It has been known since early in this century that endurance training alters the rates at which various fuels are used during exercise. As early as 1939, for example, Christensen and Hansen (5) observed that training reduced the respiratory exchange ratio during strenuous exercise, indicative of a decrease in carbohydrate oxidation and a corresponding increase in fatty acid oxidation. Subsequent studies using more invasive procedures have demonstrated a slower decline in muscle glycogen concentration(9,20-23,30,32,36) and a more rapid utilization of intramuscular triglycerides(20,21) and/or plasma free fatty acids(23,36) during exercise in the trained state. By postponing depletion of the body's limited carbohydrate reserves, this training-induced shift in substrate source plays an important role in enhancing an individual's capacity to perform prolonged exercise.
As indicated above, the training-induced decline in carbohydrate oxidation is largely a result of a decrease in muslce glycogen utilization. However, recent studies have demonstrated that, at least in humans, training also reduces the production(7,11,28,30,32) and utilization(7,8,11,21,28,30,32,36) of plasma-borne glucose during exercise. Notably, the latter is true not only during moderate exercise performed at the same absolute intensity (i.e., at the same absolute power output or rate of oxygen uptake (˙VO2)) before and after training(7,11,28,30,32), but also during intense exercise performed at the same relative intensity (i.e., at the same percentage of maximal oxygen uptake (˙VO2max)) in the untrained and trained states (8). Moreover, this adaptation is often just as important as the decrease in muslce glycogenolysis in accounting for the overall carbohydrate sparing effect of endurance training(7,11,21,28,30,32,36). This recent research is the focus of this review.
ENDURANCE TRAINING AND GLUCOSE UTILIZATION DURING EXERCISE
Although direct data are relatively recent, it has long been suspected that training diminished the reliance on plasma glucose as an energy source during work (cf. 18). This hypothesis arose primarily from the observation that trained animals used less liver glycogen than did untrained animals during a standardized bout of exercise(1,15). Nevertheless, early studies of humans using the arteriovenous (a-v) balance approach were unable to detect any effect of training on the rate of limb glucose uptake during exercise(17,34). The one-legged training programs used in these studies were limited, however, and resulted in only minimal changes in other indices of muscle carbohydrate utilization (e.g., respiratory quotient, glycogen utilization). Perhaps more importantly, because of the high blood flow the a-v difference for glucose across exercising muscle is quite small(i.e., 0.1-0.3 mmol·L-1, or 2-5 mg·dL-1). Hence, even a large training-induced reduction in muscle glucose uptake would result in only a small absolute decrease in glucose extraction. Even a 33% decline in glucose uptake, for example, would reduce the a-v glucose difference by<0.1 mmol·L-1, or by <2 mg·dL-1. Thus, in light of subsequent data (discussed below) it seems likely that these early investigators simply overlooked a training-induced decrease in muslce glucose utilization during exercise. Consistent with this interpretation, a later cross-sectional study demonstrated that the rate of leg glucose uptake was significantly lower in highly trained cyclists than in untrained men during exercise at 65-70% ˙VO2max (21). Still, because this difference could also have been a result of other factors (e.g., genetics, diet), the effects of training on glucose utilization during exercise remained somewhat ambiguous.
The limitations of these earlier studies led us to reinvestigate the effects of training on glucose metabolism during exercise using tracer dilution methodology (7). This approach was chosen not only for its high sensitivity, but also because it allowed simultaneous assessment of the effect of training on both glucose utilization and glucose production during prolonged exercise, the latter of which had not been studied previously. Furthermore, by using carbon-labeled glucose, it was possible to determine the rate of glucose oxidation (as opposed to just uptake), and thereby directly quantify the contribution of glucose to oxidative energy metabolism during exercise in the untrained and trained states.
