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J Appl Physiol 100: 1883-1894, 2006; doi:10.1152/japplphysiol.01431.2005
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Glucose kinetics differ between women and men, during and after exercise

Tracy J. Horton,1,3 Gary K. Grunwald,2 Jennifer Lavely,1 and W. Troy Donahoo4

1Section of Nutrition, Department of Pediatrics, and 2Department of Preventive Medicine and Biostatistics, University of Colorado at Denver and Health Sciences Center, Denver; 3Department of Food Science and Human Nutrition, Colorado State University, Fort Collins; and 4Department of Preventive Medicine, Kaiser Permanente, Denver, Colorado

Submitted 14 November 2005 ; accepted in final form 16 January 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
As exercise can improve the regulation of glucose and carbohydrate metabolism, it is important to establish biological factors, such as sex, that may influence these outcomes. Glucose kinetics, therefore, were compared between women and men at rest, during exercise, and postexercise. It was hypothesized that glucose flux would be significantly lower in women than men during both the exercise and postexercise periods. Subjects included normal weight, healthy, eumenorrehic women and men, matched for habitual activity level and maximal oxygen uptake per kilogram lean body mass. Testing occurred following 3 days of diet control, with no exercise the day before. Subjects were tested in the overnight-fasted condition with women studied in the midluteal phase of the menstrual cycle. Resting (120 min), exercise (85% lactate threshold, 90 min), and postexercise (180 min) measurements of glucose flux and substrate metabolism were made. During exercise, women had a significantly lower rate of glucose appearance (Ra) (P < 0.001) and disappearance (Rd) (P < 0.002) compared with men. Maximal values were achieved at 90 min of exercise for both glucose Ra (mean ± SE: 22.8 ± 1.12 µmol·kg body wt–1·min–1 women and 33.6 ± 1.79 µmol·kg body wt–1·min–1 men) and glucose Rd (23.2 ± 1.26 and 34.1 ± 1.71 µmol·kg body wt–1·min–1, respectively). Exercise epinephrine concentration was significantly lower in women compared with men (P < 0.02), as was the increment in glucagon from rest to exercise (P < 0.04). During the postexercise period, glucose Ra and Rd were also significantly lower in women vs. men (P < 0.001), with differences diminishing over time. In conclusion, circulating blood glucose flux was significantly lower during 90 min of moderate exercise, and immediately postexercise, in women compared with men. Sex differences in the glucagon increase to exercise, and/or the epinephrine levels during exercise, may play a role in determining these sex differences in exercise glucose turnover.

sex; carbohydrate metabolism; catecholamines; glucagon

HABITUAL EXERCISE FORMS THE cornerstone of chronic disease prevention and treatment, including conditions characterized by the dysregulation of carbohydrate (CHO) and glucose metabolism, such as diabetes and obesity. Understanding the physiological basis for the beneficial effects of exercise, along with elucidation of biological factors that affect the metabolic response to exercise is, therefore, of high importance. One biological factor that has recently been shown to affect exercise metabolism is sex (6, 10, 12, 18–20, 25, 40, 45, 46, 50, 51, 53). Determining male and female differences in the metabolic effects of exercise on glucose and CHO metabolism, therefore, is an important step in the delineation of biological factors that may impact the physiological benefits of exercise.

With respect to whole body CHO metabolism, lean, eumenorrheic women have generally been observed to oxidize proportionally less CHO, and more lipid, compared with their male counterparts (2, 19, 25, 40, 51, 54), although not all studies report this (48, 50). Observations of a sex difference in exercise CHO oxidation have been made with exercise of mild to moderately high intensity [40–75% maximum O2 consumption (VO2max)], where both circulating blood glucose and intramuscular glycogen contribute to total CHO oxidation. The lesser relative CHO oxidation in women vs. men during mild to moderately high-intensity exercise could be due to a lower utilization of circulating blood glucose and/or muscle glycogen. Furthermore, sex differences in the use of these CHO sources could occur, even without differences in whole body CHO oxidation. In the few studies that have utilized stable isotope techniques to determine sex differences in exercise glucose flux, within the same study, both a similar (6, 48) and a lower (46) rate of exercise glucose turnover have been reported in women compared with men. The direct measurement of muscle glycogen changes from pre- to postexercise also provides conflicting data with regard to sex differences, with both no difference (46) and a lower muscle glycogen utilization (51, 53) being reported in women compared with men. Factors related to differences in study design likely explain these inconclusive data. Nevertheless, whether or not sex differences in glucose turnover occur during exercise, and the contribution of blood glucose to total CHO utilization relative to muscle glycogen, warrants further investigation.

The healthful effects of exercise are not limited to the increased energy expenditure and substrate utilization during the exercise bout itself. Indeed, the beneficial effects of exercise with respect to substrate metabolism may be equally, if not more, important in the postexercise period. This is a time when factors come in to play to reestablish metabolic homeostasis and to replete fuel stores, especially hepatic and muscle glycogen, that have been utilized during exercise (33). Insulin action has been observed to increase by ~4 h after exercise has ended (14, 38, 43, 44), and this effect may be maintained for up to 48 h (37). Concurrently, there is a decrease in CHO oxidation and a reciprocal increase in fat oxidation (25, 55). These factors promote glycogen repletion and the reestablishment of resting glucose homeostasis in the postexercise period. Sex-based differences in postexercise substrate metabolism are an area that has received little attention. Indeed, any potential sex differences in glucose and overall nutrient and hormone metabolism during exercise could result in sex differences in metabolism postexercise. For example, if men were to deplete muscle glycogen stores more than women during exercise, as some data would suggest (51, 53), this could increase glucose uptake more in men than women during the postexercise period, as lower muscle glycogen levels are associated with increased glucose uptake (42, 43). What may also be important is the impact of depleted glycogen stores, and changes in insulin action, on the partitioning of ingested nutrients between storage and oxidation during the postexercise period (7, 32). It could be hypothesized that a lesser reliance on blood glucose as a fuel source during exercise, and a greater utilization of muscle glycogen, and/or greater changes in postexercise insulin action, would result in more ingested CHO being directed toward storage vs. oxidation, thus increasing fat oxidation and decreasing net fat storage. Our laboratory has previously shown that, when subjects continue to fast for 2 h after 2 h of exercise at 40% VO2max, whole body substrate oxidation does not differ between men and women (25). This does not, however, exclude the possibility that there are sex differences in glucose production and disposal, or between partitioning of glucose uptake between storage (glycogen repletion) and oxidation, especially after a meal. Hence, understanding potential sex-based differences in CHO metabolism during exercise and postexercise is relevant to our overall understanding of the regulation of glucose and nutrient metabolism.

