Vol. 81, No. 1
Prmted in U.S.A.
0021-972x/96/$03.00/0
Journal
of Clinical
Endocrinology
and Metabolism
Copyright
0 1996 by The Endocrine
Society
Glucose Homeostasis
during
Normal Human Pregnancy*
PIERRE C. MAHEUX,
DANIELLE
MONIER,
Research Group on Diabetes
and H&el-Dieu de Mont&al
Quebec, Canada H2W lT8
BRIGITTE
BONIN,
JOSkE BOURQUE,
Spontaneous
ANNE DIZAZO,
JEAN-LOUIS
AND
and Metabolic
Regulation,
Institut
Hospital, Department
of Medicine,
in
PIERRE
GUIMOND,
CHIASSON
de Recherche Clinique
University of Montreal,
ABSTRACT
Using stable isotope, glucose turnover
was measured
in six normal
pregnant
women during the various
stages of labor: during the latent
(Al) and active (A2) phases of cervical
dilatation,
during fetal expulsion (B), and during
placental
expulsion
(Cl. These data were compared to measurements
made in five postpartum
women.
Pancreatic
hormones
and cortisol
were also measured.
In four other normal
women undergoing
spontaneous
labor, catecholamines
and free fatty
acids were measured.
Plasma
glucose
increased
throughout
labor
from 4.0 + 0.2 (Al) to 5.5 -t 0.5 mmob’L (C) (P < 0.011, compared
to
4.7 t- 0.1 in the postpartum
women.
Glucose utilization
and production were increased
throughout
labor at 33.4 + 3.1 and 32.8 t 3.1
pmol/kgmin,
respectively,
compared
to 8.2 % 0.9 in postpartum
women.
Glucose metabolic
clearance
was also increased
to 7.5 t 0.8
mL/kgmin
compared
to that in nonpregnant
women
(1.8 + 0.3).
Labor
de Montreal
Montreal,
Plasma insulin
remained
at 59 ? 5 pmol/L during stages Al, A2, and
B, but increased
to 115 f 15 pmol/L during stage C. Plasma glucagon
was increased
throughout
labor at 127 + 7 pg/mL, compared
to 90 Z?
4 pg/mL
in control
postpartum
women.
Plasma
cortisol
increased
during
labor from 921 +- 136 to 2018 -+ 160 nmol/L,
compared
to 645
+ 355 during
the postpartum
period.
Epinephrine
and norepinephrine also increased
during
labor from 218 2 132 pmol/L and 1.09 +
0.16 nmol/L
to 1119 i- 158 and 3.61 ? 1.04, respectively.
It is concluded that labor is associated
with a marked
increase
in glucose
utilization
and production.
These findings
suggest that muscle contraction
(uterus
and skeletal)
independent
of insulin
is a major regulator of glucose utilization
during
labor. Furthermore,
the increase
in hepatic
glucose
production
could be favored
by an increase
in
glucagon,
catecholamines,
and cortisol.
(J Clin Endocrinol Metab 81:
209-215,
1996)
M
ANY METABOLIC and hormonal changestake place
during pregnancy (1,2). Among these is a profound
adaptation of carbohydrate metabolism characterized by a
progressive state of insulin resistancethat impedes maternal
glucoseutilization and consequently increasesglucose fluxes
to the developing fetus (3-5). The phenomenon of labor is a
physiological and dynamic process leading to the birth of a
new human being. Several important changes in the endocrine milieu culminate with labor, and others arise with its
initiation (6-8). The factors leading to the initiation of labor,
however, are poorly understood. These changesalong with
the high energetic demands of labor are expected to further
modify whole body fuel metabolism. Although it is fairly
well established that the plasma glucose concentration increasesduring normal parturition (9-ll), it is interesting to
realize that little is known about glucose metabolism during
parturition in normal women. Holst et al. (9) observed an
increasein blood glucose levels during labor associatedwith
a decreasein insulin concentrations in six healthy women.
This increase in plasma glucose could be due to an increase
in hepatic glucose production, a decreasein peripheral utiReceived
June 8, 1995. Revision
received
July 20, 1995. Accepted
August 7, 1995.
Address
all correspondence
and requests
for reprints
to: Dr. JeanLouis Chiasson,
Centre
de Recherche/HBtel-Dieu
de Montreal,
3850
Saint-Urbain
Street, Montreal,
Quebec,
Canada
H2W
lT8. E-mail:
[email protected].
* This work was supported
by a grant from the Canadian
Diabetes
Association.
Presented
in a Symposium
on Gestational
Diabetes at the
52nd Annual
Meeting
of the American
Diabetes
Association,
San
Antonio,
TX, June 1992.
209
lization, or both. Interpretation is difficult, however, because
there is no information on glucose turnover during labor. In
an attempt to further define the underlying physiological
mechanisms, glucose turnover measurements were performed during labor in normal women, using a stable isotope
technique. In addition, these changes were correlated with
levels of several gestational and nongestational hormones as
well as some important substrates, such as free fatty acids
(FFA).
Materials
and
Methods
Materials
The stable isotopes
n-[2,3,4,6,6-‘HIglucose
and o-[6,6-2H]glucose
were purchased
from Merck, Sharp, and Dohme (Pointe Claire, Canada),
and tracer infusions
were performed
using a Harvard
pump 11 (Ealing
Scientific
Co., Saint-Laurent,
Canada).
Subjects
The study population
consisted
of a total of 10 healthy and primigravid women
recruited
at the Department
of Gynecology
and Obstetrics of Hopital
Maisonneuve-Rosemont.