In this study (7), seven healthy but initially untrained men cycled for 120 min at 60% of ˙VO2max, with the rates of appearance (Ra), disappearance (Rd), and oxidation of plasma glucose measured using a primed, constant infusion of [U-13C]glucose. The men were then retested during exercise performed at the same absolute power output after they had completed 12 wk of strenuous endurance training. During the final 30 min of exercise, steady-state glucose Ra and Rd were ≈30% lower in the trained state (Fig. 1). The decrease in Rd must have been a result of diminished tissue(presumably muscle; see below) glucose demand and was not simply a result of reduced glucose availability resulting from the lower Ra, because the rate of glucose clearance (i.e., Rd/plasma glucose concentration) was also ≈30% lower after training. Since essentially all of the glucose taken up during exercise was oxidized, both before and after training, the rate of glucose oxidation fell by a similar extent (Fig. 2). Interestingly, this decline in glucose oxidation accounted for just over one-half of the overall training-induced reduction in total carbohydrate oxidation, as estimated using indirect calorimetry. This was so even though muscle glycogen appeared to be the major source of carbohydrate energy during exercise in both the untrained and trained states.
This study was therefore the first to show that training reduces the Rd of plasma glucose during prolonged exercise, a finding that has been confirmed in a number of subsequent investigations(11,28,30,32). These more recent studies have also established that this adaptation is evident throughout exercise (11,28,30,32), as well as very early in training (i.e., after only 10 d) (28,30). Although the site of this reduction in glucose uptake cannot be determined from such whole body data, tissues other than exercising muscle (e.g., the brain) are known to account for ≤ 15% of total glucose disposal during moderate exercise (25). It is, therefore, clear that the 30-50% decline in glucose Rd that results from training must be the result, at least in part, of a decrease in muscle glucose uptake. This conclusion is further supported by recent cross-sectional studies using the traditional a-v balance approach (21,36), which have consistently observed lower rates of limb glucose uptake in trained compared with untrained persons. The latter is particularly true beyond the first 30-60 min of exercise, when differences in whole body glucose Rd are also the greatest(10,11,28,30,32). As discussed above, the failure of one-legged training studies(17,23,34) to yield the same result is probably simply a result of an inadequate training stimulus coupled with the limited sensitivity of the a-v balance method.
These subsequent investigations(11,28,30,32) have also confirmed the original finding that, after the initial stages of exercise, the reduction in glucose utilization can account for roughly one-half of the training-induced decrease in total carbohydrate oxidation. In one recent study(28), for example, 10 d of training reduced the overall rate of carbohydrate oxidation during 120 min of exercise at 60%˙VO2max from 124 ± 8 to 111 ± 10μmol·min-1·kg-1, or by 13 ± 5μmol·min-1·kg-1. At the same time, glucose Rd (and therefore probably glucose oxidation; cf.6) fell from 37 ± 4 to 29 ± 4μmol·min-1·kg-1, or by 8 ± 2μmol·min-1·kg-1. After 12 wk of training, total carbohydrate oxidation had fallen by 36 ± 7μmol·min-1·kg-1, whereas glucose Rd had decreased by 15 ± 4 μmol·min-1·kg-1. Again, similar results have been obtained in recent cross-sectional studies that have used the a-v balance method to assess total carbohydrate oxidation and glucose uptake by the exercising limbs (21,36). Thus, even though muscle glycogen is generally the major source of carbohydrate energy during exercise, much of the overall carbohydrate-sparing effect of endurance training is due to reduced uptake and oxidation of plasma glucose. In this sense, training can be considered to result in a“preferential” sparing of plasma glucose during exercise(7). As a result, plasma glucose concentration tends to decrease less during prolonged exercise in the trained state(7,10,26,28,30,32).
