J Appl Physiol 93: 42–50, 2002;
10.1152/japplphysiol.01080.2001.
Luteal and follicular glucose fluxes during rest and
exercise in 3-h postabsorptive women
SANG-HOON SUH, GRETCHEN A. CASAZZA, MICHAEL A. HORNING,
BENJAMIN F. MILLER, AND GEORGE A. BROOKS
Exercise Physiology Laboratory, Department of Integrative Biology,
University of California, Berkeley, California 94720-3140
Received 29 October 2001; accepted in final form 19 February 2002
Suh, Sang-Hoon, Gretchen A. Casazza, Michael A.
Horning, Benjamin F. Miller, and George A. Brooks.
Luteal and follicular glucose fluxes during rest and exercise in
3-h postabsorptive women. J Appl Physiol 93: 42–50, 2002;
10.1152/japplphysiol.01080.2001.—We examined the effects of
exercise intensity and menstrual cycle phase on glucose flux
rates during rest and exercise in rested and fed (3-h postabsorp-
tive) women. Eight moderately active, eumenorrheic women
were studied under conditions of rest (90 min) and exercise (60
min, leg ergometer cycling at 45 and 65% peak oxygen con-
sumption) during follicular and luteal phases. In both men-
strual phases, an effect of exercise intensity was evident with
glucose rates of appearance and disappearance and metabolic
clearance rates: rest ⬍ 45% intensity ⬍ 65% intensity (P ⬍
0.05). In addition, we observed no significant effect of menstrual
phase on glucose rates of appearance and disappearance and
metabolic clearance rate during rest or exercise at either inten-
sity. These results are interpreted to mean that in women fed
several hours before study 1) glucose flux is directly related to
exercise intensity, 2) menstrual cycle phase does not alter glu-
cose flux during rest and exercise, and 3) the subtle effects of
endogenous ovarian hormones on glucose kinetics are subordi-
nate to the much larger effects of exercise and recent carbohy-
drate nutrition.
glucose kinetics; exertion; ovarian hormones
THE MIX OF SUBSTRATES USED during exercise is influenced
by numerous factors, including, but not limited to,
exercise intensity and duration (5–7, 14, 35), training
status (7, 14, 15, 27), muscle fiber type (23), diet (8, 43),
and gender (13, 22, 38). Although the effects of these
factors on substrate utilization are well studied in men,
similar studies on women are less prevalent, and still
less attention has been paid to menstrual cycle effects
on glucose flux during exercise.
Results of studies on cohorts of men and women
matched on habitual physical activity levels suggest
that during moderate-intensity exercise women oxidize
a smaller proportion of carbohydrate (CHO) relative to
lipid than do men, as indicated by lower respiratory
exchange ratio (RER) values (16, 22, 38, 39). Recent
studies on glucose flux from women in the midfollicular
phase have shown no gender differences during rest
Address for reprint requests and other correspondence: G. A. Brooks,
Dept. of Integrative Biology, 3060 Valley Life Science Bldg., Univ. of
California, Berkeley, CA 94720 (E-mail: gbrooks@socrates.berkeley.edu).
42 8750-7587/02 $5.00 Copyright © 2002 the American Physiological Society
and exercise of moderate (14) and high (30) intensities.
Given similar glucose flux and lower CHO oxidation,
the results are consistent with reports of greater lipid,
lesser muscle glycogen and relatively higher blood
glucose use in women. The potential mechanism for
lower CHO oxidation in women compared with men
may be the decreased rate of glycogenolysis, which may
be partially attributable to lower circulating epineph-
rine concentrations (38) and lesser muscle glycogen
levels (20).
The metabolic effects of the ovarian hormones have
been addressed by investigating the response to acute
exercise during the follicular (FP) and luteal (LP) men-
strual phase (25, 29, 43, 44) or by comparing men with
women (11, 14, 22, 39). Those studies showed discrep-
ancies in glucose flux [rate of appearance and rate of
disappearance (Ra and Rd, respectively)], in muscle
glycogen utilization rates, and in circulating levels of
glucose and lactate during rest and exercise. For ex-
ample, two recent studies (8, 44) observed that, when
women were allowed to fast for 10–12 h, significant
reductions occurred in glucose flux rates during exer-
cise in LP compared with FP. However, the menstrual
phase difference disappeared when CHO was supplied
in a fluid-energy-electrolyte replacement beverage dur-
ing exercise (8). In addition to differences in dietary
controls imposed, some of the discrepancies found in
data that compared men with women and that exam-
ined the role of ovarian hormones may be attributed to
the difficulties involved with matching subjects and
with timing of the measurements relative to the men-
strual cycle, respectively. Collectively, these previous
studies have shown a trend toward lower levels of
blood lactate and small differences in the levels of blood
glucose during rest and exercise in the LP. In addition,
muscle glycogen appears to be utilized less in LP com-
pared with FP (18).
Because limited data are available on blood glucose
flux rates in response to menstrual cycle phase changes
and because of the potential effects of dietary and
activity histories, we examined the effects of exercise
intensity and menstrual cycle phase on blood glucose
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solely to indicate this fact.
http://www.jap.org
 GLUCOSE FLUX IN FED WOMEN
flux during rest and exercise. We hypothesized that 1)
blood glucose flux would scale to exercise intensity and
that menstrual cycle effects, if any, would be small by
comparison; 2) dietary status would have a greater
effect than menstrual cycle phase on glucose flux and
overall CHO and lipid oxidation rates in exercising
women; and 3) blood glucose flux would be similar
during high-intensity exercise [at 65% peak oxygen
consumption (V̇O2 peak)] regardless of menstrual cycle
and dietary status because of the overriding effects of
exercise stimulating muscle glycogenolysis and glycol-
ysis (7).