To further elucidate sex effects on exercise metabolism, the present study aimed to determine glucose kinetics, nutrient oxidation, and substrate and hormone responses to moderate-intensity exercise of 90-min duration, and during the immediate 3 h postexercise in women relative to men. Care was taken to match the level of habitual activity, and VO2max relative to lean body mass (LBM), between the sexes. In contrast to most previous investigations, women were studied in the midluteal phase of the menstrual cycle, rather than the follicular phase of the menstrual cycle, and steady-state exercise intensity was determined based on each individual’s lactate threshold (LT).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects

Lean, healthy women and men (20–45 yr) were recruited for the study. Female subjects were required to have a regular menstrual cycle (>11 cycles over the past year), and all subjects were habitually active with men and women closely matched for activity level (Table 1). Medical exclusions included past or present history of cardiovascular disease, high blood pressure, diabetes, any hormonal imbalance or metabolic abnormality, and use of oral contraceptives or other hormones. A total of 24 subjects (11 women, 13 men) took part in the study. One woman was excluded, based on her study day hormone concentrations, indicating she was not in the luteal phase of her menstrual cycle. One man was excluded due to an extended delay between his prestudy VO2max test and main study day testing, along with a significant decrease in activity level (reported after the fact), which brought into question the accuracy of the relative intensity of the exercise on the main study day. This gave a total of 10 women and 12 men who completed the study. Ten of the men and women were pair-matched based on habitual activity level and VO2max per kilogram LBM per minute. The remaining two men were typical of the group average; therefore, their data were included in the study analysis. Subject characteristics are shown in Table 1. The study protocol was approved by the University of Colorado Committee Institutional Review Board for the Protection of Human Subjects. All subjects read and signed an informed consent form before admission into the study.


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  		Table 1. Subject characteristics

 
Preliminary assessments.   A health and physical examination was completed on all subjects, including blood and urine analysis, to confirm that there was no medical reason for exclusion. Resting metabolic rate (RMR) was measured using indirect calorimetry via a metabolic cart system (Sensormedics 2900, Sensormedics, Yorba Linda, CA). Oxygen consumption and carbon dioxide production were used to calculate metabolic rate (62). This RMR value was used to determine energy intake of subjects during the period of prestudy diet control. Body composition was determined via dual-energy X-ray absorptiometry (Lunar, Madison, WI) (41). VO2max was determined using a graded exercise test on a cycle ergometer (Lode Medical Technology, Groningen, The Netherlands). Subjects cycled at a constant revolutions per minute (70–90), while the resistance was gradually increased until volitional exhaustion. Workload commenced at 25–50 W (depending on sex and habitual activity level) and was increased by 25 W every 2 min. To ensure maximum effort was achieved, two of the following criteria had to be fulfilled: whole body respiratory quotient ≥1.1, achieved maximum heart rate within 5% of the age-predicted maximum, and/or an increase in oxygen consumption in response to the final workload of <2.0 ml·kg body wt–1·min–1. For determination of LT, a retrograde dorsal hand intravenous (IV) catheter was placed, and the heated hand technique (36) was used to arterialize the blood. At the end of each workload stage (every 2 min), 0.5 ml of blood was drawn, placed in 8% perchloric acid (1.5 ml), vortexed, and placed on ice. Tubes were pre- and postweighed, and lactate concentrations were measured and adjusted for dilution. The log of the lactate concentration was plotted against the log of the oxygen consumption at the time of sampling. A two-line regression model was used to describe the two phases of the lactate accumulation. The point of intersection of these two lines was taken as the LT (59). Measurement of VO2max, body composition, and RMR was performed in the luteal phase of the menstrual cycle for female subjects.

Prestudy diet and exercise control.   Subjects were fed a controlled diet for 3 days before the study day. All food was prepared by the General Clinical Research Center (GCRC) diet kitchen at the University of Colorado, and subjects were required to consume breakfast in the GCRC with other food prepared to take away. No other food was permitted, and subjects were required to consume all the food given. The only optional part of the diet were two food modules (840 kJ each, same composition as the overall diet), one or both of which the subjects could eat if they were hungry. The diet composition was 25% fat, 15% protein, and 60% CHO, and initial energy intake was calculated at 1.6–1.8 x RMR based on subject’s habitual activity level. This period of diet control helped minimize fluctuations in energy balance, as suggested by body weight (BW) changes of <2%. Subjects were allowed to follow their usual activity routine for the first 2 days of the diet, and on the last day they refrained from any planned exercise (energy intake, 1.6 x RMR). Testing was, therefore, performed at least 36 h after the last exercise bout.

Study Days

Subjects stayed overnight on the GCRC the evening before the study. Between 1900 and 2000, subjects consumed their evening meal and had a light snack at 2200. After this, subjects remained fasted until the end of the study the following day. The study involved measurement of resting, exercise, and postexercise glucose kinetics, as well as respiratory gas exchange. Confirmation of menstrual cycle phase in women was based on serum estrogen and progesterone (>2.5 ng/ml) levels measured on the day of the study (Table 1).

