Glucose kinetics and substrate oxidation during exercise in the follicular and luteal phases.

The purpose of this investigation was to determine whether plasma glucose kinetics and substrate oxidation during exercise are dependent on the phase of the menstrual cycle. Once during the follicular (F) and luteal (L) phases, moderately trained subjects [peak O(2) uptake (V(O(2))) = 48.2 +/- 1.1 ml. min(-1). kg(-1); n = 6] cycled for 25 min at approximately 70% of the V(O(2)) at their respective lactate threshold (70%LT), followed immediately by 25 min at 90%LT. Rates of plasma glucose appearance (R(a)) and disappearance (R(d)) were determined with a primed constant infusion of [6,6-(2)H]glucose, and total carbohydrate (CHO) and fat oxidation were determined with indirect calorimetry. At rest and during exercise at 70%LT, there were no differences in glucose R(a) or R(d) between phases. CHO and fat oxidation were not different between phases at 70%LT. At 90%LT, glucose R(a) (28.8 +/- 4.8 vs. 33.7 +/- 4.5 micromol. min(-1). kg(-1); P < 0.05) and R(d) (28.4 +/- 4.8 vs. 34.0 +/- 4.1 micromol. min(-1). kg(-1); P < 0.05) were lower during the L phase. In addition, at 90%LT, CHO oxidation was lower during the L compared with the F phase (82.0 +/- 12.3 vs. 93.8 +/- 9.7 micromol. min(-1) .kg(-1); P < 0.05). Conversely, total fat oxidation was greater during the L phase at 90%LT (7.46 +/- 1.01 vs. 6.05 +/- 0.89 micromol. min(-1). kg(-1); P < 0.05). Plasma lactate concentration was also lower during the L phase at 90%LT concentrations (2.48 +/- 0.41 vs. 3.08 +/- 0.39 mmol/l; P < 0.05). The lower CHO utilization during the L phase was associated with an elevated resting estradiol (P < 0.05). These results indicate that plasma glucose kinetics and CHO oxidation during moderate-intensity exercise are lower during the L compared with the F phase in women. These differences may have been due to differences in circulating estradiol.

Fat metabolism during high-intensity exercise in endurance-trained and untrained men.

To determine whether trained individuals rely more on fat than untrained persons during high-intensity exercise, six endurance-trained men and six untrained men were studied during 30 minutes of exercise at 75% to 80% maximal oxygen consumption (VO2max). The rates of appearance (Ra) and disappearance (Rd) of glycerol and free fatty acids (FFAs) were determined using [1,1,2,3,3-2H]glycerol and [1-13C]palmitate, respectively, whereas the overall rate of fatty acid oxidation was determined using indirect calorimetry. During exercise, the whole-body rate of lipolysis (ie, glycerol Ra) was higher in the trained group (7.1 +/- 1.2 v 4.5 +/- 0.7 micromol x min(-1) x kg(-1), P < .05), as was the Ra (approximately Rd) of FFA (9.0 +/- 0.9 v 5.0 +/- 1.0 micromol x min(-1) x kg(-1), P < .001). FFA utilization was higher in trained subjects even when expressed as a percentage of total energy expenditure (10% +/- 1% v 7% +/- 1%, P < .05). However, this difference in plasma FFA flux could not account for all of the difference in fatty acid oxidation between trained and untrained subjects (20.8 +/- 3.3 v 7.9 +/- 1.6 micromol x min(-1) x kg(-1), or 23% +/- 3% v 13% +/- 2% of total energy expenditure, both P < .05). Thus, the oxidation of fatty acids derived from some other source also must have been greater in the trained men. We conclude that trained athletes use more fat than untrained individuals even during intense exercise performed at the same percentage of VO2max. The additional fatty acids appear to be derived from both adipose tissue and, presumably, intramuscular triglyceride stores.

Assessment of methods for improving tracer estimation of non-steady-state rate of appearance.