METHODS
Subjects. Eight healthy, moderately active women between
the ages of 22 and 30 yr with normal menstrual cycles (24–32
days) were recruited from the University of California,
Berkeley campus, community by posted notices and E-mail.
Subjects were nulliparous, reported having normal men-
strual flows (for at least 6 mo), had not taken oral contracep-
tives, and had not experienced any large weight, exercise, or
diet changes within the last 6 mo. Subjects had a percent
body fat between 19 and 25%, a V̇O2 peak between 38 and 54
ml 䡠 kg⫺1 䡠 min⫺1, and a normal lung function (forced expira-
tory volume in 1 s of 70% or more) and were injury and
disease free as determined by a health history questionnaire
and physical examination. Subjects provided informed con-
sent, and the study protocol was approved by the University
of California Committee for the Protection of Human Sub-
jects (no. 2000-8-30).
Experimental design. After the initial screening interview
and physical examination were completed, to determine the
V̇O2 peak, subjects performed continuous graded exercise tests
in randomized order in each phase of the menstrual cycle.
Subjects were subsequently tested in a random order during
early FP (days 3–9) and LP (days 18–24 or 4–9 days past the
luteinizing hormone surge). Urinary luteinizing hormone
levels were measured with ovulation kits (First Response,
Carter Products) starting at day 10 after the start of menses
until a positive test was achieved. A positive test result
indicated the surge in luteinizing hormone that occurred
within 48 h. Cycle phases were later confirmed by plasma
estradiol and progesterone concentrations (FP: estradiol ⬍
50 pg/ml and progesterone ⬍ 1 ng/ml; LP: estradiol ⬎ 50
pg/ml and progesterone ⬎ 3 ng/ml) (6, 8, 32). Four stable
isotope tracer infusion trials were conducted within two se-
quential menstrual cycles, with each trial consisting of a
90-min rest period followed by a 60-min exercise protocol.
Exercise tasks involved leg ergometer cycling at 45 and 65%
V̇O2 peak.
Screening tests. V̇O2 peak during leg cycling was determined
during a continuous graded exercise test on a bicycle ergome-
ter (Monark Ergometric 839E) beginning at 75 W and in-
creasing 25 W every 3 min until voluntary cessation. Respi-
ratory gases were continuously monitored via an open-circuit
system (Ametek S-3A1 O2 and Ametek CD-3A CO2 analyz-
ers) recorded every minute by an on-line, real-time PC-based
mixing chamber system that our laboratory has used previ-
ously (4, 14, 41). This system was calibrated against two stan-
dard gases before, during, and after trials; runs at 100 Hz;
and calculates and reports respiratory parameters over 10-s
and 1-min intervals. In each trial, the open-circuit system
was calibrated twice before rest and exercise with room air
and a certified calibration gas (16% O2 and 4% CO2). V̇O2 peak
tests were accepted as maximal if heart rate was within 10%
J Appl Physiol • VOL
43
of predicted and RER values exceeded 1.1. Immediately be-
fore the second exercise screening test, a catheter was placed
in a forearm vein for withdrawal of blood for the determina-
tion of lactate threshold. The second screening test was done
to ensure reliability of the measures, evaluate the possibility
of a menstrual cycle phase effect on V̇O2 peak, and determine
lactate threshold; lactate threshold was determined as the
intensity of exercise at which blood lactate concentration is 1
mM above baseline (10). Body composition was determined
by skinfold measurement (six-site skinfold with a Harpenden
skinfold caliper) (24). Three-day diet records were collected
four times to assess dietary habits and to monitor the sub-
ject’s caloric intake and macronutrient composition. Analysis
of dietary records was performed with the Nutritionist III
program (N-squared Computing, Salem, OR).
Tracer protocol. Subjects were studied in a postabsorptive
state in the morning, and dietary intake was controlled for
the 24 h immediately preceding each of the four isotope
trials. Subjects rested the day before tracer trials and were
given a standardized daily diet [2,183 kcal: 63% CHO (5.5
g 䡠 kg⫺1 䡠 day⫺1), 15% protein, and 22% fat] to consume the day
before trials. In addition, subjects consumed a standardized
breakfast [308 kcal: 75% CHO (55 g), 16% protein, and 9% fat
(cereal, milk, and apple juice)] in the laboratory 3 h before
exercise. We chose to test our subjects in a rested and re-
cently fed, postabsorptive state to control for effects of meal
size, composition, and timing as well as to mimic conditions
in a nonlaboratory environment. On the morning of the trial,
a catheter was placed in a hand or wrist vein to obtain
“arterialized” blood samples by using the “heated hand vein”
technique, and a forearm venous catheter was placed in the
contralateral arm for continuous infusion of tracers. After
collection of background blood and expired gas samples, a
priming bolus of [6,6-2H]glucose (D2-glucose), at 125⫻ the
resting minute infusion rate, was given, and the subjects
rested supine or semisupine for 90 min while the D2-glucose
was continuously infused (Baxter Travenol 6300 infusion
pump). The glucose tracer was infused at 1.6 mg/min. Infu-
sion rates were increased to 4.8 and 6.4 mg/min during
exercise at 45% and 65% V̇O2 peak, respectively.
