the membranes of muscles consisting predominantly of type IIb fibers
are barriers to MGU. The fact that [G]im rose with
increasing arterial glucose in soleus is indicative of a barrier at
glucose phosphorylation in muscle consisting predominantly of type I
fibers. Such a barrier was not existent in muscle consisting of a
predominance of type IIb fibers, as [G]im did not rise
with increasing arterial glucose. The relative association among
[G]om, [G]im, and arterial glucose was
independent of whether the
-distribution (glucose confined to
neglible intracellular volume) or
-distribution (glucose evenly
distributed intracellularly) of intracellular glucose was assumed.
Previous work (36) showed that the sarcolemma of type I
muscle fibers is freely permeable to glucose at the insulin infusion rate used in these studies (4 mU · kg1 · min
1).
The equivalent relationships of [G]om and
[G]im to arterial glucose in Fig. 4 extend this finding
by demonstrating that the sarcolemma of the soleus does not become a
site of resistance to MGU during physiological hyperinsulinemia at
glucose concentrations that create a range of glucose fluxes that
extend from ~20% of Vmax to
Vmax. Limitations to insulin-stimulated MGU at
rates of uptake that approach Vmax in type I
fibers of the soleus are those factors required to sustain the
transsarcolemmal glucose gradient (i.e., glucose delivery to muscle and
intracellular glucose phosphorylation). The transsarcolemmal glucose
gradient in muscle containing a preponderance of type IIb fibers was
consistently greater than zero at all glucose concentrations despite
the hyperinsulinemia, indicating that the sarcolemma was a significant
barrier to MGU at all glucose concentrations. These findings are
consistent with a study that showed that GLUT4 protein was closely
coupled to glucose uptake in rat muscle consisting of type II fibers
but was disassociated from glucose uptake in muscle consisting of type
I fibers (42). One reason for this could be that the
greater number of GLUT4 transporters in type I fibers (30)
creates a situation wherein membrane transport is not a limitation even
at high rates of insulin-stimulated glucose uptake.
The ability to sustain a glucose gradient across the sarcolemma is
dependent on the ability to deliver glucose to the muscle and
phosphorylate glucose once it is within the cell. Muscle
perfusion/extracellular diffusion was a determinant of
Vmax to MGU in all muscles. The barrier role of
the extracellular space is reflected by the fact that
[G]om did not increase proportionally to the increment in arterial glucose in any of the muscles studied. [G]om
rose by only ~40-60% of the increment in arterial glucose
assuming the - distribution and by only ~20-40% assuming the
-distribution. This is consistent with the work of Baron
(2). The difference between the increment in arterial
glucose and the increments in [G]om was similar in
muscles, regardless of predominant fiber type. Because, however, the
glucose flux rate (Rg) in type I fibers of the soleus was
so much higher, the extracellular barrier to muscle glucose uptake must
be much less. This is consistent with the greater vascularization and
the associated shorter extracellular diffusion distances of muscles
comprised of slow-twitch fibers (39).
The second determinant of the glucose gradient across the sarcolemma, the effectiveness with which glucose is phosphorylated after it crosses the sarcolemma, showed considerable fiber type dependence. The barrier role of glucose phosphorylation in the soleus was evident by the significant increment in [G]im that occurred when glucose concentration approached Vmax. In contrast to the soleus, phosphorylation was not a major site of resistance to MGU in the gastrocnemius and SVL, which are both composed primarily of type IIb fibers, at Vmax. Type I muscle fibers of the soleus have ~30% more hexokinase activity than the gastrocnemius and ~80% more hexokinase activity than the SVL (35). The difference in glucose uptake in soleus is even higher than in gastrocnemius and SVL (~240% higher; Fig. 3). Thus, although hexokinase activity is higher in type I fibers, rates of glucose delivery and transport into this muscle are even greater. It is not surprising, when one considers these factors, that phosphorylation is a greater barrier in soleus.
The advantage of glucose flux measurements in vivo is that a true functional measure of glucoregulation is obtained, inclusive of all circulatory and neural factors. At the lowest plasma glucose concentration (2.5 mM), epinephrine, norepinephrine, and cortisol were increased due to hypoglycemic stimulation. It is possible that epinephrine in particular could have acutely attenuated MGU and affected its determinants. The transsarcolemmal glucose gradient and [G]im were not increased at the lowest glucose concentration, indicating that neither transport nor phosphorylation was markedly impaired by the counterregulatory response in any of the muscles studied. This may not reflect the absence of physiological regulation so much as the manifestation of offsetting physiological effects. Epinephrine has been shown to reduce insulin-stimulated glucose transport by inhibiting the intrinsic activity of the transporter (20) and phosphorylation by causing a buildup of glucose 6-phosphate (6). [G]om did not fall disproportionately to circulating glucose at the lowest glucose clamp concentration, so it is unlikely that extracellular barriers are increased relatively more compared with euglycemic levels. These studies suggest that the decrease in MGU during hypoglycemia is primarily a result of the decreased arterial glucose concentration and the associated mass action effect.