The most common approach for estimating substrate rate of appearance (R(a)) is use of the single-pool model first proposed by R. W. Steele, J. S. Wall, R. C. DeBodo, and N. Altszuler. (Am. J. Physiol. 187: 15-24, 1956). To overcome the model error during highly non-steady-state conditions due to the assumption of a constant volume of distribution (V), two strategies have been proposed: 1) use of a variable tracer infusion rate to minimize tracer-to-tracee ratio (TTR) variations (fixed-volume approach) or 2) use of two tracers of the same substrate with one infused at a constant rate and the other at a variable rate (variable-volume approach or approach of T. Issekutz, R. Issekutz, and D. Elahi. Can. J. Physiol. Pharmacol. 52: 215-224, 1974). The goal of this study was to compare the results of these two strategies for the analysis of the kinetics of glycerol and glucose under the non-steady-state condition created by a constant infusion of epinephrine (50 ng. kg(-1). min(-1)) with the traditional approach of Steele et al., which uses a constant infusion and fixed volume. The results showed that for glucose and glycerol the estimates of R(a) obtained with the constant and the variable tracer infusion rate and the equation of Steele et al. were comparable. The variable tracer infusion approach was less sensitive to the choice of V in estimating R(a) for glycerol and glucose, although the advantage of changing the tracer infusion rate was greater for glucose than for glycerol. The model of Issekutz et al. showed instability when the ratio TTR(1)/TTR(2) approaches a constant value, and the model is more sensitive to measurement error than the constant-volume model for glucose and glycerol. We conclude that the one-tracer constant-infusion technique is sufficient in most cases for glycerol, whereas the one-tracer variable-infusion technique is preferable for glucose. Reasonable values for glucose R(a) can be obtained with the constant-infusion technique if V = 145 ml/kg.

Use of stable isotopes to study carbohydrate and fat metabolism at the whole-body level.

The present review discusses the advantages and limitations of using stable-isotope tracers to assess carbohydrate and fat metabolism at the whole-body level. One advantage of stable- (v. radioactive-) isotope tracers is the relative ease with which the location of a label within a molecule can be determined using selected-ion-monitoring GC-mass spectrometry (SIM-GC-MS). This technique minimizes potential problems due to label recycling, allows the use of multiple-labelled compounds simultaneously (e.g. to quantify glucose cycling), and perhaps most importantly, has led to the development of unique stable-isotope methods for, for example, quantifying gluconeogenesis. However, the limited sensitivity of SIM-GC-MS sometimes requires that relatively large amounts of a stable-isotope tracer be used, thus increasing cost and potentially altering metabolism. At least theoretically, stable- (or radioactive-) isotope tracers can also be used in conjunction with indirect calorimetry to estimate utilization of muscle glycogen or triacylglycerol stores, thus potentially circumventing the need to obtain muscle biopsies. These calculations, however, require certain critical assumptions, which if incorrect could lead to major errors in the values obtained. Despite such limitations, stable-isotope tracers provide a powerful and sometimes unique tool for investigating carbohydrate and fat metabolism at the whole-body level. With continuing advances in availability, instrumentation and methods, it is likely that stable-isotope tracers will become increasingly important in the immediate future.

Training-induced alterations in fat and carbohydrate metabolism during exercise in elderly subjects.

Compared with young adults, fat oxidation is lower in elderly persons during endurance exercise performed at either the same absolute or relative intensity. We evaluated the effect of 16 wk of endurance training on fat and glucose metabolism during 60 min of moderate intensity exercise [50% of pretraining peak oxygen consumption (VO2peak)] in six elderly men and women (74 +/- 2 yr). Training caused a 21% increase in mean VO2peak. The average rate of fat oxidation during exercise was greater after (221 +/- 28 mumol/min) than before (166 +/- 17 mumol/min) training (P = 0.002), and the average rate of carbohydrate oxidation during exercise was lower after (3,180 +/- 461 mumol/min) than before (3,937 +/- 483 mumol/min) training (P = 0.003). Training did not cause a significant change in glycerol rate of appearance (Ra), free fatty acid (FFA) Ra, and FFA rate of disappearance during exercise. However, glucose Ra during exercise was lower after (1,027 +/- 95 mumol/min) than before (1,157 +/- 69 mumol/min) training (P = 0.01). These results demonstrate that a 16-wk period of endurance training increases fat oxidation without a significant change in lipolysis (glycerol Ra) or FFA availability (FFA Ra) during exercise in elderly subjects. Therefore, the training-induced increase in fat oxidation during exercise is likely related to alterations in skeletal muscle fatty acid metabolism.

Regulation of fatty acid oxidation in untrained vs. trained men during exercise.