The isotope tracer infusion rates employed have been pre-
viously demonstrated by our laboratory to maintain stable
plasma isotopic enrichment for the measurement of sub-
strate kinetics throughout rest and the two exercise intensi-
ties (13, 14). Isotope tracers were obtained from Cambridge
Isotope Laboratories (Woburn, MA), diluted in 0.9% sterile
saline, and pharmacologically tested for sterility and pyroge-
nicity (School of Pharmacy, University of California, San
Francisco, CA); on the day of the experiment, tracers were
passed through a 0.2-␮m Millipore filter (Nalgen, Rochester,
NY) before infusion.
Blood sampling and analysis. Blood samples were taken at
0, 60, 75, 90 min of rest and at 15, 30, 45, 60 min of exercise
and were immediately chilled on ice before centrifugation at
2,800 g for 13 min. Supernatants were stored at either ⫺20°C
or ⫺80°C until analysis. Blood samples for glucose isotopic
enrichment and glucose and lactate concentrations were col-
lected in 8% perchloric acid and thoroughly mixed before
centrifugation. Blood samples for determination of hormones
were collected in heparinized syringes and transferred to
sterile vacutainers containing EDTA and mixed before cen-
trifugation. Aprotinin (4 mg/ml of blood) was added to pre-
vent cross-reaction of glucagon fragments arising from pro-
teolytic degradation. Blood glucose concentrations were
determined with hexokinase kits (Sigma Chemical, St. Louis,
MO), whereas blood lactate concentrations were determined
by using the methods of Gutmann and Wahlefeld (17).
93 • JULY 2002 • www.jap.org
44 GLUCOSE FLUX IN FED WOMEN
Plasma hormone concentrations were determined by 125I
radioimmunoassay (Coat-A-Count kits; Diagnostic Products,
Los Angeles, CA). Samples for each subject trial were ana-
lyzed together. The intra-assay coefficient of variations ranged
from 2–5%, and the sensitivities of the assays were 2.9 pmol/l
for estradiol, 0.06 nmol/l for progesterone, 1.2 ␮IU/ml for
insulin, and 13 pg/ml for glucagon. Hematocrit was measured
at each sampling point with the use of circular microcapillary
tube readers (no. 2201, International Equipment) to ensure
metabolite concentrations and isotopic enrichments were not
affected by changes in plasma volume. Subjects drank tap
water during each trial to maintain hydration status.
Isotopic enrichment analysis. Glucose isotopic enrichments
were determined by using gas chromatography-mass spec-
trometry (GCMS) (GC model 5890 series II and MS model
5989A, Hewlett-Packard) of the penta-acetate derivative. In
preparation for GCMS analysis, samples were neutralized
with 2 N KOH and transferred to cation (AG 50W-X8, 50–100
mesh H⫹ resin) and anion (AG 1-X8, 100–200 mesh formate
resin) exchange columns, and the glucose was eluted with
distilled deionized water. Samples were then lyophilized,
resuspended in methanol, and transferred to a 1-ml GCMS
vial. One hundred microliters of 2:1 acetic anhydride-pyri-
dine solution were added to each vial, and each vial was
heated at 60°C for 10 min. Samples were subsequently dried
under nitrogen, resuspended in 100 ␮l of ethyl acetate, and
transferred to GCMS vials for analysis. For GCMS analysis,
the injector temperature was set at 200°C and initial oven
temperature was set at 110°C. Oven temperature was grad-
ually increased by 35°C/min until it reached a final temper-
ature of 255°C. Helium was used as the carrier gas for all
analyses with a 35-to-1 ml/min splitless injection ratio. The
transfer line temperature was set at 250°C, the source tem-
perature was set at 200°C, and the quadrupole temperature
was set at 116°C. Chemical ionization was performed with
methane gas, and selected ion monitoring was used to mon-
itor ion mass-to-charge ratios (331.20 and 333.20 for
[12C]glucose and [6,6-2H]glucose, respectively).