Determination of glucose kinetics and circulating substrates and hormones.   On the study day, IV catheter placement occurred between 6:45 and 7:30 AM. An infusion IV was placed in an antecubital vein for delivery of the stable isotope. In the contralateral arm, a sampling catheter was placed retrograde fashion into a dorsal hand vein or, if necessary, in a wrist vein. The heated hand technique (36) was used to obtain arterialized blood samples. Basal blood samples were taken, for determination of background enrichment of glucose, before the start of the tracer infusion at 0800 (time 0 at rest). A primed (17.6 µmol/kg), constant (0.2 µmol·kg–1·min–1) infusion of [6,6-2H2]glucose began and continued for 120 min at rest. Subjects remained semirecumbent in bed over this time, and four blood samples were taken over the final 30 min of rest (time t = –45, –35, –25, and –15 relative to the start of exercise) for the determination of resting glucose kinetics, substrate, and hormone concentrations. Subjects were then transferred to an electronically braked stationary bike (Lode Medical Technology) and began the exercise period, which included a 5-min warm-up, followed by 90 min of steady-state exercise at 85% of each individual’s LT. At the start of the exercise (warm-up), the glucose isotope infusion rate was increased twofold to minimize changes in isotope enrichment (63). Blood samples were drawn at t = 10, 20, 30, 45, 60, 75, and 90 min of steady-state exercise. After completion of the exercise bout, subjects moved into bed and remained resting for 3 h postexercise. The isotope infusion rate was decreased to preexercise levels. Blood samples were drawn at t = 110, 120, 135, 150, 180, 210, 240, and 270 min during the postexercise period.

Respiratory gas exchange.   In the 30 min before blood sampling at rest, a 15- to 20-min measurement of respiratory gas exchange was made via indirect calorimetry (Sensormedics 2900, Sensormedics, Yorba Linda, CA). During exercise, 3 x 20-min measurements of respiratory gas exchange were performed every 30 min. CHO and fat oxidation were calculated from the volume of O2 consumed and volume of CO2 expired after correcting for protein oxidation (26, 62). Protein oxidation within each period (rest, exercise, and postexercise) was estimated from urinary nitrogen excretion.

Determination of circulating hormone and substrate levels.   Two to three milliliters of blood were added to EDTA tubes for the measurement of tracer enrichment and plasma substrate concentrations. Samples were immediately placed on ice and spun, and plasma was separated. Approximately 0.5 ml of whole blood was added to a preweighed tube containing 1.5 ml of iced perchloric acid (8%). After vortexing, the tube was postweighed and spun to separate the supernatant. This was used to measure blood lactate. Two and one-half milliliters of whole blood were added to 40 µl of preservative (EGTA 3.6 mg plus glutathione 2.4 mg in distilled water), for plasma catecholamine determinations. Blood for glucagon measurement (2 ml) was added to tubes containing EDTA plus 500 kallikrein-inhibitor units of aprotinin. Samples were immediately placed on ice and spun. Approximately 7 ml of whole blood were allowed to clot, and the serum was separated off after spinning. This was used for determination of the remaining hormone and substrate concentrations. All plasma, serum, and supernatant samples were stored at –70°C until analysis. Catecholamines were determined in duplicate by high-performance liquid chromatography with electrochemical detection [intra-assay coefficients of variation (CVs) 6.2% epinephrine (Epi), 4.9% norepinephrine (Norepi)] (8). Radioimmunoassays were used to determine serum insulin (Kabi Pharmacia, Piscataway, NJ), cortisol, progesterone, estradiol (Diagnostic Products, Los Angeles, CA), and glucagon (Linco Research, St. Louis, MO). Samples were run in duplicate with intra-assay CVs of 10, 6.7, 8.8, 7.5, and 9.4%, respectively. Blood lactate (Sigma Diagnostics, St. Louis, MO) was run in duplicate with intra-assay CV of 4.2%.

Lactate concentrations and plasma catecholamines (Epi and Norepi) were measured on samples drawn at t = –35, –15, 10, 20, 30, 45, 60, 75, 90, 110, 120, 150, 210, and 270 min. Glucagon, cortisol, and insulin were measured on samples drawn at t = –15, 30, 60, 75, and 90 min. Postexercise, insulin was measured at t = 120, 150, 180, 210, 240, and 270 min, whereas glucagon and cortisol were measured at t = 120, 150, 210, and 270 min. Estradiol and progesterone were measured on samples drawn at t = –45 min only.

Determination of glucose isotope enrichment and concentration.   This was measured via gas chromatography-mass spectrometry (GC-MS; GC model 6890 and 5973N, Agilent, Palo Alto, CA). First, plasma samples were thawed and 80 µg of [U-13C]glucose added to act as an internal standard. The pentacetate derivative of glucose was then generated as follows. Samples were deproteinized with iced ethanol, and the supernatant was dried in a Speedvac at 50°C for 2.5 h. Samples were then derivatized using 100 µl of acetic anhydride-pyridine solution (1:1) and heating for 30 min at 100°C. Ethyl acetate (100 µl) was then added, and the samples were vortexed and then transferred to GC-MS vials for analysis. Injector temperature of the GC-MS was set at 250°C, and initial oven temperature was set at 150°C. The column used was an Agilent HP-5MS 0.25 mm x 30 m with a 0.25-mm film thickness. Oven temperature was increased 30°C/min until a final temperature of 250°C was achieved. Helium was used as the carrier gas with a 20:1 ml/min pulsed split injection ratio. Transfer line temperature was set at 280°C, source temperature at 250°C, and quadruple temperature at 150°C. Methane chemical ionization (63) was used to monitor selective ions with mass-to-charge ratios of 331 (M+0 from natural glucose), 333 (M+2 from [6,6-2H2]glucose), and 337 (M+6 from the [U-13C]glucose, internal standard).