Of these, 6 underwent
isotopic
measurements
of glucose turnover
using stable isotopes
(as described
below), and 4 others were studied to obtain additional
data on plasma
levels of FFA and catecholamines
during parturition.
There is no known
maternal
or fetal risk of using nonradioactive
stable isotope tracers, and
the safety of these naturally
occurring
substances
has been addressed
by
others
(12, 13). The Institutional
Review
Boards
of both Hopital
Maisonneuve-Rosemont
and Clinical Research Institute
of Montreal
approved
the research project, and informed
consent was signed by all
volunteers.
Each woman
had normal
routine
blood chemistries
at the
beginning
of pregnancy
and a normal
O’Sullivan
screening
glucose
MAHEUX
210
tolerance
test between
24-28 weeks gestation
(14). None was taking
medication
known
to affect glucose metabolism,
was considered
a high
risk pregnancy,
or had evidence
of uterine
malformations
or echographic fetal abnormalities.
Each volunteer
was closely followed
by an
obstetrician
and had an uneventful
pregnancy.
Results were compared
to those from a control group of 5 age-matched
healthy and nonlactating
women
studied 6 months postpartum.
Experimental
protocol
The pregnant
women were admitted
to the hospital at term, and the
experiment
was started in early spontaneous
labor. The latter was defined as a cervical dilatation
of at least 2-3 cm and an effacement
of 70%.
The time of the last meal taken was determined
by history
upon admission,
and all women
had been fasting for at least 10 h before the
study. Shortly after admission,
an indwelling
catheter was inserted into
a forearm
vein and kept patent with a saline drip. Each woman
was
assessed by the same obstetrician,
and fetal and uterine
contractions
were continuously
monitored.
Labor was divided,
as illustrated
in Fig.
1, into different
phases according
to a modification
of Friedman’s
cervical dilatation
curve (15): phase Al or latency, phase A2 or active phase,
phase B or fetal expulsion,
and phase C or immediate
postpartum
period
(until 1 h after placental expulsion).
Vaginal examination
was performed
by the same obstetrician
every hour or more frequently
if required
by
the progression
of labor. No tocolytic
agents, oxytocin,
local or general
anesthetics,
or analgesics
were used before, during,
or after delivery.
Two subjects were helped by an amniotomy
because the obstetrician
felt
that the latency phase was prolonged.
All subjects underwent
a normal
spontaneous
labor ended by normal
nonbreech
vaginal
expulsion
of a
healthy baby. Nursing
was withhold
for 1 h after placental
expulsion.
In addition,
each volunteer
had within minutes a spontaneous
return of
the uterus to a normal size.
In six of the volunteers,
a catheter was inserted
into a forearm
vein
for the isotopic glucose infusion.
o-[6,6-2HlGlucose
(150-mg bolus followed by a 1.5-mg/min
infusion)
was administered
as a prime-constant
infusion.
Infusion was started early enough in the latent phase to allow
a steady state in plasma specific activity.
The mean infusion
time during
the phase Al was 4.9 2 1.2 h (range, 1.5-9.5 h). The isotopic infusion
was
continued
until 1 h after expulsion
of the placenta. The duration
of the
isotopic infusion
averaged
8.8 2 1.6 h (range, 3.3-13.8 h). Isotopic
enrichment
in latent and active phases of labor was constant throughout
parturition
at 0.72 -+ 0.04%. A bolus of n-[2,3,4,6,6-‘HIglucose
(100 mg)
I
CERVICAL
LATENT
DILATATION
(Al
)
IInn
10
FETAL
(A)
ACTIVE
f
’ (6)
(AZ)
EXPULSION
(C)-;!$;;~;
/
ET AL
JCE & M . 1996
Volt31 . No 1
was also given in a subset of four women at the beginning
of phases A2,
B, and C for measurement
of volume
distribution,
as determined
by
isotope dilution.
The volume of distribution
did not change significantly
during
the various
phases of labor and averaged
18.3 2 1.1% (range,
16.2-25.4%)
of the total body weight
(P = 0.82). Saline was the only iv
fluid given throughout
labor and delivery.
Finally,
glucose turnover
was assessed in a control group of postpartum
women
using a prime-constant
infusion
of o-[2,3,4,6,6-‘Hlglucase (200-mg bolus followed
by a 2.0-mg/min
infusion).
The infusion
was started after an overnight
fast and continued
for 3 h. Blood samples
were drawn
every 15 min over the last hour of the experiment
for
measurement
of the same parameters.
Blood
samples
Blood samples were collected from a venous catheter contralateral
to
the isotopic infusion
site. Baseline samples were obtained before starting
the isotopic infusion
and at regular intervals
during each phase of labor.
A minimum
of three blood samples per phase were taken, and this
number
varied obviously
according
to the duration
of each phase. For
example,
there was an average of 5.3 t 0.7 blood drawings
(range, 3-7
blood drawings)
in phase Al, which was the longest phase, and 3.3 t
0.2 during
phase C or fetal expulsion.
Blood was collected
on ethylenediamine
tetraacetate
for glucose, insulin,
PRL, estradiol,
progesterone, and cortisol measurements;
on ethylenediamine
tetraacetate
plus
1% aprotinin
(Trasylol)
for glucagon
determination;
and on glutathione
for plasma
catecholamine
measurements.
During
the experiments,
blood was immediately
centrifuged
and kept at 4 C. Plasma was then
aliquoted
and stored at -70 C until assayed in batches.