Calculations. Glucose Ra, glucose Rd, and metabolic clear-
ance rate (MCR) were calculated by using equations defined
by Steele (37) and modified for use with stable isotopes
F ⫺ V[(C1 ⫹ C2)/2][(IE2 ⫺ IE1)/(t2 ⫺ t1)]
Ra (mg 䡠 kg⫺1 䡠 min⫺1) ⫽
[(IE2 ⫹ IE1)/2]
R d (mg 䡠 kg ⫺1 䡠 min ⫺1) ⫽ R a ⫺ V[(C 2 ⫺ C 1)/(t2 ⫺ t1)]
MCR (ml 䡠 kg ⫺1 䡠 min ⫺1) ⫽ R d/[(C 1 ⫹ C 2)/2]
where F represents the isotopic infusion rate, V is the esti-
mated volume distribution of glucose (180 ml/kg), C1 and C2
are concentrations at sampling times t1 and t2, respectively,
and IE1 and IE2 are the glucose isotopic enrichments of
[2H]glucose at sampling times t1 and t2, respectively. Values
for isotopic enrichment were corrected for baseline enrich-
ments from background blood samples taken before infusion
of the isotopes. Energy derived from total CHO and lipid
oxidation was calculated (12)
%Energy from CHO ⫽ [(RER ⫺ 0.707)/0.293] ⫻ 100
%Energy from lipid ⫽ 100 ⫺ [(RER ⫺ 0.707)/0.293] ⫻ 100
Energy from CHO oxidation (kJ/min)
⫽ [(%CHO/100) ⫻ (V̇O2)] ⫻ (21.1 kJ/liter O2)
Energy from lipid oxidation (kJ/min)
⫽ [(1 ⫺ %CHO/100) ⫻ (V̇O2)] ⫻ (19.7 kJ/liter O2)
J Appl Physiol • VOL
Statistics. Representative values for hormone concentra-
tions and glucose kinetics were obtained by averaging results
from the final 15 min (75, 90 min) of rest and 30 min (30, 45,
60 min) of exercise. Despite concerted efforts to control prior
activity and diet and to standardize time of day and men-
strual cycle phase, cell sizes in ANOVA varied because en-
docrine status criteria were not always met, mainly due to
inconsistencies in progesterone rise after luteinizing hor-
mone surge. Hence, data are presented as means ⫾ SE of
parameters for which paired (luteal-follicular) data are avail-
able. Because there were no significant differences between
resting values for the two trials in each phase of the men-
strual cycle, the resting values were pooled to obtain one
follicular (n ⫽ 7) and one luteal (n ⫽ 5) value. Significance of
differences between mean values for physical characteristics
was determined by paired t-tests. Significance of differences
among mean values representing metabolic concentrations
and flux rates for the four conditions were determined by
using two-way ANOVA with repeated measures followed by
multiple comparisons (S-Plus 2000, Professional Release 2).
Significance of differences over time during exercise was
determined by using one-way ANOVA with post hoc Scheffé’s
test. Statistical significance (␣) was set at 0.05.
RESULTS
Subject characteristics. Physical characteristics of
subjects are listed in Table 1. Subjects were weight
stable throughout the study period, with no changes in
percent body fat or V̇O2 peak between menstrual phases.
RER, CHO, and lipid oxidation. There was an in-
crease in RER in the transition between rest and ex-
ercise at both intensities in both menstrual phases
(Table 2), but this increase was not significant, except
for the 65% trial in FP (P ⬍ 0.05). Values for RER
during exercise were higher for the 65% trials com-
pared with the 45% trials in both menstrual phases,
but these values were not significantly different be-
tween phases.
At rest, ⬎50% of the energy was derived from CHO
sources for both menstrual phases, but no significant
phase difference was observed. During exercise in all
isotope trials, there was a shift to a greater reliance on
CHO sources, which was significant (P ⬍ 0.05, Table
2). Total energy coming from CHO during exercise at
Table 1. Physical characteristics of subjects in
follicular and luteal menstrual phases
Variable FP LP
n 7 5
Age, yr 24.9 ⫾ 1.4 26.0 ⫾ 1.8
Height, cm 165.6 ⫾ 1.6 165.9 ⫾ 2.2
Weight, kg 61.4 ⫾ 1.1 60.2 ⫾ 1.4
Body fat, % 23.3 ⫾ 1.6 21.4 ⫾ 1.5
Fat mass, kg 14.4 ⫾ 0.8 12.9 ⫾ 0.7
Fat-free mass, kg 47.0 ⫾ 0.8 47.3 ⫾ 1.1
V̇O2peak,
ml 䡠 kg⫺1 䡠 min⫺1 44.2 ⫾ 1.8 42.9 ⫾ 2.1
l/min 2.7 ⫾ 0.1 2.5 ⫾ 0.1
Lactate threshold, %V̇O2peak NM 67.0 ⫾ 3.2
Values are means ⫾ SE; n ⫽ no. of women. FP, follicular phase;
LP, luteal phase; V̇O2peak, peak oxygen consumption; NM, not mea-
sured.