Although the studies discussed above have clearly established that training reduces the rate of glucose utilization during moderate intensity exercise, they do not provide any insight into the mechanism by which this occurs. In general, though, training-induced alterations in substrate metabolism during exercise are though to be largely a result of an increase in muscle mitochondrial content, which minimizes the disturbance to cellular energy homeostasis during exercise (cf. 18). In keeping with this concept, when two groups of subjects equal in ˙VO2max but differing in muscle respiratory capacity (as indicated by citrate synthase(CS) activity) were studied during 90 min of exercise at 55%˙VO2max, the rate of glucose oxidation was 25% lower in the group with the higher muscle CS activity (10). The percentage of total energy derived from plasma glucose was also inversely related to muscle CS activity when the data were considered on an individual basis(Fig. 2). Similarly, McConnell et al.(27) recently observed an inverse relationship (r =-0.72; P < 0.05) between glucose Rd and muscle CS activity in a heterogeneous group of men cycling for 40 min at 75% ˙VO2max. These findings support the hypothesis that the reduction in glucose utilization with training is related to the increase in muscle respiratory enzyme activity. Phillips et al. (30), on the other hand, recently reported that short-term (10 d) training reduced the rate of glucose utilization during moderate intensity exercise even in the absence of a training-induced increase in muscle respiratory capacity. Others, however, have found significant increases in muscle mitochondrial marker enzyme activities with similar short-term training programs(4A,34A). Moreover, as reported elsewhere(31) the subjects in the study of Phillips et al.(30) did exhibit a training-induced attenuation in the fall in muscle phosphocreatine and rise in inorganic phosphate during exercise, which is consistent with the notion that the decline in glucose utilization with training is related to an improvement in muscle energetics. Thus, the recent data of Phillips et al. (30) do not necessarily conflict with the above hypothesis.
Despite such studies, the specific step at which training affects glucose use by muscle during exercise remains to be determined. A number of years ago it was proposed (18) that training reduced muscle glucose uptake and oxidation (as well as glycogen utilization) during exercise via operation of the glucose-fatty acid cycle (33), i.e., via citrate-mediated inhibition of phosphofructokinase (PFK) and, consequently, inhibition of glucose phosphorylation. Indeed, recent studies have found that muscle citrate concentration tends to be higher during exercise in the trained state (9,21,32). However, these same studies have also shown that muscle glucose-6-phosphate concentration is actually lower during exercise after training, which is inconsistent with a training-induced inhibition of PFK. Furthermore, training increases muscle hexokinase activity (9,29), which makes a training-induced inhibition of glucose phosphorylation during exercise also seem unlikely. It has therefore been hypothesized(7,12) that the decrease in glucose uptake and oxidation with training is the result of a reduction in the rate of glucose transport. This hypothesis may at first seem contradictory, since the number of glucose transporters in skeletal muscle is higher in the trained state(19). However, an increase in total transporter number does not rule out the possibility that training somehow reduces activation of the glucose transport process itself during exercise. (In fact, McConnell et al. (27) recently demonstrated a strong inverse relationship between total muscle glucose transporter content and the rate of glucose uptake during exercise.) Unfortunately, testing this hypothesis will be difficult because of the technical challenge of measuring muscle glucose transport and/or glucose transporter recruitment in exercising humans. Furthermore, studies of rats (e.g., 35) are unlikely to yield any useful information in this regard, because in this species training does not affect the clearance of glucose from plasma during exercise(3,13,35). Ipso facto, the rat cannot be used as a model for determining the mechanism by which training reduces the rate of glucose utilization during exercise.
ENDURANCE TRAINING AND GLUCOSE PRODUCTION DURING EXERCISE
During moderate intensity exercise, the lower glucose Rd after training is accompanied by smaller rise in glucose Ra (7,11,28,30,32). The magnitude of this decline in glucose production (i.e., up to 40%) is greater than the expected contribution from gluconeogenesis (i.e., 15-20%)(6), implying that training reduces the rate of hepatic glycogen breakdown during exercise. However, training-induced changes in glucoregulatory hormone concentrations during exercise (i.e., higher isulin and lower glucagon and catecholamine concentrations (28)) should affect gluconeogenesis as well as glycogenolysis. Furthermore, training reduces the availability (i.e., the plasma concentration) of lactate and glycerol, the two most important gluconeogenic precursors during exercise (cf.6). The rate of gluconeogenesis would therefore also be expected to be lower after training.