We have recently shown that increased carbohydrate flux decreases fat oxidation during exercise by inhibition of fatty acid entry into the mitochondria. Because endurance training reduces the rate of carbohydrate flux during exercise, we hypothesized that training increases fat oxidation by relieving this inhibition. To test this hypothesis, five sedentary and five endurance-trained men exercised on a cycle ergometer at an oxygen consumption (VO2) of approximately 2.0 l/min, representing 80 and 40% peak VO2, respectively. [1-13C]oleate and [1-14C]octanoate, long- and medium-chain fatty acids, respectively, were infused for the duration of the studies. Carbohydrate oxidation was significantly higher in the sedentary group (196 +/- 9 vs. 102 +/- 17 mumol.kg-1.min-1, P < 0.05). Oleate oxidation was higher in the trained group (3.8 +/- 0.6 vs. 1.9 +/- 0.3 mumol.kg-1.min-1, P < 0.05), whereas octanoate oxidation was not different between the two groups. The percentage of oleate that was taken up by tissues and oxidized was higher in the trained group (76 +/- 7 vs. 58 +/- 3%, P < 0.05). However, the percentage of octanoate taken up and oxidized was not different (82 +/- 3 vs. 85 +/- 4%, not significant). Because octanoate, unlike oleate, can freely diffuse across the mitochondrial membrane, the present results suggest that the difference in fatty acid oxidation between trained and untrained individuals may be due to enhanced fatty acid entry into the mitochondria.

The glucose crossover concept is not an important new concept in exercise metabolism.

1. The basic premise of the 'crossover' concept (i.e. that the balance of carbohydrate (CHO) and fat utilization during exercise depends on the interaction between exercise intensity and the individual's endurance training status) has been accepted since at least the 1930s. 2. The crossover concept differs from earlier perspectives mostly in its greater emphasis on the absolute exercise intensity as an important determinant of substrate selection during exercise. Because of this emphasis, it is argued that while trained subjects may utilize less CHO than their untrained counterparts during low- or moderate-intensity exercise, this is not true during high-intensity exercise, because during such exercise even trained persons must 'crossover' to CHO dependency. In fact, the crossover concept predicts that utilization of at least one CHO source (i.e. plasma-borne glucose) should be greater in trained subjects during intense exercise. This increase in glucose utilization is hypothesized to be supported by an enhanced rate of gluconeogenesis. 3. In direct contradiction of the crossover concept, the literature consistently shows that, compared with untrained individuals, trained subjects rely less on CHO for fuel, even during high-intensity exercise. In particular, it has been shown that the rate of glucose utilization is lower in trained subjects under these conditions. Recent data from Dr Brooks' own laboratory support this conclusion and also show that this reduction in glucose use is associated with a decrease in the rate of gluconeogenesis. These recent observations confirm prior studies of moderate-intensity exercise. 4. Based on the above, it is clear that the crossover concept cannot be considered an important new concept in exercise metabolism. Instead, the crossover concept actually serves to hinder understanding in this area.

Regulation of glucose production during exercise at 80% of VO2peak in untrained humans.

To determine whether alterations in insulin and/or glucagon secretion play an important role in stimulating glucose production (Ra) during intense but submaximal exercise, we studied six untrained subjects during 30 min of cycling at 80% of peak oxygen uptake on two occasions: once under control conditions and once when alterations in insulin and glucagon secretion were prevented with the use of the pancreatic islet clamp technique. In the latter experiments, glucose was infused during exercise to match glycemia with control levels. Glucose kinetics were measured in both trials using a primed, continuous infusion of [6,6-2H]glucose. In the control trial, glucose Ra rose from 11.9 +/- 0.8 mumol.min-1.kg-1 at rest to 42.5 +/- 4.3 mumol.min-1.kg-1 by the end of exercise. A similar increment was observed in the islet clamp experiments, with endogenous Ra peaking at 37.2 +/- 7.9 mumol.min-1.kg-1. This was true even through glucagon concentration did not change from basal and insulin concentration actually rose (the latter apparently due to a decrease in insulin clearance during intense exercise). Thus neither decrements in insulin or increments in glucagon are apparently required to stimulate glucose Ra under the present conditions. Because epinephrine levels rose only slightly, it appears that either neurally released norepinephrine or some other, as yet unidentified, factor is responsible for stimulating glucose Ra during intense but submaximal exercise.

Plasma glucose metabolism during exercise: effect of endurance training in humans.