93 • JULY 2002 • www.jap.org
 GLUCOSE FLUX IN FED WOMEN 45

Table 2. Ergometric and physiological parameters of subjects during rest and exercise
in follicular and luteal menstrual phases
Rest Exercise

Variable FP LP FP45 LP45 FP65 LP65

n 7 5 7 6 7 5
Workload, W 0 0 59.1 ⫾ 5.8* 58.2 ⫾ 5.2* 97.9 ⫾ 6.8*† 97.5 ⫾ 6.6*†
V̇O2, ml 䡠 kg⫺1 䡠 min⫺1 4.0 ⫾ 0.1 4.0 ⫾ 0.1 20.2 ⫾ 0.9* 19.5 ⫾ 1.2* 29.4 ⫾ 1.3*† 28.7 ⫾ 1.9*†
V̇CO2, ml 䡠 kg⫺1 䡠 min⫺1 3.4 ⫾ 0.1 3.5 ⫾ 0.1 18.0 ⫾ 0.9* 17.4 ⫾ 1.0* 27.2 ⫾ 1.2*† 26.8 ⫾ 1.9*†
RER 0.85 ⫾ 0.02 0.88 ⫾ 0.01 0.90 ⫾ 0.01 0.90 ⫾ 0.01 0.93 ⫾ 0.01* 0.93 ⫾ 0.02
EE
kJ/min 4.9 ⫾ 0.1 4.9 ⫾ 0.0 25.3 ⫾ 1.0* 23.6 ⫾ 1.4* 37.3 ⫾ 1.5*† 35.6 ⫾ 1.5*†
kcal/min 1.2 ⫾ 0.0 1.2 ⫾ 0.0 6.1 ⫾ 0.3* 5.7 ⫾ 0.3* 8.9 ⫾ 0.4*† 8.5 ⫾ 0.4*†
Energy from CHO
kJ/min 2.5 ⫾ 0.3 3.0 ⫾ 0.2 17.1 ⫾ 1.2* 15.5 ⫾ 1.0* 28.1 ⫾ 0.9*† 28.0 ⫾ 2.9*†
kcal/min 0.6 ⫾ 0.1 0.7 ⫾ 0.1 4.1 ⫾ 0.3* 3.7 ⫾ 0.2* 6.7 ⫾ 0.2*† 6.7 ⫾ 0.7*†
Energy from lipid
kJ/min 2.5 ⫾ 0.3 1.9 ⫾ 0.2 8.2 ⫾ 0.6* 8.2 ⫾ 1.8* 9.2 ⫾ 1.0* 7.6 ⫾ 2.1*
kcal/min 0.6 ⫾ 0.1 0.4 ⫾ 0.1 2.0 ⫾ 0.1* 2.2 ⫾ 0.4* 2.2 ⫾ 0.2* 1.8 ⫾ 0.5*
Minute ventilation, l/min 7.4 ⫾ 0.1 7.5 ⫾ 0.2 28.7 ⫾ 0.6* 28.6 ⫾ 1.3* 46.6 ⫾ 1.4*† 47.2 ⫾ 2.5*†
Heart rate, beats/min 63.5 ⫾ 2.2 67.0 ⫾ 2.5 131.1 ⫾ 3.8* 132.0 ⫾ 3.3* 168.5 ⫾ 3.3*† 169.3 ⫾ 4.5*†
Blood pressure, mmHg
Systolic 107.6 ⫾ 1.5 106.8 ⫾ 1.6 130.0 ⫾ 3.4* 128.9 ⫾ 3.0* 143.3 ⫾ 3.8*† 136.7 ⫾ 1.6*
Diastolic 69.3 ⫾ 2.4 68.6 ⫾ 2.2 67.9 ⫾ 3.6 65.2 ⫾ 2.4 61.5 ⫾ 1.6 65.7 ⫾ 5.4
Mean arterial 82.1 ⫾ 2.0 81.3 ⫾ 1.8 88.7 ⫾ 3.1 86.4 ⫾ 2.2 88.8 ⫾ 1.0 89.4 ⫾ 3.8
Hematocrit, % 41.1 ⫾ 0.6 41.0 ⫾ 0.5 42.6 ⫾ 0.7 41.3 ⫾ 0.7 42.5 ⫾ 0.4 42.8 ⫾ 0.5
Values are mean ⫾ SE; n ⫽ no. of women. 45 and 65, Exercise intensities in % of V̇O2peak; CHO, carbohydrate; EE, energy expenditure;
RER, respiratory exchange ratio; V̇O2, oxygen consumption; V̇CO2, carbon dioxide production. * Significantly different from resting conditions,
P ⬍ 0.05. † Significantly different from 45% trials, P ⬍ 0.05.

45% V̇O2 peak was 9.7% lower in LP compared with FP,
but the difference was not significant. During exercise
at 65% V̇O2 peak in both menstrual phases, as much as
6.7 kcal/min (⬎75%) of the energy used to do work was
derived from CHO sources. The contribution of lipid to
energy expenditure was similar to that of CHO at rest.
In all four isotope trials, there was a significant in-
crease in energy derived from lipid in response to
exercise compared with resting values (P ⬍ 0.05, Table
2), but no significant phase or intensity effect was
observed.
Ovarian hormone responses. Individual estradiol and
progesterone concentrations at rest and during exer-
cise are shown in Table 3. Values that did not meet the
endocrine status criteria were excluded from mean
value representation and statistical analyses. Estra-

Table 3. Ovarian hormone concentrations during rest and exercise for each subject
Rest Exercise

Subject No. FP45 LP45 FP65 LP65 FP45 LP45 FP65 LP65

Estradiol, pg/ml
1 238.7§ 82.7 88.7§ 47.9§ 269.3§ 98.3 91.8§ 74.0§
2 20.8 110.5 32.5 116.3 33.5 146.5 44.5 210.2
3 32.3 81.5 40.1 70.1 47.1 116.5 81.9 120.3
4 24.6 23.3§ 22.7 27.9§ 36.4 32.3§ 38.9 42.8§
5 43.8 69.4 38.3 79.5 65.9 127.9 58.6 126.2
6 19.4 98.6 23.3 90.1 26.1 109.7 44.4 203.1
7 10.8 18.3§ 15.6 202.4§ 15.9 33.7§ 25.8 353.5§
8 27.1 64.1 27.6 67.4 36.4 117.6 41.1 97.0
Mean ⫾ SE 25.5 ⫾ 4.0 84.5 ⫾ 7.2‡ 28.6 ⫾ 3.4 84.7 ⫾ 8.9‡ 37.3 ⫾ 6.0 119.4 ⫾ 6.7‡ 47.9 ⫾ 6.7* 151.3 ⫾ 23.1*‡
Progesterone, ng/ml
1 0.4§ 4.9 0.3§ 2.3§ 0.8§ 6.0 0.7§ 3.6§
2 0.6 13.3 0.5 4.8 0.7 14.0 0.8 7.3
3 0.3 16.2 0.3 9.7 0.3 19.6 0.4 11.5
4 0.4 0.5§ 0.3 0.4§ 0.4 0.4§ 0.7 0.9§
5 0.3 12.2 0.5 0.9 0.6 16.0 0.8 2.6
6 0.6 13.1 0.4 14.1 0.6 12.6 0.7 16.3
7 0.6 4.4§ 0.3 0.6§ 1.0 5.4§ 0.6 0.8§
8 0.2 14.1 0.3 10.6 0.3 18.6 0.3 14.8
Mean ⫾ SE 0.4 ⫾ 0.1 12.3 ⫾ 1.6‡ 0.4 ⫾ 0.0 8.0 ⫾ 2.3‡ 0.6 ⫾ 0.1 14.5 ⫾ 2.0* 0.6 ⫾ 0.1 10.5 ⫾ 2.5‡
* Significantly different from resting conditions, P ⬍ 0.05. ‡ Significantly different between FP and LP at rest, 45%, or 65% trials, P ⬍ 0.05.
