ArticlePDF Available

Cortisol increases gluconeogenesis in humans: Its role in the metabolic syndrome

Authors:

Abstract and Figures

Android obesity is associated with increased cortisol secretion. Direct effects of cortisol on gluconeogenesis and other parameters of insulin resistance were determined in normal subjects. Gluconeogenesis was determined using the reciprocal pool model of Haymond and Sunehag (HS method), and by the Cori cycle/lactate dilution method of Tayek and Katz (TK method). Glucose production (GP) and gluconeogenesis were measured after a 3 h baseline infusion and after a 4-8 h pituitary-pancreatic infusion of somatostatin, replacement insulin, growth hormone (GH), glucagon and a high dose of cortisol (hydrocortisone). The pituitary-pancreatic infusion maintains insulin, GH and glucagon concentrations within the fasting range, while increasing the concentration of only one hormone, cortisol. Two groups of five subjects were each given high-dose cortisol administration, and results were compared with those from a group of six 'fasting alone' subjects (no infusion) at 16 and 20 h of fasting. Fasting GP (12 h fasting) was similar in all groups, averaging 12.5+/-0.2 micromol x min(-1) x kg(-1). Gluconeogenesis, as a percentage of GP, was 35+/-2% using the HS method and 40+/-2% using the TK method. After 16 h of fasting, GP had fallen (11.5+/-0.6 micromol x min(-1) x kg(-1)) and gluconeogenesis had increased (55+/-5% and 57+/-5% of GP by the HS and TK methods respectively; P<0.05). High-dose cortisol infusion for 4 h increased serum cortisol (660+/-30 nmol/l; P<0.05), blood glucose (7.9+/-0.5 mmol/l; P<0.05) and GP (14.8+/-0.8 micromol x min(-1) x kg(-1); P<0.05). The increase in GP was due entirely to an increase in gluconeogenesis, determined by either the HS or the TK method (66+/-6% and 65+/-5% of GP respectively; P<0.05). Thus cortisol administration in humans increases GP by stimulating gluconeogenesis. Smaller increases in serum cortisol may contribute to the abnormal glucose metabolism known to occur in the metabolic syndrome.
Content may be subject to copyright.
739Clinical Science (2001) 101, 739–747 (Printed in Great Britain)
Cortisol increases gluconeogenesis in humans:
its role in the metabolic syndrome
Samina KHANI and John A. TAYEK
Department of Internal Medicine, Harbor-UCLA Medical Center, 1000 W. Carson Street, Box 428, Torrance, CA 90509, U.S.A.
ABSTRACT
Android obesity is associated with increased cortisol secretion. Direct effects of cortisol on gluco-
neogenesis and other parameters of insulin resistance were determined in normal subjects.
Gluconeogenesis was determined using the reciprocal pool model of Haymond and Sunehag (HS
method), and by the Cori cycle/lactate dilution method of Tayek and Katz (TK method). Glucose
production (GP) and gluconeogenesis were measured after a 3 h baseline infusion and after a
4–8 h pituitary–pancreatic infusion of somatostatin, replacement insulin, growth hormone (GH),
glucagon and a high dose of cortisol (hydrocortisone). The pituitary–pancreatic infusion
maintains insulin, GH and glucagon concentrations within the fasting range, while increasing the
concentration of only one hormone, cortisol. Two groups of five subjects were each given high-
dose cortisol administration, and results were compared with those from a group of six fasting
alone subjects (no infusion) at 16 and 20 h of fasting. Fasting GP (12 h fasting) was similar in all
groups, averaging 12.5p0.2 µmol:min
1
:kg
1
. Gluconeogenesis, as a percentage of GP, was
35p2% using the HS method and 40p2 % using the TK method. After 16 h of fasting, GP had
fallen (11.5p0.6 µmol:min
1
:kg
1
) and gluconeogenesis had increased (55p5 % and 57p5 % of
GP by the HS and TK methods respectively ; P 0.05). High-dose cortisol infusion for 4 h
increased serum cortisol (660p30 nmol/l ; P 0.05), blood glucose (7.9p0.5 mmol/l; P 0.05)
and GP (14.8p0.8 µmol:min
1
:kg
1
; P 0.05). The increase in GP was due entirely to an
increase in gluconeogenesis, determined by either the HS or the TK method (66p6% and 65p5%
of GP respectively; P 0.05). Thus cortisol administration in humans increases GP by stimulating
gluconeogenesis. Smaller increases in serum cortisol may contribute to the abnormal glucose
metabolism known to occur in the metabolic syndrome.