It has long been recognized that endurance training reduces the reliance on carbohydrate as a source of energy during submaximal exercise. Historically, this has been ascribed to a decrease in muscle glycogen utilization. However, recent studies have demonstrated that, at least in humans, training also reduces the production and utilization of plasma-borne glucose during exercise. The latter is true not only during moderate exercise performed at the same absolute intensity before and after training, but also during intense exercise performed at the same relative intensity in the trained and untrained states. Moreover, this adaptation is often quantitatively just as important as the decline in muscle glycogen utilization in accounting for the overall carbohydrate-sparing effect of training. This reduced reliance on plasma glucose, which appears to result from a decrease in muscle glucose transport, seems to be related to the training-induced increase in muscle mitochondrial respiratory capacity. On the other hand the training-induced decrease in glucose production (which is the result of reductions in both hepatic glycogenolysis and gluconeogenesis) is probably largely due to alterations in the glucoregulatory hormone response to exercise, although other factors (such as changes in hepatic hormone sensitivity and/or responsiveness) may also play a role. By minimizing the possibility of hypoglycemia, these adaptations in glucose production and utilization likely contribute to the increased endurance that results from exercise training.

Fat and carbohydrate metabolism during exercise in elderly and young subjects.

We evaluated the effect of aging on fat and carbohydrate metabolism during moderate intensity exercise. Glycerol, free fatty acid (FFA), and glucose rate of appearance (Ra) in plasma and substrate oxidation were determined during 60 min of cycle ergometer exercise in six elderly (73 +/- 2 yr) and six young adults (26 +/- 2 yr) matched by gender and lean body mass. The elderly group was studied during exercise performed at 56 +/- 3% of maximum oxygen uptake, whereas the young adults were studied during exercise performed at the same absolute and at a similar relative intensity as the elderly subjects. Mean fat oxidation during exercise was 25-35% lower in the elderly subjects than in the young adults exercising at either the same absolute or similar relative intensities (P < 0.05). Mean carbohydrate oxidation in the elderly group was 35% higher than the young adults exercising at the same absolute intensity (P < 0.001) but 40% lower than the young adults exercising at the same relative intensity (P < 0.001). Average FFA Ra in the elderly subjects was 85% higher than in the young adults exercising at the same absolute intensity (P < 0.05) but 35% lower than the young adults exercising at a similar relative intensity (P < 0.05). We conclude that fat oxidation is decreased while carbohydrate oxidation is increased during moderate intensity exercise in elderly men and women. The shift in substrate oxidation was caused by age-related changes in skeletal muscle respiratory capacity because lipolytic rates and FFA availability were not rate limiting in the older subjects.

Effect of theophylline on substrate metabolism during exercise.

We tested the hypothesis that adenosine is involved in regulating substrate metabolism during exercise. Seven trained cyclists were studied during 30 minutes of exercise at approximately 75% maximal oxygen uptake (VO2max). Lipid metabolism was evaluated by infusing [2H5]glycerol and [1-13C]palmitate, and glucose kinetics were evaluated by infusing [6,6-2H]glucose. Fat and carbohydrate oxidation were also measured by indirect calorimetry. The same subjects performed two identical exercise tests, but in one trial theophylline, a potent adenosine receptor antagonist, was infused for 1 hour before and throughout exercise. Theophylline did not increase whole-body lipolysis (glycerol rate of appearance [Ra]) or free fatty acid (FFA) release during exercise, but fat oxidation was lower than control values (9.5 +/- 3.0 v 18.0 +/- 4.2 micromol x min(-1) x kg(-1), P < .01). Glucose Ra was not affected by theophylline infusion, but glucose uptake was lower (31.6 +/- 4.1 v 40.4 +/- 5.0 micromol x min(-1) x kg(-1), P < .05) and glucose concentration was higher (6.4 +/- 0.6 v 5.8 +/- 0.4 mmol/L, P < .05) than in the control trial. Total carbohydrate oxidation (302.3 +/- 26.2 v 265.5 +/- 11.7 micromol x min(-1) x kg(-1), P < .06), estimated muscle glycogenolysis (270.7 +/- 23.1 v 225.1 +/- 9.7 micromol x min(-1) x kg(-1), P < .05), and plasma lactate concentration (7.9 +/- 1.6 v 5.9 +/- 1.1 mmol/L, P < .001) were also higher during the theophylline trial. These data suggest that adenosine may play a role in stimulating glucose uptake and restraining glycogenolysis but not in limiting lipolysis during exercise.