§ Values excluded because endocrine status criteria were not met.

J Appl Physiol • VOL 93 • JULY 2002 • www.jap.org

46 GLUCOSE FLUX IN FED WOMEN
diol and progesterone concentrations before the com-
mencement of exercise were significantly higher in LP
compared with FP (P ⬍ 0.05, Table 3). Increases in
estradiol and progesterone occurred during exercise in
both menstrual phases, with estradiol concentration
being significantly greater at 65% trials (P ⬍ 0.05,
Table 3). Estradiol and progesterone levels remained
significantly elevated during exercise at both intensi-
ties in LP compared with FP (P ⬍ 0.05, Table 3). The
overall pattern of response was similar in the two
phases of the menstrual cycle.
Blood glucose and lactate concentrations. Blood glu-
cose concentrations tended to fall in response to exer-
cise. However, the change was not significant for any of
the four trials, and concentrations remained relatively
constant at 4.2–4.7 mM throughout exercise. Further-
more, there were no significant differences in blood
glucose concentration between any of the four trials
during rest or exercise at each time point (Fig. 1A).
Blood lactate concentrations increased in the transi-
tion between rest and exercise in both menstrual
phases in an intensity-dependent manner. (Fig. 1B).
The increase in blood lactate concentrations was sig-
nificant during exercise at 65% V̇O2 peak in both men-
Fig. 1. Blood glucose (A) and lactate (B) concentrations over time for
the 4 isotope trials. Values are means ⫾ SE at each time point for 7
women (FP45, FP65), 6 women (LP45), and 5 women (LP65). FP,
follicular phase; LP, luteal phase; 45 and 65, exercise intensities in
percent of peak oxygen consumption. *Significantly different from
resting conditions, P ⬍ 0.05. ⫹Significantly different from 45% trials,
P ⬍ 0.05.
J Appl Physiol • VOL 93 • JULY 2002 •
strual phases. Lactate concentrations during exercise
were significantly higher for the 65% compared with
the 45% trials in both menstrual phases (P ⬍ 0.05), but
there was no significant phase effect on blood lactate
response during exercise at either intensity.
Blood glucose kinetics. The [6,6-2H]glucose isotopic
enrichments are shown in Fig. 2A. The isotopic enrich-
ments for all four trials were stable during rest and the
last 30 min of exercise. Glucose Ra increased signifi-
cantly during exercise compared with at rest (P ⬍ 0.05)
for all four of the exercise conditions, and values are
presented as the average of the last 15 min of rest and
30 min of exercise (Fig. 2B). Glucose Ra was 30% higher
during the 65% trials compared with the 45% trials
(P ⬍ 0.05), demonstrating a significant intensity effect
in both menstrual phases (P ⬍ 0.05). However, there
was no significant effect of menstrual cycle phase on
glucose Ra during rest and exercise (P ⬎ 0.05).
Responses of glucose Rd to rest and exercise in both
menstrual phases were similar to those of Ra (Fig. 2C).
The similarity between our glucose Ra and Rd is con-
sistent with the observed stable glucose concentrations
and isotopic enrichments during exercise. The MCR of
glucose (Fig. 2D) was similar to glucose Rd among the
four trials because there was no significant difference
in blood glucose concentrations between exercise trials.
Insulin and glucagon responses. In all exercise-iso-
tope trials, insulin concentrations decreased signifi-
cantly in response to exercise compared with resting
values (P ⬍ 0.05, Fig. 3A). There was a significant
intensity effect in FP (P ⬍ 0.05, rest ⬎ 45% ⬎ 65%), but
no significant phase effect was observed during rest
and exercise in both menstrual phases.
Glucagon concentrations increased significantly dur-
ing exercise at 65% V̇O2 peak in both menstrual phases
(P ⬍ 0.05, Fig. 3B). However, no significant phase or
intensity effect was observed. There was one signifi-
cant menstrual cycle effect on the insulin-to-glucagon
ratio during exercise at 45% V̇O2 peak (insulin-to-gluca-
gon ratio in LP ⬍ FP; P ⬍ 0.05).