Substrates
and hormonal
assays
Plasma glucose was measured
in duplicate
by the hexokinase
method
after deproteinization
with 6% perchloric
acid and neutralization
with
potassium
hydroxide
(16). Plasma insulin, glucagon,
estradiol,
progesterone, cortisol,
PRL, and catecholamines
were measured
with commercially
available
RIAs. Plasma FFAs were measured
by spectrophotometry
(Wake).
Glucose turnover
assessment
Plasma isotopic enrichment
was determined
throughout
each phase
of labor. For the determination
of plasma enrichment,
samples were
deproteinized,
neutralized,
and purified
by ion exchange
chromatography as described
by Kreisberg
(17). The isotopes o-[2,3,4,6,6-‘Hlglucase and o-[6,6-*HIglucose
were determined
by combined
gas chromatography-mass
spectrometry
(Hewlett-Packard
5890-5970,
Palo Alto,
CA) under electron impact in the mode of selected ion monitoring.
The
glucose isotopes were measured
as their 6-acetyl-(1,2,3,5)-bis-butylburonyl-cY-o-glucofuranose
derivative.
In each case, the m-butyl+
ions were
monitored
at m/z 297,299,
and 302 (18) for o-glucose,
o-[2H,]glucose,
and o-[*H,]glucose,
respectively.
Calculations
1
,
2
4
ELAPSED
/
I 1
I
,
6
8
10
TIME
IN LABOR
I
,I
I
12
14
(h)
FIG. 1. Based on Friedman’s
cervical
dilatation
curve, labor was divided into three phases: phase A or cervical
dilatation
(Al for latent
period and A2 for active period), phase B or fetal expulsion,
and phase
C or placental
expulsion.
The D,-glucose
was given as a primeconstant
infusion
starting
in the latent period of cervical
dilatation
and continued
until
1 h after placental
expulsion.
Boluses
of D,glucose were administered
at the beginning
of phases A2, B, and C for
measurement
of the volume
of distribution.
The rates of total glucose appearance
(R,) and disappearance
(R,)
were calculated
using Steele’s nonsteady
state equation
as modified
by
De Bodo et al. (19). Distribution
volume
was calculated
after bolus
injection
of o-[2,3,4,6,6-*HIglucose
or o-[6,6-‘HIglucose
using a semilogarithmic
transformation
of the decrement
over time of their respective plasma enrichment.
The glucose MCR was calculated
by dividing
R, by the plasma glucose concentration.
This index was used to evaluate
the active transport
of glucose
or the capacity
of tissues to take up
glucose independently
of small changes in blood glucose concentration.
R,, R,, and MCR as well as the different
hormonal
and substrate
concentrations
were averaged
for each individual
phase of labor because
their lengths were different
between
subjects.
Statistical
analyses
Results are reported
as the mean 5 SEM. To evaluate
the differences
between
the various phases, data were analyzed
using a repeated mea-
GLUCOSE
TURNOVER
DURING
LABOR
211
surement
one-way
ANOVA.
When Ho (u, = u,,) was rejected, we performed multiple
comparison
using Bonferonni’s
method
(20). The comparison
between
parturition
and postpartum
data was assessed by
nonpaired
Student’s
t tests. Two-tailed
P < 0.05 was considered
statistically significant.
Results
Characteristics
of the parturient and control postpartum
women are shown in Table 1. Despite a difference in their
weights when metabolic studies were performed, there was
no difference in their nonpregnant weights. The mean duration of labor was 10.9 ~fr 1.0 h (range, 7.0-13.8 h), and the
durations of phases Al, A2, B, and C were, respectively, 7.0
+ 0.9, 2.2 2 0.6, 0.9 +- 0.1, and 0.9 i 0.1 h.
Glucose homeostasis
during
labor
Plasmaglucose concentrations during each phaseof labor
and in the control postpartum group are listed in Table 2. The
plasma glucose concentration was 4.0 + 0.2 mmol/L during
phaseAl, compared to 4.7 ? 0.1 mmol/L for the postpartum
women (P < 0.01). It increased gradually but significantly
throughout labor to 4.7 C 0.2 during phase A2 (P < O.Ol),5.4
? 0.3 mmol/L during phase B (P < O.Ol), and 5.5 + 0.5
mmol/L during phase C (P < 0.02). R, was increased over
3-fold in all phasesof labor, as shown in Fig. 2 (mean, 32.8
+ 3.1 pmol/kgmin) and Table 2. More specifically, R, values
were estimated to be 32.4 2 6.1, 36.5 2 9.0, 29.2 ? 5.1, and
33.2 t 5.5 pmol/kgmin in phasesAl, A2, B, and C, respectively. These values were significantly higher than that in the
control postpartum group (8.2 2 0.9 Fmol/kg*min), with P
values ranging from 0.003-0.02. Similarly, the R, was increasedto 32.1 2 6.1 in phaseAl, 36.6 t- 8.7 in phaseA2,30.2
+ 6.0 in phase B, and 34.8 ? 4.6 kmol/kgmin in phase C
(mean, 33.4 2 3.1 pmol/kgmin). The R, in each of these
phaseswas also significantly higher than that in the control
postpartum group (P values ranging from <O.OOl to 0.02).
Glucose MCRs were also higher throughout parturition, averaging 7.8 -C 1.5 in phase Al, 8.5 2 2.2 in phase A2, 5.7 +
1.1 in phase B, 8.1 -C1.9 in phaseC, and 1.8 -+ 0.3 mL/kgmin
in the postpartum control group (P < 0.02 compared to Al,
A2, B, and C).