Muscle torque in young and older untrained and endurance-trained men.

Plantar flexor torque was measured in 24 young (25 +/- 1.4 y) and older (62 +/- 2 y) untrained and endurance-trained men to test the hypothesis that age-associated declines in muscle function would be attenuated in older men who also endurance trained. Endurance-trained subjects averaged 7-9 h/wk of aerobic activity for 10-12 years. These subjects had not engaged in resistance training previously in the past 10 years. Plantar flexor torque was measured at velocities between 0 and 5.23 rads. s-1. In absolute terms, maximal isometric torque was 23% lower in older men compared to young men, regardless of their training status. On the other hand, relative measures of isometric strength (i.e., torque.muscle cross-sectional area-1 and torque.muscle volume-1) were similar in young and older men but were higher in trained than in untrained men. Isokinetic torque.muscle cross-sectional area-1 and torque.muscle volume-1 was greater at contraction velocities of 0.26-2.09 rads.s-1 for trained subjects. These data suggest that endurance training does not attenuate the age-associated loss of muscle mass or absolute strength. However, endurance training might reduce the extent of loss of relative strength because torque-muscle cross-sectional area-1 and torque.muscle volume-1 are greater in endurance-trained older men than in untrained older men.

Endurance exercise training decreases capillary basement membrane width in older nondiabetic and diabetic adults.

The objectives of these studies were to 1) evaluate the relationships among age, glucose intolerance, and skeletal muscle capillary basement membrane (CBM) width (CBMW) and 2) determine the effects of exercise training on CBMW by comparing values of young (28 +/- 4 yr) and older (63 +/- 7 yr) athletes with those of age-matched sedentary control subjects and by measuring CBMW in older men and women before and after a 9-mo endurance-exercise training program. CBMW was measured in tissue samples obtained from the gastrocnemius muscle. CBMW in sedentary 64 +/- 3-yr-old subjects was 25% thicker than in sedentary 24 +/- 3-yr-old subjects. CBMW was similar in young and older athletes and was thinner than the CBMW of age-matched sedentary control subjects. There were no differences in CBMW among older sedentary individuals with normal or impaired glucose tolerance or mild non-insulin-dependent diabetes mellitus. Nine months of endurance exercise training reduced CBMW in older men and women by 30-40%, to widths that were not different from those of the young subjects; this response was independent of glucose tolerance status. These findings suggest that habitual exercise prevents the thickening of the skeletal muscle CBM that is characteristic of advancing age. Moreover, the thickening of the CBM appears to be readily reversed as a result of exercise training, even in older individuals.

Muscle biopsy as a tool in the study of aging.

The needle biopsy procedure provides a minimally invasive means of obtaining small samples of skeletal muscle from human volunteers. Such samples can be used to examine a variety of structural and functional characteristics of muscle, including fiber type and size, capillarization, enzymatic capacities, energy substrate or protein/mRNA concentrations, metabolic responses, and contractile properties. In conjunction with other methods, biopsy sampling can also be used to estimate total muscle mass and fiber number, and to determine rates of protein synthesis and degradation. Optimal handling and storage conditions vary widely, but in general, most of the above measurements can be made using frozen tissue, so that samples can be stored almost indefinitely. The procedure is also safe and generally well-tolerated, making it possible to perform longitudinal studies of the same person. The biopsy technique is therefore well suited for examining the underlying physiological mechanisms responsible for muscle wasting in the elderly, as well as for assessing the effects of nutritional, hormonal, and/or lifestyle (e.g., exercise) interventions intended to combat this problem. Although sample size limitations have been largely overcome by the development of microtechniques, more information is needed on how to minimize the variability introduced by studying only a small fraction of the whole muscle. Studies are also required to determine whether it is sufficient to biopsy only one muscle (and if so, which is optimal), or whether there are differential effects of aging in various muscle groups that would preclude extrapolating from one muscle to all muscles in the body.(ABSTRACT TRUNCATED AT 250 WORDS)

Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis.