DISCUSSION
Results of the present investigation corroborate
those of previous studies that demonstrated a direct
relationship between exercise intensity and blood glu-
cose flux (13, 14, 35). Furthermore, this study demon-
strates that in a 3- to 4-h postabsorptive state there
were no significant effects of menstrual cycle phase on
blood glucose Ra, Rd, MCR, or whole body CHO and
lipid oxidation rates during moderate-intensity exer-
cise. In the aggregate, our results and those of others
reveal overriding effects of exercise and CHO nutrition
on glucose flux, CHO, and lipid oxidation rates in
women exercising during various menstrual cycle
phases.
Our results present similarities as well as differ-
ences compared with results of others (8, 13, 14, 44).
Similar to a study of men (13) and a study of women
tested in the FP (14), in our study, glucose flux rose
during exercise and as exercise intensity increased in
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 GLUCOSE FLUX IN FED WOMEN 47

Fig. 2. A: isotopic enrichments (IE) of [6,6-2H]glucose (D2-glucose) over time. Also shown is effect of menstrual
cycle phase and exercise intensity on [6,6-2H]glucose rate of appearance (Ra; B), rate of disappearance (Rd; C), and
metabolic clearance rate (MCR; D). Values for IE are means ⫾ SE at each time point, and values for Ra, Rd, and
MCR are means ⫾ SE of last 15 and 30 min of rest and exercise, respectively, for 7 women (FP45, FP65), 6 women
(LP45), and 5 women (LP65). *Significantly different from resting conditions, P ⬍ 0.05. ⫹Significantly different
from 45% trials, P ⬍ 0.05.

LP. When women were studied fasted as opposed to
postabsorptive, the glucose flux rates between men-
strual cycle phase were small, ranging from 14% (44) to
26% (8). Hence, small differences in glucose flux due to
menstrual cycle phase are easily overridden by other
factors, such as exercise and recent CHO intake.
Although not previously recognized, the overriding
effect of recent CHO nutrition shifting the balance of
substrate use to CHO oxidation in resting exercising
humans has been reported (3). Several studies have
found similar RER during rest and exercise between
menstrual phases when the subjects were studied in a
3-h postabsorptive state (2, 5, 6). In our investigation,
women were studied after 1 day of rest and with
controlled energy and CHO intake. Our subjects con-
sumed a standardized supper that we provided and
consumed a prescribed breakfast in the laboratory;
hence, we report data on fed and rested 3- to 4-h
postabsorptive subjects. Furthermore, the two exercise
tasks we used raised metabolic rate five to seven times
J Appl Physiol • VOL
above resting and resulted in 5- to 11-fold increments
in CHO oxidation. More energy was derived from CHO
sources during exercise (in an intensity-dependent
manner) in both menstrual phases. At higher intensi-
ties, it is likely that glycolytic flux governs substrate
selection (7). Thus the presence of relatively full mus-
cle and liver glycogen stores as well as the exercise-
induced crossover to dependence on CHO oxidation
overcame the relatively smaller, if any, effects of ovar-
ian hormones in promoting lipid oxidation.
Consistent with our interpretation of the influence of
CHO intake on energy substrate partitioning in women
are results of two recent reports in which glucose flux
in fasted subjects was measured (8, 44). Zderic et al.
(44) reported a significant (14%) decrease in glucose Ra
in women exercising in LP compared with FP. Simi-
larly, in their studies of glucose kinetics in women
exercising at 70% V̇O2 peak, Campbell et al. (8) observed
that the consumption of a CHO-containing “sports
drink” abolished differences in glucose Ra between
93 • JULY 2002 • www.jap.org
48 GLUCOSE FLUX IN FED WOMEN
Fig. 3. Effect of menstrual cycle phase and exercise intensity on
insulin (A) and glucagon (B) concentrations. Values are means ⫾ SE
of last 15 and 30 min of rest and exercise, respectively, for 7 women
(FP45, FP65), 6 women (LP45), and 5 women (LP65). *Significantly
different from resting conditions, P ⬍ 0.05. ⫹Significantly different
from 45% trials, P ⬍ 0.05.
menstrual phases. Because maternal glucose is the
main fuel for fetal development and growth, there may
be an evolutionary adaptation in women that acts to
preserve blood glucose under situations of physiologi-
cal stress. These adaptations may be unmasked only
under extreme conditions, such as when fasting and
vigorous exercise combine.
Several lines of evidence indicate that estradiol and
progesterone participate in the regulation of substrate
utilization during rest and prolonged exercise, but
studies examining the relationship between ovarian
hormones and metabolic responses in humans (6, 36,
43, 44) and rodents (1, 19, 21, 26) have produced
equivocal results. This is not surprising given the dif-
ficulty in trying to assess metabolic actions of a single
hormone in vivo. For example, as in the present inves-
tigation, no between-phase differences in blood glucose
(2, 5, 25, 32) concentrations or glucose flux (44) or
lactate (5, 25, 32, 34) concentrations in resting women
have been reported (44). Similarly, Ruby and col-
leagues (36) reported no differences in resting levels of
glucose or lactate or resting glucose flux in response to
transdermal estradiol administration in amenorrhic
J Appl Physiol • VOL 93 • JULY 2002 •
women. In addition, Minson et al. (31) found no differ-
ences in resting plasma epinephrine concentrations
between menstrual phases, which could partially explain
the absence of differences in resting blood glucose flux.