To test these hypotheses, we recently examined the specific effect of training on the different pathways of hepatic glucose production(11). As in our previous studies, subjects were studied during 120 min of exercise at 60% of ˙VO2max, both before and after 12 wk of training. The overall Ra of glucose was determined using a primed, continuous infusion of [6,6-2H]glucose, while the rate of gluconeogenesis was determined from the incorporation of 13C into glucose from simultaneously infused [13C]bicarbonate. (Although bicarbonate is not a gluconeogenic precursor in a net sense, glucose becomes labeled as a result of pyruvate carboxylation and subsequent isotopic exchange in the tricarboxylic acid cycle.) The rate of hepatic glycogenolysis was then estimated from the difference between these two measurements. As expected based on prior research (7,10,28), training markedly diminished the overall Ra of glucose during exercise(Fig. 3). The rate of 13C incorporation into glucose was also considerably reduced, indicating that the decline in glucose production was a result, in part, of a decrease in the rate of gluconeogenesis during exercise (Fig. 3). The latter most likely reflects a reduction in glucose synthesis from lactate since the latter accounts for almost all pyruvate-level gluconeogenesis during exercise (cf.6). Nevertheless, this decrease in gluconeogenesis could explain only about one-third of the overall training-induced decline in glucose production. Thus, the fall in glucose Ra with training appeared to be mostly the result of a slowing in the rate of hepatic glycogenolysis(Fig. 3).
The results of the study described above are therefore similar to previous investigations which have demonstrated that trained animals use less liver glycogen during work (1,15,35). However, the data seemingly conflict with studies of rats by Donovan and Sumida(14) indicating that training enhances the rate of gluconeogenesis during exercise. As indicated previously, though, rats appear to adapt differently than humans to the stress of endurance training, at least in terms of glucose metabolism. Specifically, in rats training does not affect the use of plasma glucose as a fuel during exercise(3,13,35), with the reduction in liver glycogenolysis apparently compensated for by an increase in gluconeogenesis(13). In contrast, in human training improves glucose homeostasis during prolonged exercise simply by reducing the rate of glucose utilization(7,8,10,11,21,28,30,32,36). This reduced demand for glucose apparently then allows for the lesser stimulation of glucose production via hepatic glycogenolysis and gluconeogenesis (11). As suggested previously(11), this differing strategy of adaptation may be a result of inherent differences between rats and humans in hepatic gluconeogenic capacity.
Like the mechanism accounting for the decline in glucose utilization, the mechanism responsible for the lower glucose production during exercise after training has not been firmly established. As mentioned previously, though, it seems probable that an attenuated counter-regulatory hormone response to exercise plays a significant role in explaining the smaller rise in glucose Ra in the trained state. Consistent with this is the fact that, during the initial stages of training (i.e., the first 1-4 wk), alterations in the major glucoregulatory hormones and in glucose Ra tend to parallel one another (28,32). Nevertheless, studies in which hormone concentrations are experimentally manipulated are still needed to directly test this hypothesis. Furthermore, glucose production during exercise continues to decrease as training is extended (e.g., to 12 wk;Fig. 4, even though circulating insulin, glucagon, and catecholamine concentrations remain unchanged (28). Thus, as previously discussed (28) other mechanisms (such as alterations in hepatic hormone sensitivity and/or responsiveness) must also contribute to the lower rates of hepatic glycogenolysis and gluconeogenesis observed during exercise in the trained state.