Aging men develop a significant loss of muscle strength that occurs in conjunction with a decline in serum testosterone concentrations. We investigated the effects of testosterone administration to six healthy men [67 +/- 2 (SE) yr] on skeletal muscle protein synthesis, strength, and the intramuscular insulin-like growth factor I (IGF-I) system. Elderly men with serum testosterone concentrations of 480 ng/dl or less were given testosterone injections for 4 wk to produce serum concentrations equal to those of younger men. During testosterone administration muscle strength (isokinetic dynamometer) increased in both right and left hamstring and quadricep muscles as did the fractional synthetic rate of muscle protein (stable-isotope infusion). Ribonuclease protection assays done on total RNA from muscle showed that testosterone administration increased mRNA concentrations of IGF-I and decreased mRNA concentrations of insulin-like growth factor binding protein-4. We conclude that increasing testosterone concentrations in elderly men increases skeletal muscle protein synthesis and strength. This increase may be mediated by stimulation of the intramuscular IGF-I system.

A new correction factor for use in tracer estimations of plasma fatty acid oxidation.

The purpose of this study was to acquire a new correction factor for use in tracer estimations of plasma fatty acid oxidation that would fully account for label fixation during the infusion of fatty acid tracers. Thus volunteers were infused with 13C-labeled fatty acids and [1-14C]acetate in the basal state, during hyperinsulinemia-hyperglycemia (clamp), and during 1 h of cycling exercise. The fractional recovery of acetate label (i.e., the acetate correction factor) was 0.56 +/- 0.02, 0.50 +/- 0.03, and 0.80 +/- 0.03 in the basal state and during the clamp and exercise, respectively. Isotopically determined plasma fatty acid oxidation rates (mumol.kg-1.min-1) were 1.7 +/- 0.2, 0.8 +/- 0.2, and 6.4 +/- 0.5 (no correction); 2.1 +/- 0.2, 1.0 +/- 0.2, and 6.7 +/- 0.5 (bicarbonate correction); and 3.1 +/- 0.2, 1.5 +/- 0.2, and 8.2 +/- 0.4 (acetate correction). We conclude that use of the acetate correction factor in place of the bicarbonate correction factor should improve the accuracy of isotopic measurements of plasma fatty acid oxidation, because it accounts for label fixation that might occur at any step between the entrance of labeled acetyl-CoA into the tricarboxylic acid cycle until the recovery of label in breath CO2.

Lipid and carbohydrate metabolism in IDDM during moderate and intense exercise.

Insulin-dependent diabetes mellitus (IDDM) is characterized by a metabolic and hormonal disarray that may be more evident during exercise. However, the metabolic response to exercise of different intensities has not been evaluated in IDDM. We therefore used stable isotope techniques and indirect calorimetry to quantify substrate kinetics and oxidation during 30 min of exercise at 45 and 75% of maximal oxygen uptake (Vo2max) in seven men with IDDM (D group) infused with insulin at a constant basal rate. Normal control subjects (C group) matched for age, weight, and Vo2max were also studied. During moderate exercise, glucose uptake (Rd) was lower in the D than in the C group (15.3 +/- 1.0 vs. 20.8 +/- 1.6 mumol.min-1.kg-1; P < 0.05). Carbohydrate oxidation also tended to be lower in the D group (71.0 +/- 7.2 vs. 87.5 +/- 10.6 mumol.min-1.kg-1; P = 0.08). The D group relied on fat oxidation to a greater extent than did the C group (16.9 +/- 1.1 vs. 10.4 +/- 1.6 mumol.min-1.kg-1; P < 0.05). The enhanced fat oxidation was not due to increased lipolysis because no differences occurred in glycerol release (Ra) or in plasma free fatty acid Ra or concentration, and the source of the extra lipid appeared to be intramuscular fat stores. These differences in substrate metabolism were not evident during exercise at 75% of Vo2max. The lower glucose uptake and oxidation in the diabetic subjects during moderate, but not intense, exercise suggest that glucose metabolism is regulated differently depending on exercise intensity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of endurance training on hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men.