Natural glucose standards from 10 to 200 mg/dl were prepared and spiked with 80 µg [U-13C]glucose to enable the generation of a calibration curve for determining the concentration of natural glucose. The calibration curve was constructed by comparing the known ratio of glucose/[U-13C]glucose to the measured area ratio of 331:337. Natural glucose concentration in the samples was then determined by measuring the sample 331:337 area ratio and using the linear equation obtained from the calibration curve to calculate the natural glucose concentration in milligrams per deciliter.

Calculations.   Glucose moles percent excess (MPE) and concentration data were spline fitted to remove noise introduced by analytical and sampling errors (56). Glucose rates of appearance (Ra) and disappearance (Rd) were then calculated using the Steele equation, as modified for use with stable isotopes (47, 63).

Formula

Formula
where Ra is for the tracee (µmol/min), F is infusion rate of tracer (µmol·kg–1·min–1), pV is effective volume of tracee distribution (100 ml/kg BW) (47), t1 is time 1 of sampling, t2 is time 2 of sampling, C1 is tracee concentration at t1, C2 is tracee concentration at t2, E1 is plasma MPE at t1, and E2 is plasma MPE at t2. For exercise substrate kinetics, no value was calculated for t = 10 min; rather the t = 10 min glucose concentration and MPE values were used to calculate the t = 20 min value only. This was due to the 30-min duration of time between the final t = –15 min resting blood draw and the t = 10 min exercise blood sample (the 30 min include the 5-min warm up), and the change in infusion rate part way through (infusion rate increasing at t = 0 of steady-state exercise), which present suboptimal conditions for reliable tracer kinetic calculations.

Data Analysis

Subject characteristics were compared using an unpaired t-test. For each dependent variable, a general linear multivariate model (30), estimated using SAS PROC MIXED (SAS Institute, Cary, NC), was used to account for correlation between repeated measurements on the same subject. This model allowed different variances at the different measurement times, as well as different variances for men and women. This analysis provides a valid handling of the missing values that occurred randomly across subjects and study phase due to occasional problems with blood sampling. Differences in time courses between men and women were examined, as were interactions between time and sex. Comparisons of particular interest (e.g., men vs. women at a given time, differences between times, trends over time, and differences between men and women in the changes between two times) were estimated and tested using contrasts within the multivariate model. Comparisons between periods were made by averaging the values during the period for each subject and again using a multivariate model to account for correlations between periods on the same subject. Several variables (lactate, Epi, Norepi, and estrogen) were log transformed for the significance tests in the multivariate model to account for skewness in the distributions. However, results are reported in the original units for easier interpretation. Results are presented as means ± SE.

For glucose kinetic data, results are expressed both in terms of BW and LBM. The latter mode of expression adjusts for differences in the most metabolic active tissue mass between men and women and is consistent with the matching of men and women for VO2max/kg LBM. For glucose disposal, glycogen utilization, and CHO oxidation during exercise, data were again expressed relative to LBM, as this parameter is the primary determinant of metabolic rate and glucose disposal during exercise. This effectively adjusts for exercise differences in energy expenditure between men and women. In addition, data were expressed relative to leg lean mass, which would be the major energy-consuming tissue mass during cycle exercise.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Table 2 shows the exercise parameters for women and men. The relative intensity of the exercise was almost identical in women and men: 51% of VO2max in both sexes, and 87 and 88% of LT, respectively.


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  		Table 2. Exercise parameters

 
Energy Expenditure and Whole Body Substrate Oxidation

The average metabolic rate and respiratory exchange ratio (RER) for rest, exercise, and postexercise are shown in Table 3. The expected increase in metabolic rate and RER between rest and exercise was observed. In addition, metabolic rate postexercise was significantly elevated compared with preexercise (P = 0.03 for women, P < 0.0001 for men), whereas RER postexercise was significantly reduced compared with preexercise (P = 0.006 for women, P = 0.0003 for men). Metabolic rate, relative to LBM, was not different between men and women during exercise, but it was significantly greater in women vs. men at rest and postexercise (P < 0.0001). No significant sex differences were observed in RER, or nonprotein RER, for any study phase.


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  		Table 3. Metabolic rate and respiratory exchange ratio

 
During exercise, absolute rates of protein and CHO oxidation were lower in women vs. men (P = 0.0001 and P = 0.0023, respectively, Table 4), with a nearly significant difference in absolute fat oxidation (P = 0.06). Relative nutrient oxidation, however, was not different between the sexes, whether data were expressed as a percentage of total energy expended (Table 4), or relative to LBM (data not shown). It is noteworthy that the nonprotein RER postexercise was below 0.70. This meant that it would have been erroneous to use the postexercise respiratory gas exchange data to estimate substrate oxidation. Results suggest that, as subjects continued to fast in the postexercise period (after the 2-h rest period followed by 90-min exercise), there was significant production of CO2 and/or utilization of O2, due to metabolic processes unrelated to direct nutrient oxidation.