INTRODUCTION
The metabolic syndrome is associated with increased
cardiovascular mortality. Several studies have shown a
significant association between android fat distribution
and increased cortisol secretion [1]. This syndrome is
associated with increases in serum and urinary free
cortisol, and it has also been associated with increased
blood glucose and glucose intolerance [2]. Recently, 90
patients with Type II diabetes were shown to have an
Key words: cortisol, gluconeogenesis, glycogenolysis.
Abbreviations: GH, growth hormone; GP, glucose production; HS method, reciprocal pool method of Haymond and Sunehag;
M
n
, glucose molecule with n
"$
C and 6kn
"#
C atoms (in any position); MIDA, mass isotopomer distribution analysis; P–P clamp,
pituitary–pancreatic clamp; TK method, Cori cycle\lactate dilution method of Tayek and Katz.
Correspondence: Dr John A. Tayek (e-mail tayek!humc.edu).
elevated serum cortisol concentration compared with
weight-matched controls [3]. Earlier work in humans
demonstrated that cortisol administration can increase
hepatic glucose production (GP) and the blood glucose
concentration, but an inability to measure gluconeo-
genesis directly in the past has prevented the direct
determination of the effect of cortisol on gluconeogenesis
in humans [4].
We have shown previously in normal subjects and in
cancer patients that, after an overnight fast, approx. 20%
# 2001 The Biochemical Society and the Medical Research Society
740 S. Khani and J. A. Tayek
of GP is derived from non-glucose carbon sources, 20%
by recycling of glucose (the Cori cycle) and 60% from
hepatic glycogen [5]. We found in normal subjects that,
during a period of 20–40 h of fasting, glycogenolysis is
reduced, so that 90% of the GP is due to gluconeogenesis
[6]. Theoretical arguments state that the current equations
overestimate gluconeogenesis by a factor of two [7];
however, results obtained using the current method
[5,6] for the measurement of gluconeogenesis are similar
to those obtained using both the
#
H
#
O and mass
isotopomer distribution analysis (MIDA) methods, as
demonstrated recently in children [8]. Use of the re-
ciprocal pool model of Haymond and Sunehag (HS
method) [9] eliminates the argument about the factor of
2, and provides results similar to those obtained using the
Cori cycle\lactate dilution method of Tayek and Katz
(TK method) [6]. In the present study, gluconeogenesis
determined by both methods will be evaluated to de-
termine the importance of the role of cortisol in the
metabolic syndrome.
Several studies support a role for cortisol in the
metabolic syndrome. A 5-day infusion of cortisol (hy-
drocortisone) in dogs increased GP and the conversion of
alanine into glucose in the liver (a marker of gluconeo-
genesis) [10]. However, in the dog model, acute cortisol
infusion has no effect on GP [11], except when insulin
concentrations are reduced [12]. In humans, gluconeo-
genesis begins to increase at 2 h and reaches a maximum
at 3 h during hypoglycaemia [13]. Whereas glucagon has
been shown to increase gluconeogenesis as early as 3–4 h,
there are no published data about the effects of adrenaline
on gluconeogenesis in humans [14]. While the effects of
adrenaline and glucagon are additive with regard to rates
of GP and fasting glucose, the addition of cortisol to an
adrenaline and glucagon infusion doubles the effect on
GP and glucose concentration compared with that seen
with the combined adrenaline and glucagon infusion
alone [15].