Plasma
insulin
and glucagon
concentrations
during
labor
The mean plasma insulin level was 65 ? 2 pmol/L during
stage Al, which was very similar to that in the postpartum
women (67 C 4 pmol/L; Table 3). Plasma insulin had a
TABLE
1. Demographic
data
on subjects
Al
A2
B
FIG. 2. The R, (0) and R, (FQ) during
A2, B, and C) and in the postpartum
as the mean 2 sem. *, P < 0.001-0.02
of labor.
C
PP
the different
phases of labor (Al,
period (PP). Data are expressed
compared
to the various phases
tendency to decreaseduring stagesA2 (55 t 5 pmol/L) and
B (56 ? 6 pmol/L), but did not reach significance. At placenta
expulsion (stage C), however, plasma insulin increased to
115 -C15 pmol/L (P < 0.05). Glucagon, on the other hand,
remained stable, but significantly increased, throughout labor (127 -+ 7 rig/L) compared to that in postpartum women
(90 ? 4 rig/L; P < 0.02; Table 3).
Counterregulatory
and pregnancy
hormones
during
labor
Plasma epinephrine increased from 218 ? 132 pmol/L to
a maximal value of 1119 +- 158 pmol/L in phase B (Table 4).
The difference between these meanswas significant at a level
less than 0.05. Similarly, plasma norepinephrine increased
from 1.09 ? 0.16 nmol/L in phase Al to 3.61 + 1.04 nmol/L
at placental expulsion (P < 0.05). Plasmacortisol in phaseAl
was 921 nmol/L and increased during phasesA2, B, and C
to a mean of 1871nmol/L. This rise was statistically significant (P < 0.01). Estradiol and progesterone levels were very
elevated during labor compared to those in the control group
(P < 0.01) and decreasedto 31.9 2 5.1 and 237 2 24 nmol/L
in phase C (P > 0.05). Finally, PRL levels during labor were
significantly higher than those in the postpartum group (P <
O.Ol), but did not change significantly over time.
Groups
Parameters
Parturients
(n = 10)
26 t 2
Age b-1
Wt (kg)
Nonpregnant
At delivery
Gestational
age
(week)
Duration
of labor
Values
56.3
70.6
38.9
(h)
are the mean
(20-37)
2 3.1(42.0-75.7)
2 3.3 (55.0-90.5)
2 0.5 (37.3-41.5)
Postpartum
(n = 5)
28 + 11
57.2
(2530)
2 2.5 (52.2-63.9)
10.9 -C 1.0 (7.0-13.8)
-C SE, with
the range
in parentheses.
FFA concentrations
during
labor
FFA levels were increased throughout labor to values significantly higher than those in controls (Table 5). They increasedfrom 0.76 + 0.13 in phase Al to a peak of 1.43 + 0.10
milliequivalents (mEq)/L in phase A2. These means were
statistically different from each other (by repeated measures
ANOVA, P < 0.01) and from the control postpartum levels
(P < 0.01).
MAHEUX
212
TABLE
2. Plasma
glucose
concentrations
and glucose
Al
Plasma glucose (mmol/LJ
Ra @mol/kg
. min)
Rd (PmoL’kg
. min)
MCR (mLkg
. min)
a P < 0.01 compared
’ P < 0.02 compared
‘P < 0.02 compared
3. Plasma
4.0
32.4
32.1
7.8
to Al.
to Al.
to Al,
insulin
concentrations
a P < 0.05 compared
b P < 0.02 compared
+
k
ik
0.2
6.1
6.1
1.5
4.7
36.5
36.6
8.5
Postpartum
B
-c
t
-t
t
to Al,
to Al,
5.4
29.2
30.2
5.7
2
?
2
2
0.3”
5.1
6.0
1.1
5.5
33.2
34.8
8.1
labor
and in the postpartum
z
k
-c
-c
0.56
5.5
4.6
1.9
4.7
8.2
8.2
1.8
during
period
(n = 5)
55 2 5
130 + 10
56 t- 6
130 2 14
115 t 15”
130 t 8
67 f 4
90 t 4h
A2, B, and postpartum.
A2, B, and C.
of counterregulatory
218
1.09
921
56.4
478
259
acids
to Al,
Postpartum
65 t 2
120 t 9
and gestational
Labor
D P < 0.01 compared
0.1”
0.9’
0.9”
0.3’
C
Al
(mEa/L)
2
2
2
2
B
concentrations
free fatty
(n = 5)
C
0.2”
9.0
8.7
2.2
k
k
2
z
-tk
during
hormones
during
132
0.16
136’
7.8
66
60
labor
464
1.08
1770
72.1
485
163
in only
and in the postpartum
65
0.10
151
9.9
49
27
1119
2.73
2018
61.9
456
167
parturients.
and in the postpartum
period
Postpartum
B
t
k
2
k
2
k
four
labor
stages (n = 6)
A2
Labor
FFA
stages (n = 6)
A2
and norepinephrine
were measured
compared
to other phases.
compared
to Al, A2, B, and C.
compared
to Al and A2.
compared
to A2, B, and C.
compared
to A2, B, and C.
5. Serum
period
Al
Epinephrine
(pmoI0-J”
Norepinephrine
(nmol/L)”
Cortisol
(nmol/L)
Estradiol
(nmol/L)
Progesterone
(nmol/L)
PRL (p.gL)
TABLE
and in the postpartum
A2
and glucagon
Parameters
a Epinephrine
b P < 0.05
‘P < 0.01
d P < 0.05
‘P < 0.01
f P < 0.01
labor
JCE & M . 1996
Vol81
. No 1
Labor stages (n = 6)
Insulin
(pmol/L)
Glucagon
(rig/L)
4. Plasma
AL.