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  		Table 4. Whole body nutrient oxidation

 
Glucose kinetics.   Figure 1 shows the MPE (%) for glucose at rest, during the 90-min exercise, and over the 3 h postexercise. Although values tended to drift downward in men during exercise, large changes in isotope enrichment were avoided by doubling the isotope infusion rate at the onset of exercise and decreasing this postexercise. At rest, glucose turnover did not differ between women and men, whether data were expressed relative to BW (Fig. 2) or LBM (Fig. 3). Average glucose Ra at rest was 12.5 ± 0.5 µmol·kg BW–1·min–1 in women and 12.6 ± 0.5 µmol·kg BW–1·min–1 in men, while glucose Rd equaled 12.4 ± 0.6 and 12.8 ± 0.7 µmol·kg BW–1·min–1, respectively. During exercise, glucose Ra and Rd increased over time, but less so in women than in men (sex x time interaction, P < 0.0001 for data expressed relative to BW or LBM). In addition, the average glucose Ra and Rd during exercise, expressed per kilogram BW, were significantly lower in women vs. men (P < 0.001, glucose Ra and P < 0.002, glucose Rd), with maximal rates occurring at 90 min of exercise for both glucose Ra (women 22.8 ± 1.1 µmol·kg BW–1·min–1, men 33.6 ± 1.8 µmol·kg BW–1·min–1) and glucose Rd (23.2 ± 1.3 and 34.1 ± 1.7 µmol·kg BW–1·min–1, respectively). Average exercise glucose Ra, per kilogram LBM, was also significantly lower in women vs. men (P < 0.04), whereas average glucose Rd per kilogram LBM tended to be lower (P = 0.065) due to smaller differences in the first 45 min of the exercise. Sex differences in glucose kinetics were maintained in the postexercise period. There was a significant sex x time interaction (P < 0.0003 for glucose Ra and Rd expressed relative to BW or LBM) due to a more immediate vs. gradual decline in postexercise glucose turnover in women compared with men. Furthermore, the average glucose Ra and Rd postexercise were significantly lower in women vs. men, whether data were expressed relative to BW (P < 0.001, Ra and Rd) or LBM (P < 0.03 and P < 0.05 for Ra and Rd, respectively).


Figure 1
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  		Fig. 1. Glucose tracer enrichment, expressed as mole percent excess (MPE). Values are means ± SE.

 

Figure 2
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  		Fig. 2. Glucose rate of appearance (Ra; A) and glucose rate of disappearance (Rd; B) (per kg body weight) at rest (–35 to –15 min), during cycle exercise (0–90 min), and postexercise (90–270 min). Values are means ± SE. A: significant effect of time (P < 0.0001) and sex x time interaction (P < 0.0001) for exercise and postexercise periods. Significantly higher average glucose Ra in men vs. women during exercise (P < 0.001) and postexercise (P < 0.001). B: significant sex x time interaction (P < 0.0002) for exercise and postexercise periods. Significantly higher average glucose Rd in men vs. women during exercise (P < 0.002) and postexercise (P < 0.001).

 

Figure 3
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  		Fig. 3. Glucose rate of appearance (Ra; A) and glucose rate of disappearance (Rd; B) (per kg lean body mass) at rest (–35 to –15 min), during cycle exercise (0–90 min), and postexercise (90–270 min). Values are means ± SE. A: significant sex x time interaction during exercise and postexercise (P < 0.0002). Significantly higher average glucose Ra in men vs. women during exercise (P < 0.04) and postexercise (P < 0.03). B: significant sex x time interaction during exercise (P < 0.0001) and postexercise (P < 0.0003). Higher average glucose Ra in men vs. women during exercise (P = 0.065) and postexercise (P < 0.05).

 
Estimated glucose and glycogen oxidation during exercise.   It was assumed that all glucose uptake during exercise was directed toward oxidation, i.e., a maximal estimate. Thus estimated glycogen oxidation = total CHO oxidation – glucose oxidation. Table 5 shows results expressed in absolute terms and relative to measures of LBM and total CHO oxidation. Estimated blood glucose oxidation was significantly lower in women vs. men in absolute terms (P < 0.0001), when expressed relative to total LBM (P < 0.04) or leg lean mass (P < 0.02), but was not different when expressed as a percentage of total CHO oxidation. In contrast, estimated glycogen oxidation was only significantly lower in absolute terms (P < 0.003) in women vs. men.


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  		Table 5. Estimated blood glucose and muscle glycogen oxidation during exercise

 
Circulating substrate concentrations.   Figure 4 shows the changes in glucose and lactate concentrations during the study. Glucose concentration preexercise was significantly lower in women vs. men (P = 0.009), but it increased with the onset of exercise to achieve a similar level as that in men (P = 0.59). There was a gradual decline in glucose concentration during exercise (P < 0.0001 for decrease within each sex). Postexercise glucose levels fell initially in women, more so than in men, but the average glucose levels postexercise were not different between the sexes (P = 0.12). In both women and men, postexercise glucose levels were significantly lower compared with initial resting levels (P < 0.0001).


Figure 4
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  		Fig. 4. A: glucose concentrations at rest (–45 to –15 min), during cycle exercise (0–90 min), and postexercise (90–270 min). Significant effect of time during exercise (P < 0.0001 for men and women). Significantly lower blood glucose in women vs. men at rest (P = 0.009). B: lactate concentrations at rest (time t –15 = average of t – 35 and –15 min measures), during cycle exercise (0–90 min), and postexercise (90–270 min). Significant effect of time during exercise (P < 0.0007 for men and women) and postexercise. Significantly lower average lactate concentration in women vs. men during exercise (P < 0.02) and significantly lower decrease in lactate concentration from exercise to postexercise (P < 0.04). Values are means ± SE.

 
Lactate concentration showed the expected changes with exercise and postexercise (Fig. 4B). Average exercise lactate levels were significantly lower in women vs. men (P < 0.02), and the decrease in the average lactate concentration from exercise to postexercise was significantly lower in women vs. men (P < 0.04).

Circulating hormone concentrations.   Insulin concentration is shown in Fig. 5. There was a small but marginally significant decline in insulin level with exercise (P < 0.03 for men, P < 0.09 for women). No sex differences in the pattern of insulin response, nor insulin concentrations during any study phase, were observed.


Figure 5
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  		Fig. 5. Insulin concentration at rest (–15 min), during cycle exercise (0–90 min), and postexercise (90–270 min). Values are means ± SE. Significant decline over time during exercise in men (P < 0.03) and near significant decline in women (P < 0.09).