The present study was performed to determine the
ability of cortisol to increase gluconeogenesis in humans.
Insulin concentrations were maintained at the fasting
level in an attempt to minimize insulin’s effect on liver
gluconeogenesis. While increased serum insulin and
cortisol levels can be seen in the metabolic syndrome, the
insulin is less likely to be effective due to the endogenous
state of insulin resistance. Two relatively new methods
were used to estimate gluconeogenesis [6,9].
METHODS
Subjects
Ten normal subjects gave informed consent to the study,
which was approved by the Harbor-UCLA Research and
Education Institute IRB. The average age of the 10
subjects was 40p4 years, and their body weight was
72p3 kg (meanpS.E.M.). On day 1, the subjects were
placed on a balanced diet delivering calories at 1.25i
their estimated basal energy expenditure, 1 g of
protein:day
"
:kg
"
and a minimum of 300 g of carbo-
hydrate per day. Daily food intake was recorded. The last
food (snack) was provided at 21.00 hours on day 2 of the
study.
Infusion protocol
Infusions were started at 06.00 hours on day 3: five
subjects (group 1) received a primed, continuous
7 h infusion, and five subjects (group 2) received
an 11 h infusion, of 0.17–0.28 µmol of [U-
"$
C
'
]glucose:min
"
:kg
"
. The isotope was 99 % pure,
and was obtained from Martek (Columbia, MD,
U.S.A.). The priming dose was 16.8 µmol\kg. Data
from group 1 (high cortisol; 16 h fast) and group 2 (high
cortisol; 20 h fast) were compared with recently pub-
lished data for six subjects who fasted for 16 and 20 h
[14]. We selected the 7 and 11 h isotope infusions to also
determine if the amount of label in the five carbon atoms
of glucose (M
"
M
&
; see Calculations section below)
would alter the estimate of gluconeogenesis when using
the reciprocal pool model (HS method) for the measure-
ment of gluconeogenesis (see calculations below). The
11 h infusion will result in more
"$
C label in M
"
M
&
of
glucose (see below), which may influence the calculation
of gluconeogenesis.
Baseline measurements of GP and gluconeogenesis
were obtained after 3 h of infusion, at 09.00 hours. High-
dose cortisol was administered to subjects in group 1 for
4 h between 09.00 and 13.00 hours, and to subjects in
group 2 between 13.00 and 17.00 hours. (Group 2 was
given a low-dose cortisol infusion between 09.00 and
13.00 hours, followed by a high-dose cortisol infusion
between 13.00 and 17.00 hours; data from the low-dose
cortisol period are not presented due to an error in the
administration of insufficient insulin.) Gluconeogenesis
was determined by sampling blood every 20 min be-
tween 3 and 4 h of cortisol infusion (between 12:00
and 13.00 hours for group 1, and between 16.00 and
17.00 hours for group 2).
We used a modified pituitary–pancreatic (P–P) clamp
technique to control levels of critical hormones [16].