A2, B, and C.
Parameters
TABLE
during
Labor
Parameters
TABLE
turnover
ET
They
2
-+
2
k
t
+were
(n = 5)
C
158b
0.34
160
8.7
70
22
also
478
3.61
1824
31.9
237
224
measured
2
2
k
-f
2
2
90
1.04d
137
5.lb
24h
71
in five
nonpregnant
17
0.09
645
0.15
7.6
13
+
+
+
+
+
+
1’
0.01’
359
0.07
5.6’
3”
women.
period
stages (n =
4)
Al
A2
B
0.76 2 0.13
1.43 t 0.1
1.17 2 0.11
C
0.89
2 0.07
Postpartum
(n = 5)
0.56 k 0.06”
A2, B, and C.
Discussion
The purpose of the present study was to evaluate the effect
of labor on glucose production and glucose utilization. This
is the first study looking at glucose turnover during labor in
normal pregnant women. Our data show clearly that parturition is a high energy-consuming process,resulting in an
increasein glucose turnover. More specifically, we observed
that whole body glucose utilization (Rd) as well as the glucoseMCR were increased by 3- to 4-fold. Glucose utilization
was already increased at 32.4 ? 6.1 pmol/kgmin in phaseAl
compared to 8.2 + 0.9 pmol/kgmin in the postpartum
women (P < 0.02) and remained increasedthroughout labor.
This emphasizes the important energetic demand of labor.
This increase in glucose utilization was independent of
insulin, as the insulin levels in phases Al, B, and C were
unchanged and not different from those in postpartum
women. In fact, there was a tendency for insulin levels to
decreaseas labor progressed from phase Al through phases
A2 and B, from 65 + 2 to 55 + 5 and 56 t 6 pmol/L,
respectively. These changes in insulin levels are similar to
those observed by Holst et al. (9), who found that the hormone had a slight tendency to decreaseduring the first stage
of labor from 9.4 2 1.7 to 7.3 -C0.8 $J/mL (P = NS). These
observations indicate either that there is an increasein insulin
sensitivity or that glucose uptake during labor is independent of insulin. The well established insulin resistance that
characterized normal pregnancy (3,4) aswell as the increase
in counterregulatory hormones and FFA would favor insulin
resistance rather than insulin sensitivity. However, the insulin resistance of pregnancy could theoretically be decreasedby labor, but our measurementscannot fully appreciate changes in insulin sensitivity
under those
circumstances. It is, therefore, suggested that the increase in
glucose uptake is due to factors other than insulin’s action.
This is also compatible with the observations by Jovanovic et
al. (21) and Golde et al. (22), who found in insulin-dependent
GLUCOSE TURNOVER DURING LABOR
diabetic women undergoing labor that insulin infusion could
be stopped altogether, and glucose infusion had to be increased to maintain euglycemia. In other words, the increase
in glucose MCR during labor suggests that muscular contraction per se is a potent stimulant of glucose uptake and that
insulin may exert only a permissive effect. There is a burgeoning literature supporting the existence of such a mechanism in the exercising muscle (23-25). The experimental
design of this study does not permit us to delineate the site
of increased glucose uptake, but it is proposed that increased
glucose transporter to the plasma membrane of the uterine
muscle as well as skeletal muscle could be responsible for the
large increase in glucose utilization during labor. It is less
likely that the fetus contributes significantly during labor to
glucose disposal. This is supported by the observation that
2-deoxy-n-glucose accumulation is reduced by 40% in the
fetus when pregnant rats are exercised (26). Although it is
well established that an increased translocation of GLUT 4
plays a major role in exercising skeletal muscles (27), few data
arc available on how glucose is transported in myometrial
smuuth muscles cells. It is possible that glucose transporters
might play a role, as they have been studied in vascular
smooth muscles (28). Glucose is obviously not the only metabolic substrate used by the uterus. There is indeed ample
evidence that FFAs are crucial substrates for the working
uterus (29).
To sustain this important peripheral outflow of glucose
and maintain glucose homeostasis, the liver plays a pivotal
role by increasing its glucose production. Endogenous glucose production or the R, derived from these experiments
clearly showed changes parallel to those in R,. Thus, it is not
surprising that these changes are also 3- to 4-fold higher than
those in the postpartum control group. This increase in R,
would be equivalent to a dextrose infusion of 25 g/h, which
is, for example, far more that the 5-10 g/h dextrose currently
recommended for the intrapartum management of the diabetic mother (21, 30, 31). We suggest that the increase in
hepatic glucose production during labor is mostly from gluconeogenesis. Indeed, at this high rate of glucose production,
hepatic glycogen would be depleted within a couple of
hours. Even though the R, is obviously important in maintaining glucose homeostasis, the trigger factor(s) responsible
for its stimulation is not well understood. Considering these
observations, many factors are likely to contribute to the
increase in hepatic glucose production. First, there is a clear
decrease in the insulin to glucagon ratio, which in other
circumstances, such as exercise (321, has proven to be of
importance in the regulation of endogenous glucose production. Indeed, it is well known that small increases in basal
glucagon in the presence of constant or suppressed levels of
insulin can greatly increase hepatic glucose production.