 
Epi and Norepi changes throughout the study are shown in Fig. 6. Women had a significantly lower Epi concentration compared with men at rest (P < 0.05; 27 ± 3 vs. 40 ± 5 pg/ml, respectively) with no difference in Norepi concentrations. During exercise, there was a time course effect for Epi due to levels significantly increasing in both women (P = 0.01) and men (P < 0.0001). Average Epi levels during exercise, however, were significantly lower in women vs. men (P < 0.02, average values, 78 ± 6 vs. 128 ± 9 pg/ml), and the magnitude of the sex difference in Epi concentration during exercise increased over time with the concentration at 90 min in women being one-half that observed in men. Postexercise, Epi was slightly lower in women vs. men (P < 0.05; average 25 ± 1 vs. 33 ± 2 pg/ml). With respect to Norepi, the time course of changes during exercise differed between the sexes (P < 0.0004), with men demonstrating a significant increase (P < 0.002) and women demonstrating a significant decrease (P < 0.003). Postexercise, there was also a sex x time interaction (P < 0.04) due to a more gradual vs. immediate decline in Norepi in women compared with men. Average circulating Norepi levels were not significantly different between men and women during any study phase.


Figure 6
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  		Fig. 6. Epinephrine (A) and norepinephrine (B) concentrations at rest (t – 15 = average of t –35 and –15 min measures), during cycle exercise (0–90 min), and postexercise (90–270 min). Values are means ± SE. A: significantly greater average concentrations during exercise than at rest or postexercise (P < 0.0001 for women and men). Significant increase during exercise (P < 0.0001 for men, P < 0.01 for women). Significantly lower average epinephrine concentration at rest (P < 0.05), during exercise (P < 0.02), and postexercise (P < 0.05) in women vs. men. B: significantly greater average concentrations during exercise than at rest or postexercise (P < 0.0001 for men and women). Significant increase during exercise for men (P < 0.002), and significant decrease during exercise for women (P < 0.003). Significant sex x time interaction postexercise (P < 0.04).

 
Figure 7 shows the glucagon and cortisol concentrations throughout the study. At rest, glucagon concentration was significantly higher in women vs. men (P < 0.002). Glucagon increased significantly during exercise (P < 0.0001 for men and P = 0.013 for women), but glucagon concentrations were no longer significantly different between the sexes. Thus the increment in glucagon from rest to exercise (average value) was significantly less in women compared with men (P < 0.04). There was no significant sex difference in glucagon concentration postexercise, but the change in glucagon concentration from rest to postexercise showed a significant sex difference (P < 0.02) due to the glucagon staying somewhat elevated in men, whereas it declined almost to resting levels in women.


Figure 7
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  		Fig. 7. Glucagon (A) and cortisol (B) concentrations at rest (–15 min), during cycle exercise (0–90 min), and postexercise (90–270 min). Values are means ± SE. A: significant increase during exercise (P < 0.0001 for men, P = 0.013 women). Significantly higher average glucagon concentration at rest in women vs. men (P < 0.002) and significantly lower increment in average glucagon from rest to exercise (P < 0.04) and lesser difference in the change from rest to postexercise (P < 0.02). B: significant effect of time postexercise (P < 0.0001). Significantly lower cortisol concentration at rest in women vs. men (P < 0.01).

 
Although resting cortisol levels were lower in women vs. men (P < 0.01), the magnitude of increase with exercise was not different between the sexes, nor was the decline after exercise (P > 0.12 for both). There was a significant decrease in cortisol over the postexercise period in both men and women (P < 0.0001).


   DISCUSSION
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 ABSTRACT
 METHODS
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The main finding from this study was that eumenorrheic women, studied in the luteal phase of the menstrual cycle, had a significantly lower exercise glucose turnover compared with men, and this was maintained for the initial (~2 h) postexercise period. Data suggest a greater exercise glucose clearance in men vs. women, as the higher rate of exercise glucose flux in men was observed at the same level of glycemia as women. Of the hormones measured, only the increase in Epi during exercise mirrored the sex differences in exercise glucose kinetics, with levels being significantly lower in women vs. men. Notably, however, there was also a lesser increment in circulating glucagon levels from rest to exercise in women compared with men.

Results from the current investigation agree with data from the study of Roepstorff et al. (46), which also reported a lower glucose turnover in highly trained women vs. men, during 90-min cycle exercise at 58% of VO2max. Both studies also observed no sex difference in relative CHO utilization and no difference in glycogen utilization. It appears that certain similarities in protocol design, including carefully matching women and men in terms of VO2max per kilogram LBM and habitual training status, stringent prestudy diet and exercise control, as well as studying subjects in the overnight-fasted state, resulted in a consensus between the results from the two studies. As exercising above or below the LT can significantly affect glucose kinetics (9) and whole body substrate oxidation (9, 10), it is noteworthy that the agreement between the two studies occurred, despite differences in the method of calculating steady-state exercise intensity, relative to LT in the current investigation (~87% LT, equivalent to 51% VO2max) and relative to VO2max (58%) in the study of Roepstorff et al. (46). It is likely, however, that the subjects in the study of Roepstorff et al. exercised below their LT, as these subject were a relatively homogeneous group of highly trained athletes.