THE CROSSOVER CONCEPT
As reviewed above, it is now firmly established that endurance training of humans reduces glucose production and utilization during moderate intensity exercise performed at the same absolute intensity in the untrained and trained states. This experimental design has been used in almost all longitudinal training studies (cf. 12) because of the profound influence of absolute exercise intensity on the metabolic responses to exercise. (Indeed, to date only one study (26) has examined substrate metabolism in subjects exercising at the same relative intensity before and after training because the resulting large difference in absolute energy expenditure makes interpretation of physiological responses nearly impossible.) Nevertheless, it has been argued that these adaptations in glucose metabolism are restricted to these specific conditons and that during intense exercise performed at the same relative intensity, trained individuals actually use more glucose than do untrained individuals(4). This “crossover” hypothesis is based in part on the fact that trained muscle theoretically has a greater capacity to take up and oxidize glucose during exercise since training increases muscle glucose transporter number (19) and hexokinase activity(9,29) and reduces intramuscular glucose-6-phosphate concentrations during exercise(9,21).
To test this hypothesis, we developed a new tracer infusion protocol to improve estimation of glucose Ra and Rd under non-steady-state conditions such as intense exercise (16), and then used this new method to measure glucose kinetics in endurance-trained athletes and in untrained subjects cycling for 30 min at 80% of ˙VO2max (8). (Since the crossover concept emphasizes the importance of absolute power output as a determinant of substrate utilization during exercise, a cross-sectional design was used to maximize differences in absolute exercise intensity between the trained and untrained groups.) Unlike the training-induced decrease in glucose production observed during exercise performed at the same absolute intensity(7,11,28,30,32), during exercise at the same relative intensity glucose Ra was similar in the trained and untrained subjects (Fig. 5, middle). This is consistent with the fact that there were no differences between the two groups in circulating norepinephrine, epinephrine, glucagon, or insulin concentrations during exercise. It is important to note, however, that glucose Ra was not higher in the trained subjects, as predicted by the crossover concept (4), even though the absolute power output and ˙VO2 during exercise were 57 and 40% higher, respectively, in the trained subjects. Furthermore, the Rd of glucose was significantly lower in the athletes than in the nonathletes(Fig. 5, bottom). This was true even though the overall rate of carbohydrate oxidation during exercise was ≈25% higher in the trained subjects, as a result of their higher absolute energy expenditure. As a result of this imbalance between Ra and Rd, plasma glucose concentration rose significantly during exercise in the trained subjects, but did not change during exercise in the untrained subjects(Fig. 5, top).
Although it is possible that at least part of this difference in glucose Rd was due to factors other than training per se, the findings of this recent cross-sectional investigation (8) are consistent with previous longitudinal studies of lower intensity exercise(7,11,28,30,32). They are also in keeping with an earlier study by Kjær et al. (24), who found that glucose clearance (although not Rd) was significantly lower in endurance trained athletes than in untrained men during treadmill running at 100-110% ˙VO2max. Thus, the available data do not support the hypothesis that training enhances the rate of glucose utilization during high intensity exercise (4). This is true even though plasma glucose concentration tends to be higher in trained than in untrained subjects during intense exercise(2,8,24), as a result of an equal(8) or possibly even greater (24) rate of glucose production.
It has long been recognized that endurance trained individuals rely less on carbohydrate and more on fat as an energy source during submaximal exercise. This carbohydrate-sparing effect of training has generally been attributed to a training-induced decrease in the rate of muscle glycogen utilization during exercise. Recent studies have demonstrated, however, that a training-induced reduction in the rate of glucose utilization during exercise also plays a significant role. This is true not only during moderate intensity exercise performed at the same absolute intensity before and after training, but also during exercise performed at the same relative (and therefore a higher absolute) intensity in the trained compared to the untrained state. By minimizing the possibility of hypoglycemia, this adaptation likely contributes to the increase in exercise performance that results from endurance training.
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Keywords:©1997The American College of Sports Medicine
GLUCOSE UPTAKE; GLUCOSE PRODUCTION; GLYCOGENOLYSIS; GLUCONEOGENESIS; STABLE ISOTOPES