Moreover, this hormone will activate enzymes involved in
both glycogenolysis and gluconeogenesis (33). It is possible
that the increase in glucagon secretion and the decrease in
insulin release could originate from a sympathetic a-adrenergic effect on pancreatic P- and u-cells (34). Circulating
levels of epinephrine and norepinephrine as well as direct
sympathetic nervous system stimulation can also increase
endogenous glucose production (35, 36). Studies in humans
using adrenergic blocking agents have shown that sympa-
213
thoadrenal activity is of importance for increasing R, during
exercise (37). More specifically, it is possible that this increase
in sympathoadrenal activity might be an important feedforward mechanism for R,. Additionally, substrates such as
glycerol, lactate, and alanine might play roles in triggering
and/or maintaining the heightened hepatic glucose production through gluconeogenesis. Other studies have shown a
marked increased in FFAs during labor (10, 38), and a padrenergic stimulation (norepinephrine) of lipolysis is the
most likely explanation (39). In addition, it is currently well
established that the subsequent hepatic oxidation of these
important substrates can contribute to an increased hepatic
glucose production through gluconeogenesis (40). Finally,
the increase in cortisol observed at the time of delivery could
participate in the increases in R, and lipolysis (41,42).
This study showed that plasma glucose increases during
labor. The increase to a maximum of 5.5 mmol/L at placental
expulsion is consistent with what other investigators have
observed (9 -11). It is not perfectly clear why plasma glucose
increases during labor. Theoretically, the rise in plasma glucose can be explained by either a decrease in Ii, and/or an
increase in R,. The former is unlikely, as we clearly observed
an augmented rate of glucose utilization during labor. On the
other hand, R, appears to be very well matched to R, in our
experiments. To explain this small elevation in plasma glucose, one could speculate that the elevation of R, either preceded the elevation of R,, or R, was just marginally increased
over R, during the entire period of labor. In these experiments, R, was never significantly higher than R,, but this
possibility is not excluded, because the sensitivity of the
methodology used might have underestimated this marginal
increase in R,. Furthermore, it is possible that a small overcompensation of R, during labor might have been maintained by the several metabolic and hormonal factors that we
discussed above. In other words, a small but significant increase in plasma glucose could have been due in part to a
feedforward or a more prolonged increase in hepatic glucose
production. This hypothesis needs to be confirmed.
Measurements of insulin during labor and after placental
expulsion are somewhat puzzling. Although insulin levels in
phases Al, A2, and B of labor were suppressed compared to
levels measured in late pregnancy (43), there was an impressive surge in insulin concentrations at placental expulsion. This marked increase in insulin levels in the immediate
postpartum period has been observed by other investigators
(9). If the suppression of insulin levels during active labor is
caused by increased sympathetic nervous activity, this does
not explain why insulin levels peak during phase C of labor
when levels of plasma catecholamines, especially norepinephrine, are even higher. This hypothesis would hold only
if catecholamines at the synaptic cleft were significantly decreased. The mechanism responsible for this burst of insulin
at delivery remains unclear, but raises the possibility that a
yet unidentified placental factor could also be involved in
restraining the expected rise in insulin secretion during labor
as plasma glucose increases. To produce this effect, this factor
would have to decrease rapidly during the postpartum
period, because changes in insulin were observed within 1 h
after delivery. Among the hormonal parameters measured in
this study, only estradiol and progesterone decreased by
214
MAHEUX
approximately 50% in phase C. Their contribution is, nevertheless, unlikely, because their respective levels are still
many-fold higher than those in the control postpartum
group. In addition, both hormones have been reported to
augment islet secretion responsiveness and enhance insulin
secretion, and their respective decrements would obviously
not be expected to further increase insulin levels (44). Human
placental lactogen decreases rapidly postpartum (45), but we
were not able to find any experimental evidence of a direct
effect on islet cells. Additionally,
there is no evidence that
there is a dramatic change in endorphin levels during the
early postpartum period (46). These endogenous opioid peptides certainly have been shown in vitro and in vivo to have
effects on pancreatic hormone secretion (47). Finally, the
increase in insulin might result from a reestablished blood
flow to the pancreas, allowing the p-cell to respond to the
higher glucose levels of labor (10, 48).
Lastly, we need to address the issue that the isotope used
to assess glucose turnover was different in the control
women from that in our parturients
(D-[2, 3, 4, 6, 6-*HI
glucose instead of D-[6, 6-2H] glucose). These postpartum
women were studied under a different protocol, and total
glucose turnover as well as gluconeogenesis were measured.
R, and R, values derived from such isotopic studies, however, should be very similar. Taking into account that some
deuterium can be recycled with D,, it is possible that total
glucose turnover could have been slightly underestimated.
However, it is unlikely that this would have obscured the
highly statistically significant difference observed between
the parturient and the control women.
In conclusion, labor in normal pregnant women is characterized by enhanced glucose disposal as well as glucose
production. A substantial proportion of this glucose disposal
appears to be insulin independent, and this peripheral increase in glucose uptake is closely matched, if not slightly
exceeded, by an increased hepatic glucose production. It
seems obvious that these changes are regulated by a complex
integrated system of neural and hormonal responses that
share some similarities with exercise. These occur obviously
in a different endocrine milieu and, for example, tend to
underestimate the well established insulin resistance of pregnancy. This elevation in glucose production and its transient
diversion to high energy-requiring
organs reemphasize the
extraordinary capability of the human body to rapidly adapt
its glucose metabolism to the important energy demands of
labor. Understanding
the scope of these changes is crucial.