Potential hormonal factors that may have played a role in the observed sex differences in exercise glucose kinetics include the glucagon response and the catecholamine increase, in particular Epi, during exercise. Glucagon is an important regulator of exercise glucose production, especially when insulin levels remain very low, as observed during exercise in the present study (57). Although women had higher absolute concentrations of glucagon than men, the increase in exercise glucagon level was significantly lower in women. It has been shown that the increment in glucagon level from rest to exercise is a major determinant of the increase in glucose release during exercise (23, 58). Assuming no sex difference in hepatic glucagon extraction, then the lesser glucagon increase in women vs. men from rest to exercise could have been driving the sex differences in glucose release and, consequently, glucose utilization. Interestingly, resting glucose production was not different between men and women, despite the higher systemic glucagon levels in women, suggesting the systemic glucagon concentration per se may not relate to glucose production in the same way in men and women. The fact that glucose levels remained higher than preexercise basal levels in women throughout exercise suggests a better defense of circulating blood glucose in women, whereas the decline in men relative to rest may have stimulated a greater glucagon secretion during exercise. Interestingly, systemic Norepi levels showed a significantly different pattern of response in women vs. men, decreasing after an initial increase in women vs. a continuous increase in men. This may also have played into the increase in glucagon release in men or could, in of itself, have played a role in the differential exercise glucose production between the sexes.

The lower Epi increase in women vs. men is consistent with previous observations (6, 12, 19, 25, 51). As Epi can play some role in glucose production during exercise (28, 34), albeit to a lesser extent than glucagon, the lower response in women could have contributed to their lower glucose production compared with men. Elevated Epi has also been shown to decrease glucose uptake (61). Such an effect would predict a lower glucose Rd in men, as they had much higher Epi levels than women. The exercise Epi response does not, therefore, explain any of the sex difference in glucose Rd, and other factors must be overriding the effects of Epi on glucose uptake. Epi can significantly increase muscle glycogenolysis (17, 39, 60). Estimated (muscle) glycogen utilization was significantly lower in women vs. men in absolute terms but not when expressed relative to LBM of leg lean mass. Epi levels may, therefore, be more related to the absolute utilization of glycogen rather than the relative. It needs to be borne in mind, however, that the glycogen utilization value is purely an estimate dependent on the assumption of complete oxidation of all glucose that is taken up, complete oxidation of all glycogen that is broken down, and no net lactate production. Any of these scenarios may not be entirely true, to the extent that blood-derived and/or glycogen-derived glucose could be shunted through glycolysis to generate energy and lactate. Measurement of muscle glycogen changes from muscle biopsies is devoid of such assumptions and provides a direct measure of net glycogen utilization. With the use of this technique, no sex difference in net muscle glycogen utilization has been reported (46, 52), along with no sex difference in Epi levels (46). In contrast, a lower muscle glycogen decrease has been observed in women compared with men (90–100 min of running at 65% VO2max), along with a lower Epi response (51). Thus the Epi response may relate more to muscle glycogen utilization in men and women, but the role it plays in determining sex differences in exercise glucose turnover requires further investigation.

It is notable that women maintained the same level of glycemia during exercise as men, despite a lower glucose flux. This indicates that, in response to exercise, men increased glucose clearance more than women. Reasons for this are not apparent from the current data but may be related to factors controlling glucose uptake at the muscle. Interestingly, men had significantly greater lactate levels during exercise than women, despite both groups exercising at the same percentage of LT. One possible reason for this could be a greater lactate production in men as a result of increased glycolysis. Indeed, there are data to suggest that men have a more glycolytic enzyme profile at the muscle relative to women (22). Thus the greater glucose clearance in men may have contributed to a greater glycolysis, meaning that not all the glucose that was taken up was directly oxidized. Alternatively, the lower lactate level during exercise in women could be due to a greater lactate clearance, and this could be related to testing of women in the luteal phase of the menstrual cycle. Previous studies have reported lower circulating lactate concentrations during steady-state exercise in the luteal vs. follicular phase of the menstrual cycle (3, 21, 27, 29, 64), whereas LT itself, determined by the break point in lactate level rather than the absolute lactate concentration, is not different between phases of the menstrual cycle (13, 16).

It is possible that the prevailing sex-steroid environment either directly or indirectly played a role in determining the sex differences in exercise glucose kinetics. Exogenous estradiol administration has been consistently shown to reduce exercise glucose turnover (5, 11, 49), whereas progesterone appears to have no additional, or conversely antagonistic, effect (11). There is inconsistency regarding whether or not glucose kinetics are affected by menstrual cycle fluctuations in estradiol and progesterone, with both no difference (3, 24) and a greater glucose flux (4, 64) being observed in the follicular vs. luteal phase. Reasons for these conflicting data may be related to differences in the level of circulating estrogen in female subjects and/or the demands placed on glucose production (24). In the present investigation, women were tested in the midluteal phase of the menstrual cycle, whereas, in the study of Roepstorff et al. (46), women were studied, on average, at day 9 of the follicular phase of the menstrual cycle. Despite what would have been very different progesterone levels, estradiol would have been elevated in women in the two studies, and both studies observed a significantly lower glucose turnover relative to men, thus potentially supporting a role for estradiol in determining the sex difference in exercise glucose kinetics.

An indirect effect of the sex steroids could occur via interaction with the endocrine response, through a decrease or increase in other hormone release or through an enhancement or suppression of the action of glucoregulatory hormones. In the present study, we observed a significantly lower increase in glucagon from rest to exercise in women vs. men. In a previous study (unpublished data), we also observed a greater exercise increase in plasma glucagon with exercise (120 min of 40% VO2max exercise) in men (57 ± 3.5 to 80 ± 6.9 pg/ml) compared with women (51 ± 3.9 and 59 ± 3.7 pg/ml). It is notable that, despite a similarly reduced increment in glucagon level with exercise in women tested in the present study and our previous study, the absolute glucagon concentrations were much higher in women in the present study. This may be due to the phase of the menstrual cycle in which the two groups of women were tested: midluteal phase in the present study and follicular phase in the previous study. Greater glucagon levels have been observed in the luteal vs. follicular phase of the menstrual cycle (24, 31), and progesterone receptors are present on the {alpha}-cells of the pancreas (15), suggesting progesterone may increase tonic glucagon secretion. Nevertheless, it appears that, although progesterone may affect basal glucagon level, it does not affect the response to exercise. The lower exercise glucagon response in women may, therefore, be due to a greater estrogen level in women, a higher testosterone level in men, or may be unrelated to the circulating sex steroid environment per se.