In humans, endurance training markedly reduces the rate of hepatic glucose production during exercise. To determine whether this is due to a reduction in glycogenolysis, in gluconeogenesis, or in both processes, six men were studied at rest and during 2 h of cycle ergometer exercise at 60% pretraining peak O2 consumption (VO2peak), both before and after completion of a strenuous endurance training program (cycling at 75-100% VO2peak for 45-90 min/day, 6 days/wk for 12 wk). The overall rate of glucose appearance (Ra) was determined using a primed continuous infusion of [6,6-2H]glucose, whereas the rate of gluconeogenesis (Rgng) was estimated from the incorporation of 13C into glucose (via pyruvate carboxylase) from simultaneously infused [13C]bicarbonate. Training did not affect glucose kinetics at rest but reduced the average Ra during exercise by 42% [from 36.8 +/- 3.8 to 21.5 +/- 3.6 (SE) mumol.min-1.kg-1; P < 0.001]. This decrease appeared to be mostly due to a reduction in hepatic glycogenolysis. However, the estimated Rgng during exercise also decreased significantly (P < 0.001) with training, falling from 7.5 +/- 1.6 mumol.min-1.kg-1 (23 +/- 3% of total Ra) before training to 3.1 +/- 0.6 mumol.min-1.kg-1 (14 +/- 3% of total Ra) after training. These training-induced adaptations in hepatic glucose metabolism were associated with an attenuated hormonal response to exercise (i.e., higher insulin and lower glucagon, norepinephrine, and epinephrine concentrations) as well as a reduced availability of gluconeogenic precursors (i.e., lower lactate and glycerol concentrations). We conclude that endurance training reduces both hepatic glycogenolysis and gluconeogenesis during prolonged exercise in men.

Glucose kinetics during high-intensity exercise in endurance-trained and untrained humans.

In humans, endurance training reduces the rates of glucose production and utilization during moderate-intensity exercise. It is uncertain, however, whether this is also true during high-intensity exercise. Accordingly, we studied eight endurance-trained cyclists and eight untrained subjects during 30 min of cycling at approximately 80% of maximal oxygen uptake (VO2max). Rates of glucose appearance (Ra) and disappearance (Rd) were determined using a primed, continuous infusion of [6,6-2H]glucose. Average glucose Ra during exercise did not differ in the trained and untrained subjects (34.3 +/- 3.6 vs. 36.0 +/- 1.7 mumol.min-1.kg-1; mean +/- SE; P, not significant). Plasma insulin, glucagon, norepinephrine, and epinephrine concentrations were also similar in the two groups. In contrast, glucose Rd during exercise was 19% lower in the trained compared with the untrained subjects (27.0 +/- 2.6 vs. 33.2 +/- 1.5 mumol.min-1.kg-1; P < 0.001). Consequently, during exercise, plasma glucose concentration rose significantly (P < 0.05) in the trained subjects but did not change in the untrained subjects. We conclude that utilization of plasma glucose is lower in trained subjects during high-intensity exercise, even when the exercise is performed at the same relative (and therefore a higher absolute) intensity as in the untrained state. Hyperglycemia in trained subjects during intense exercise appears to be due to this lower rate of glucose utilization rather than a higher rate of glucose production.

Pathway of free fatty acid oxidation in human subjects. Implications for tracer studies.

To determine the pathway of plasma FFA oxidation and the site(s) of label fixation observed during infusion of FFA tracers, [1-13C]palmitate and [1-14C]acetate were infused intravenously for 3 h in five volunteers. Breath 13CO2 enrichment and 14CO2 specific activity were followed for 6 h to determine the labeled CO2 decay rates. Acetate enters directly into the TCA cycle; hence, if palmitate transits a large lipid pool before oxidation, 13CO2 enrichment (from palmitate) should decay slower than 14CO2 specific activity (from acetate). Breath 13CO2 enrichment and 14CO2 specific activity decayed at a similar rate after stopping the tracer infusions (half-lives of 13CO2 and 14CO2 decay: mean [+/- SE] 106.6 +/- 8.9 min, and 96.9 +/- 6.0 min, respectively, P = NS), which suggests that palmitate enters the TCA cycle directly and that label fixation occurs after citrate synthesis. Significant label fixation was shown in plasma glutamate/glutamine and lactate/pyruvate during infusion of either [1,2-13C]acetate or [U-13C]palmitate, suggesting that TCA cycle exchange reactions are at least partly responsible for label fixation. This was consistent with our finding that the half-lives of 13CO2 enrichment and 14CO2 specific activity decreased significantly during exercise to 14.4 +/- 3 min and 16.8 +/- 1 min, respectively, since exercise significantly increases the rate of the TCA cycle in relation to that of the TCA cycle exchange reactions. We conclude that plasma FFA entering cells destined to be oxidized are directly oxidized and that tracer estimates of plasma FFA oxidation will underestimate the true value unless account is taken of the extent of label fixation.