Blood glucose and lactate concentrations in our
study were not affected by menstrual phases during
prolonged exercise. In this respect, our results are
consistent with those of some previous studies showing
no effect of menstrual cycle phases on blood glucose (2,
5, 6, 25) or lactate (5, 6, 25) concentration responses to
prolonged exercise. However, others observed greater
blood glucose concentrations in women during pro-
longed exercise in LP (9, 44). This result may be be-
cause blood glucose concentration was elevated before
exercise in LP compared with FP. In contrast, Lavoie et
al. (29) observed lower glucose concentrations during
prolonged exercise in LP compared with FP in over-
night-fasted women previously fed a CHO-poor diet.
The investigators speculated that ovarian hormones
impaired hepatic gluconeogenesis, contributing to
lower glucose concentrations observed in LP (29).
Hence, differences between our findings and those of
Lavoie et al. may be due to differences in nutritional
status of subjects studied. To summarize, our results
and those in the literature can reasonably be inter-
preted to indicate that blood glucose and lactate re-
sponses to prolonged exercise are similar in the FP and
LP when subjects are several hours postabsorptive. It
may require a stronger stress (⬎12 h of fasting, ⬎60
min of prolonged exercise) to elicit a change in glucose
homeostasis. Long-term adaptation to changes in ovar-
ian hormones due to the menstrual cycle may have
adapted the body to respond well to exercise to main-
tain glucose homeostasis.
Blood glucose concentrations in the present study
remained relatively constant among the four trials
during steady-state exercise. Constancy of blood glu-
cose concentrations over time in exercising women
(Fig. 1A) indicates good matching of glucose production
and disposal rates when liver and muscle glycogen
levels are abundant. Although we did not measure
rates of gluconeogenesis or liver glycogenolysis in the
present investigation, in other recent studies, our lab-
oratory used dual-label (2H and 13C) glucose tracers
and mass isotopomer distribution analysis to assess
carbon recycling and gluconeogenic rates in exercising
men (40–42). These studies indicated that the men-
strual cycle phase differences in glucose Ra observed by
others (8, 44), but not by us (Fig. 2B), may be attrib-
utable to the dietary controls we imposed and the
overriding (in comparison to menstrual cycle) effects of
CHO nutrition and liver glycogen storage.
The exercise intensity-dependent changes in glucose
Ra that we observed in both LP and FP were coordi-
nated with changes in insulin and glucagon concentra-
tions. In the women that we studied, insulin fell during
exercise at both intensities and glucagon rose during
exercise at 65% V̇O2 peak, but we did not observe con-
sistent menstrual phase effects on glucagon or insulin
concentrations in exercising women (Fig. 3). However,
we did observe one significant phase difference in the
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 GLUCOSE FLUX IN FED WOMEN
insulin-to-glucagon ratio in the 45% trials (LP ⬍ FP,
P ⬍ 0.05). However, because neither insulin nor gluca-
gon concentrations changed significantly between
menstrual cycle phases, at this time we cannot at-
tribute a physiological significance to the one change in
insulin-to-glucagon ratio that we observed.
The current body of knowledge of the roles of ovarian
hormones in the regulation of glucose metabolism is
also derived from studies of insulin action after admin-
istration of exogenous estradiol, progesterone, or both
in ovariectomized rats (28, 33). In ovariectomized ro-
dents, insulin-stimulated glucose uptake decreases
(28, 33). This insulin resistance of ovariectomy was
mainly an effect of estradiol deficiency because estra-
diol replacement without progesterone was followed by
full restoration of insulin action. In contrast to estra-
diol, progesterone appeared to suppress the effects of
estradiol on insulin-stimulated glucose uptake (28, 33).
The suppression by progesterone of the augmentation
of insulin-stimulated glucose uptake by estradiol may
provide a physiological counterbalance during preg-
nancy conditions, when concentrations of both ovarian
hormones are high. In addition, Hansen and colleagues
(19) also reported a significant decrease in contraction-
stimulated glucose uptake but no significant changes
in skeletal muscle glycogen concentration or glucose
transporter-4 content in ovariectomized rats. Although
it has been shown that elevations in circulating levels
of estradiol and progesterone in rodents can influence
insulin action and, therefore, glucose metabolism in
hyperinsulinemic condition (plasma insulin of ⬃5.1
nM), altered insulin-stimulated glucose disposal does
not appear to change in a major way in response to
menstrual cycle variations in concentrations of endog-
enous ovarian hormones in humans.
Summary and conclusions. Results of this study in-
dicate that 1) as seen in previous studies, glucose flux
is directly related to exercise intensity regardless of
menstrual cycle phase; and 2) menstrual cycle phase
does not alter glucose flux in rested, 3-h postabsorptive
women during rest, moderate-intensity exercise (45%
V̇O2 peak), or high-intensity exercise (65% V̇O2 peak). In
combination with the results of others (8, 44), we con-
clude that the effects of endogenous ovarian hormones
on glucose flux and overall CHO oxidation are small
compared with the much larger effects of exercise and
recent CHO nutrition.
We thank the subjects for participating in this study. We also
thank Karen Porto, Joe Vivo, and Zinta Zarins, who provided much
of the laboratory support throughout the study. We are also grateful
to Jaimyoung Kwon who assisted with the statistical analysis.
This work was supported by National Institute of Arthritis and
Musculoskeletal and Skin Diseases Grant AR-42906.
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