Indeed, it will be important to verify to what extent these
homeostatic mechanisms are modified in the diabetic mother
undergoing labor, because achievement of euglycemia during parturition is of utmost importance.
Acknowledgment
The authors
manuscript
and
thank
Susanne
the illustrations.
Bordeleau-Chenier
for
preparing
the
References
1. Freinkel
N. 1980 Banting
29:1023-1035.
Lecture
1980:
of pregnancy
and
progeny.
Diabetes.
ET AL.
JCE & M . 1996
Volt31
. No 1
2. Kiihl C. 1975 Glucose
metabolism
during
and after pregnancy
in normal
and
gestational
diabetic
women.
I. Influence
of normal
pregnancy
on serum glucose and insulin
concentration
during
basal fasting
conditions
and after a
challenge
with glucose.
Acta Endocrinol
(Copenhl.
79:709-719.
MJ, Skyler
JS. 1985 Insulin
action during
pregnancy:
3. Ryan EA, O’Sullivan
studies
with euglycemic
clamp technique.
Diabetes.
34:380-389.
4. Leturque
A, Fern? P, Bum01 AF, Kande J, Maulard
P, Girard
J. 1986 Glucose
utilization
rates and insulin
sensitivity
in viva in tissues of virgin and pregnant
rats. Diabetes.
35:172-177.
Leturque
A, Gilbert
M, Girard
J. 1981 Glucose
turnover
during
pregnancy
in
anaesthetized
post-absortive
rats. Biochem
J. 196:633-636.
Fuchs A-R, Fuchs F. 1984 Endocrinology
of human parturition:
a review.
Br
J Obstet Gynaecol.
91:948-967.
Steer PJ. 1990 The endocrinology
of parturition
in the human.
Bailliere
Clin
Endocrinol
Metab. 4:333349.
Challis
JRG. 1989 Characteristics
of parturition.
In: Greasy RK, Resnik R, eds.
Maternal-fetal
medicine:
principles
and practice,
2nd ed. Philadelphia:
Saunders; 463-476.
9. H&t
N, Jenssen TG, Burhol
PG, Jorde R, Maltau
JM. 1986 Plasma vasoactive
intestinal
polypeptide,
insulin,
gastric inhibitory
polypeptide,
and blood glucose in late pregnancy
and during
and after delivery.
Am J Obstet Gynecol.
155:126-131.
10. Kashyap
ML, Sivasamboo
R, Sothy SP, Cheah JS, G&side
PS. 1976 Carbohydrate
and lipid metabolism
during
human labor: free fatty acids, glucose,
insulin,
and lactic acid metabolism
during
normal
and oxytocin-induced
labor
for postmaturity.
Metabolism.
25:865-875.
11. Pontonnier
G, Puech F, Grandjean
H, Rolland
M. 1975 Some physical
and
biochemical
parameters
during
normal
labor: fetal and maternal
study. Biol
Neonate.
X159-173.
12. Jones PJH, Leatherdale
ST. 1991 Stable isotopes
in clinical
research:
safety
reaffirmed.
Clin Sci. 80:277-280.
13. Klein PD, Klein ER. 1986 Stable isotopes:
origins and safety. J Clin Pharmacol.
26378-382.
14. O’Sullivan
JB, Mahan
CM. 1964 Criteria
for the oral glucose
tolerance
test in
pregnancy.
Diabetes.
13:278-285.
15. Friedman
EA. 1978 Normal
labor. In: Friedman
EA, ed. Labor: clinical
evaluation and management,
2nd ed. New York: Appleton-Century-Crofts;
45-58.
HU, Bernt E, Schmidt
F, Stork H. 1974 o-Glucose:
determination
16. Bergmeyer
with hexokinase
and glucose-6-phosphate
deshydrogenase.
In: Bergmeyer
HU, ed. Methods
of enzymatic
analysis.
New York: Verlag Chemie Weinheim/
Academic
Press; vol 3:1196-1201.
17. Kreisberg
RA, Siegal AM, Owen WC. 1972 Alanine
and gluconeogenesis
in
man: effect of ethanol.
J Clin Endocrinol
Metab. 34:876-883.
A, Lecavalier
L, Falardeau
P, Chiasson
J-L. 1985 Simultaneous
18. Martineau
determination
of glucose
turnover,
alanine
turnover
and gluconeogenesis
in
human using a double
stable-isotope-labeled
tracer infusion
and gas chromatography-mass
spectrometry
analysis.
Anal Biochem.
151:495-503.
N, Dunn A, Bishop JS. 1963 On the hormonal
19. De Bodo RC, Steele R, Altszuler
regulation
of carbohydrate
metabolism;
studies with C-14 glucose.
Recent Prog
Horm Res. 19:445-448.
K. 1985 Comparing
the means of several
groups.
N Engl J Med.
20. Godfrey
313:1450-1456.
21. Jovanovic
L, Peterson
CM. 1983 Insulin
and glucose
requirements
during
the
first stage of labor in insulin-dependent
diabetic
women.
Am J Med. 75:607612.
22. Golde SH, Good-Anderson
8, Montoro
M, Artal R. 1982 Insulin
requirement
during
labor: a reappraisal.
Am J Physiol.
144~556-559.
23. Richter
EA, Ploug T, Galbo H. 1985 Increased
glucose
uptake
after exercise:
no need for insulin
during
exercise.
Diabetes.
34:1041-1048.
24. Wasserman
DH, Geer RJ, Rice DE, et al. 1991 Interaction
of exercise
and
insulin
action in humans.
Am J Physiol.