Data presented here are the first to report on postexercise differences in glucose kinetics between men and women. Mirroring what was observed during exercise, women had a significantly lower glucose turnover than men. This was mainly due to a more immediate decrease in glucose flux at the end of exercise in women, whereas in men it took a little longer to reestablish basal glucose homeostasis. The higher glucose release in men postexercise may have been facilitated by the maintenance of an elevated glucagon level compared with preexercise, basal levels. By 120 min postexercise, however, glucose flux was similar between the sexes. The lower glucose concentration in women vs. men during the initial postexercise period appeared to be due to the early fall in glucose Ra exceeding the fall in Rd. This was insufficient to trigger any form of counterregulatory response, however. With respect to postexercise glycogen resynthesis, we had hoped to obtain an estimate of this from the difference between total CHO oxidation and tracer-determined glucose disposal. As presented in the results, however, the postexercise nonprotein RER was below 0.70, invalidating the use of the gas exchange data for the estimation of fat and CHO oxidation. The extended period of fasting, along with the 90-min exercise, likely introduced metabolic processes, including ketogenesis and gluconeogenesis (not balanced by oxidation) that would have incurred metabolic gas exchange unrelated to direct substrate oxidation. Thus we were not able to estimate if there were sex differences in nonoxidative glucose disposal (NOGD) postexercise. One might speculate, however, given the fact that our laboratory has previously observed no difference in postexercise CHO and lipid oxidation between the sexes under fasted conditions (25), a large part of the greater glucose Rd in men in the initial 2 h postexercise would have been due to a greater NOGD.

It is worth considering why other studies have not observed a significant sex difference in exercise glucose kinetics. In the study of Ruby et al. (48), shorter duration exercise (25 min at 70% LT immediately followed by 25 min at 90% LT) was employed. We currently observed the greatest difference in glucose kinetics between men and women after 45 min of continuous exercise at ~87% LT. Testing of subjects ~4.5 h after a high-CHO snack and at different times of day (meal consumption likely occurring for later testing) may have masked the potential sex differences in glucose turnover in the study of Carter et al. (6). Food consumption would have somewhat increased hepatic glycogen stores, which would otherwise be significantly depleted by an overnight fast: the test condition of the current and previous study observing lower exercise glucose kinetics in women (46). It is possible, therefore, that the sex difference in exercise blood glucose production (and utilization) may only be manifest in the setting of low hepatic glycogen stores, and differences in glucose kinetics may only become apparent when hepatic stores are additionally depleted with ~45 min of moderate exercise. Further support for this comes from two other studies. In a retrospective comparison of exercise glucose kinetics in women, to that of previously tested men (19), no difference in exercise glucose kinetics (45–65% VO2max, 60 min) was observed with subjects tested ~3.5 h after a high-CHO snack. In another study of the neuroendocrine response to exercise (80% LT, 90 min) in women vs. men, no difference in exercise glucose production or utilization was observed when similar euglycemia during exercise was maintained via exogenous glucose infusion (12). Such an infusion would relieve the need for endogenous glucose release, in the face of increased glucose utilization, and again could mask any potential sex differences in exercise glucose kinetics.

These data together might suggest that, in the face of limited hepatic glycogen stores, the restraint observed in glucose release in women may be the cause of the lower glucose utilization, as opposed to the converse. As both gluconeogenesis and glycogenolysis contribute to glucose production, data might suggest that women are less able to increase the gluconeogenic contribution to glucose production in the face of low-hepatic glycogen stores and increased glucose utilization. Lower gluconeogenesis in women vs. men could be due to the lower increment in glucagon in women vs. men during exercise and/or a lower precursor delivery and/or extraction. In animal models, the female sex steroids can also decrease gluconeogenesis and glucose production at rest (1, 35). Given the importance of glucose production in terms of the regulation of normal glucose homeostasis, the mechanisms resulting in the sex differences in glucose production with exercise and the consequences with respect to glucose utilization are areas that require further investigation.

The current investigation illustrates that sex-based differences in exercise and postexercise glucose metabolism can occur independently of differences in whole body nutrient oxidation. Specifically, lean, healthy women had a significantly lower glucose production and utilization during and up to 2 h after exercise compared with lean, healthy men. Furthermore, differences in the hormonal response to exercise, specifically the glucagon response and to a lesser extent the Epi response, appear to play a role in determining these sex differences in exercise and postexercise glucose kinetics. Current data delineate sex differences in healthy individuals and form a basis from which comparisons can be made to populations characterized by the dysregulation of glucose metabolism, specifically individuals with diabetes and/or obesity. As exercise can be beneficial in the management of aberrant glucose metabolism in these populations, whether the extent of such effects is similar in men and women, and how this is hormonally mediated is of relevance. Understanding the physiological impact of sex on these factors will ultimately assist with the development of the most effective and appropriate exercise programs in men and women and enable realistic goals to be set regarding the nature and extent of anticipated benefits.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This investigation was supported by National Institutes of Health Grants HL-59331, HL-04226, DK-48520, and by Public Health Services Research Grant M01 RR-00051 from the Division of Research Resources.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank all of the subjects who volunteered for the study for their time and cooperation. We thank the GCRC nursing, dietary, and laboratory staff for valuable assistance, as well as the Mass Spectrometry and Energy Balance Core Laboratories of the Colorado Nutrition Research Unit for important provision of testing and analytical services.


   FOOTNOTES
 

Address for reprint requests and other correspondence: T. J. Horton, Sect. of Nutrition, Box C225, Univ. of Colorado Health Sciences Center, 4200 East 9th Ave., Denver, CO 80262 (e-mail: tracy.horton{at}uchsc.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
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