Total soleus and gastrocnemius glucose concentrations rose significantly with arterial glucose concentrations, whereas total SVL glucose concentration was not significantly affected by the clamp glucose concentration. The increase in glucose concentration in soleus was most marked, as it obtained levels approximately twofold greater than the two muscles comprised predominantly of type IIb muscle fibers. It is not surprising that soleus glucose concentration more closely paralleled arterial glucose concentration, because a greater fraction of soleus water volume is extracellular (Table 2). Although measurements of total muscle glucose are informative in and of themselves, they alone do not provide insight into glucose concentration in the muscle intracellular space. Estimates of intracellular glucose concentration require that interstitial glucose be known. Use of blood glucose concentrations in place of interstitial glucose (46) leads to erroneous estimates, as muscle interstitial glucose concentration is well below arterial or venous plasma concentrations (25). Glucose concentration gradients may also exist within the intracellular space as physical barriers, and spatial glucose gradients may compartmentalize glucose. This is supported by evidence that glucose transporters (10, 12, 27, 28, 30) and hexokinases (4, 22, 24, 26, 40, 43) are localized to specific regions within the skeletal muscle cell. The uncertainties created by extracellular and intracellular glucose gradients are circumvented with the use of [3H]MG. Because 3-O-MG is not metabolized, it is homogenous within the contiguous extracellular and intracellular spaces when it is at equilibrium in the blood.
The modeling approach used in this study allows for estimation of intracellular glucose concentrations. Three markedly different modeling approaches have been conducted utilizing data from rats (13, 45) or humans (5) in addition to the model used here. The results from all of these studies indicate that factors other than transport are significant barriers to insulin-stimulated glucose uptake. The model used here is based on principles of glucose countertransport, a concept that has been applied to study diverse model systems (7, 9, 11, 14, 29, 33, 34, 38). The linking of the transmembrane glucose distribution to 3-O-MG countertransport assumes that 1) glucose and 3-O-MG share the same transport system; 2) the reaction between carrier and sugar is rapid compared with carrier mobility; 3) the relative affinity of each sugar for the transport proteins is the same on the extracellular and intracellular sides of the plasma membrane; and 4) carrier mobility is independent of whether or not the transporter is bound to either sugar. The validity of these assumptions has been discussed in detail previously (11, 36).
A surprising finding in these studies is that Fe rose significantly with decreasing glycemia in the SVL, which consists of type IIb (99%) fibers, and there was a trend for such an increase in the gastrocnemius, which also consists of type IIb (71%) fibers, albeit somewhat less than the SVL. The reason for this rise in Fe specifically in type I muscle fibers has not, to our knowledge, been described. It is unlikely that the trend of a reduced Fe at higher glucose levels is due to a general systemic alteration of either physiological or technical origin, since no such effect was seen in the type I soleus muscle. It is possible that there is relative swelling of type IIb muscle cells at high compared with low glucose concentrations. One could postulate that this might be due to increased Na+-K+-ATPase and/or increased glycogen storage. Again, there is no immediate explanation for the fiber type heterogeneity of this response. It may be significant that the increased Fe at the lower glucose clamp corresponds to an increased counterregulatory response. One could speculate that a reduction in cell volume is a consequence of the resultant hormonal changes that occur with hypoglycemia, with different fiber type endocrine sensitivities causing the discrepancy in type I, type IIa, and type IIb fibers. Although the blood glucose-related changes in Fe do not alter the calculations of [G]om and [G]im to the extent that they affect the conclusions of these studies, it may reflect an as yet undefined response to a decrement in blood glucose.
Skeletal muscle comprises ~50% of total body mass and exhibits the greatest increases in glucose uptake in response to insulin. Knowledge of the regulation of skeletal muscle glucose uptake, therefore, is a prerequisite to understanding normal and pathophysiological whole body glucose uptake. These studies provide insight into the barriers that limit MGU during increased glucose flux created by raising blood glucose concentration in the presence of fixed insulin (~120 µU/ml) by showing that 1) MGU is at or near Vmax, with only modest hyperglycemia in muscle consisting predominantly of type I fibers (soleus) and type IIb fibers (gastrocnemius and SVL); 2) membranes of type I fibers are freely permeable to glucose at Vmax, suggesting that extracellular (glucose delivery to muscle) and intracellular (glucose phosphorylation) resistances limit MGU; and 3) Vmax is limited in muscles that consist predominantly of type IIb fibers by extracellular resistance and to a lesser extent transport resistance, whereas intracellular resistance plays a relatively small role. In conclusion, the mechanisms that limit MGU at Vmax are complex and may be determined at multiple sites that are critically dependent on fiber type.
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ACKNOWLEDGEMENTS |
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We thank Eric Allen, Angie Penalosa, and Wanda Snead for expert technical assistance.
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FOOTNOTES |
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This work was supported by grants from the Juvenile Diabetes Foundation International and National Institute of Diabetes and Digestive and Kidney Diseases Grants RO1-DK-47344 and P60-DK-20593.
Address for reprint requests and other correspondence: D. H. Wasserman, Dept. of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232.
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.00323.2002
Received 18 July 2002; accepted in final form 16 October 2002.
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