260:E37-E45.
25. Wallberg-Henriksson
H, Hollosky
JO. 1984 Contractile
activity
increases
glucose
uptake
by muscle
in severely
diabetic
rats. J Appl Physiol.
57:10451049.
26. Treadway
JL, Young JC. 1989 Decreased
glucose
uptake
in the fetus after
maternal
exercise.
Med Sci Sports Exert. 21:140-145.
27. Goodyear
LJ, Hirshman
MF, Horton
ES. 1991 Exercise-induced
translocation
of skeletal
muscle
glucose
transporters.
Am J Physiol.
261:E795-E799.
28. Kaiser N, Sasson S. 1990 Differential
regulation
of glucose transport
in aortic
endothelial
and smooth
muscle cells. Diabetes.
39fSuppl
1):147A.
29. Makkonen
M. 1977 Myometrial
energy
metabolism
during
pregnancy
and
normal
and dysfunctional
labor. Acta Obstet Gynecol
Stand. 71fSuppl):7-68.
30. Lean MEJ, Pearson DWM,
Sutherland
HW. 1990 Insulin
management
during
labor and delivery
in mothers
with diabetes.
Diabetic
Med. 7~162-164.
31. Nattrass
M, Alberti
KGMM,
Dennis
KJ, Gillibrand
PN, Letchworth
AT,
Buckle
ALJ. 1978 A glucose-controlled
insulin
infusion
system for diabetic
women
during
labor. Br Med J. 2:599-601.
32. Vranic
M, Kawamori
S, Pek S, Kovacevic
N, Wrenshall
GA. 1976 The essentiality
of insulin
and the role of glucagon
in regulating
glucose utilization
and production
during
strenuous
exercise
in dogs. J Clin Invest. 57:245-255.
33. Liljenquist
JE, Keller
LJ, Chiasson
J-L, Cherrington
AD. 1979 Insulin
and
glucagon
actions and consequences
of derangements
in secretion.
In: DeGroot
GLUCOSE
34.
35.
36.
37.
38.
39.
40.
TURNOVER
LJ, Martini
L, Potts JT, et al, eds. Endocrinology.
New York: Grune and Stratton;
981-996.
Woods
SC, Porte Jr D. 1974 Neural
control
of the endocrine
pancreas.
l’hysiol
Rev. 54:596-619.
Gray DE, Lickley
HLA, Vranic
M. 1980 Physiologic
effects of epinephrine
on
glucose
turnover
and plasma
free fatty acid concentrations
mediated
independently
of glucagon.
Diabetes.
29:600-608.
Chenington
AD, Fuchs H, Stevenson
RW, Williams
PE, Alberti
KGMM,
Steiner
KE. 1984 Effect of epinephrine
on glycogenolysis
and gluconeogenesis
in conscious
overnight
fasted dog. Am J I’hysiol.
247:E137-E144.
Issekutz
Jr B. 1978 Role of beta-adrenergic
receptors
in mobilization
of energy
sources in exercising
dogs. J Appl Physiol.
44:869-876.
Brockerhoff
P, Holzer
A, Schicketanz
KH, Rathgen
GH. 1989 Long-chain
non-esterified
fatty acids in pregnancy,
during
labor, and postpartum.
Z Geburtsh Perinatol.
193139-144.
Connolly
CC, Steiner
KE, Stevenson
RW, et al. 1991 Regulation
of lipolysis
and ketogenesis
by norepinephrine
in conscious
dogs. Am J Physiol.
261:
E466 -E472.
Ferrannini
E, Barrett EJ, Bevilacqua
S, DeFronzo
RA. 1983 Effect of fatty acids
on glucose
production
and utilization
in man. J Clin Invest. 721737-1747.
DURING
LABOR
215
41. Divertie
GD, Jensen MD, Miles JM. 1991 Stimulation
of lipolysis
in humans
by physiological
hypercortisolemia.
Diabetes.
40:1228-1232.
42. Lecavalier
L, Bolli G, Gerich
J. 1990 Glucagon-cortisol
interactions
on glucose
turnover
and lactate gluconeogenesis
in normal
humans.
Am J Physiol.
258:
E.569-E575.
43. Cousins
L, Riggs L, Hollingsworth
D, Brink
G, Aurand
J, Yen SSC. 1980 The
24-hour
excursion
and diurnal
rhythm
of glucose,
insulin,
and C-peptide
in
normal
pregnancy.
Am J Obstet Gynecol.
136483-488.
44. Kalkhoff
RK, Kissebah
AH, Kim H-J. 1978 Carbohydrate
and lipid metabolism during
normal
pregnancy:
relationship
to gestational
hormone
action.
Semin Perinatal.
2291307.
45. Ylikorkala
0, Kauppila
A, Pennanen
S. 1975 Human
placental
lactogen
during
and after labor. Obstet Gynecol.
46204-208.
46. Hoffman
DI, Abboud
TK, Haase
HR, Hung
TT, Goebelsmann
U. 1984
Plasma P-endorphin
concentrations
prior to and during
pregnancy,
in labor,
and after delivery.
Am J Obstet Gynecol.
150:492-496.
47. Ramabadran
K, Bansinath
M. 1990 Glucose
homeostasis
and endogenous
opioid
peptides.
Int J Clin Pharmacol
Ther Toxicol.
28:89-98.
48. Lau TS, Taubenfligel
W, Levene
R, et al. 1972 Pancreatic
blood flow and
insulin
output
in severe hemorrhage.
J Trauma.
12:880-884.