Metyrapone was not administered under the traditional
P–P clamp protocol because of its potential ability to
decrease glycogen stores [17] and hence alter the effect of
cortisol on the liver. The P–P clamp in all subjects was
started at 09.00 hours, and it consisted of a 4–8 h infusion
of insulin (0.05 m-units:min
"
:kg
"
), somatostatin
(0.1 µg:min
"
:kg
"
), glucagon (0.8 ng:min
"
:kg
"
),
human growth hormone (GH; 7 ng:min
"
:kg
"
) and
cortisol (1.8 µg:min
"
:kg
"
) (Figure 1). The goal of the
hormone infusion was to maintain all hormone concen-
# 2001 The Biochemical Society and the Medical Research Society
741Cortisol increases gluconeogenesis in humans
Figure 1 Experimental protocol
After 3 h, the subjects underwent a 4–8 h hormone infusion period. The P–P
infusion study started after 3 h of a baseline stable glucose infusion or at
09.00 hours. In five subjects, cortisol (hydrocortisone) was infused at high dose
(1.2 µg:min
1
:kg
1
) for a 4 h period (09.00 to 13.00 hours). In addition, five
subjects received a low-dose cortisol infusion first (results not shown), and
subsequently received a high-dose cortisol infusion between 7 and 11 h (13.00 to
17.00 hours). The doses of all the other hormones (insulin, GH, glucagon and
somatostatin) were the same during the 4 h cortisol infusion periods. Six subjects
were infused with glucose tracer only, and acted as 16 h and 20 h fasting alone
controls. There were five subjects in each of the two cortisol groups (16 h and
20 h).
trations in the fasting range, except for that of cortisol.
Groups 1 and 2 were selected to test if the effects of time
on liver glycogen content play a role in the ability of
cortisol to increase GP. Clearly, liver glycogen decreases
between 16 and 20 h of fasting, as does the rate of
glycogenolysis [6,14]. In addition, gluconeogenesis in-
creases between 16 and 20 h of fasting, so that com-
parisons with baseline rates of gluconeogenesis would not
be the best way to demonstrate an effect.
Plasma glucose and lactate enrichment, as well as
plasma insulin, C-peptide, glucose, glucagon, GH, cor-
tisol, catecholamines, non-esterified (‘free’) fatty acids
(NEFA) and amino acids, were determined every 20 min
over the final 60 min of each infusion period (group 1,
12.00 to 13.00 hours; group 2, 16.00 to 17.00 hours). All
hormones and substrates except for glucagon were
measured as described previously [18]. Glucagon was
assayed by RIA (Linco Research Inc., St. Charles, MO,
U.S.A.) with an antibody that reports much lower
glucagon concentrations than those reported previously
using the Unger method [6,14]. The lower values are
believed to reflect glucagon concentration more accu-
rately. Amino acids were measured using a Beckman
Gold amino acid analyser.
Calculations
The equations for the reciprocal pool model (HS method)
for the measurement of gluconeogenesis and GP have
been published recently [9]. M in the equations refers to
the isotopomer fraction (enrichment) of glucose (i.e.
glucose molecules with one
"$
C and five
"#
C atoms in any
position are designated M
"
; those with two
"$
C and four
"#
C atoms in any position are designated M
#
, etc. ). GP is
determined as the infused dose of glucose divided by the
enrichment of uniformly labelled glucose (M
'
) in plasma:
GP l infused dose (µmol:min
"
:kg
"
)\
plasma M
'
enrichment (1)
Fractional gluconeogenesis is given by
&
"
E
M
n
in
M
"
M
&
divided by the
'
"
E
M
n
of glucose in the entire
molecule (M
"
M
'
), where E
M
n
is defined as the enrich-
ment of glucose species M
n
. This is then multiplied by
the ratio of the entry rates of
"#
C and
"$
C. The ratio
of the sums of the entry rates of
"#
C and
"$
C into M
"
M
&
is given as
&
"
"#
C
M
n
divided by
&
"
"$
C
M
n
:
Gluconeogenesis (%) l
&
"
E
M
n
i
&
"
"#
C
M
n
'
"
E
M
n
i
&
"
"$
C
M
n
(2)
In the TK equation, the fractional rate of gluconeogenesis
is the product of the Cori cycle and the dilution of
hepatic lactate (eqn 3). Note that m is the enrichment in
lactate, and M is the enrichment in glucose:
Gluconeogenesis (%) l
$
"
M
'
"
M
i
'
"
M
n
2i
$
"
m
n
(3)
Absolute gluconeogenesis is the product of percentage
gluconeogenesis multiplied by GP. Non-gluconeogenic
glucose release is obtained by subtraction of gluconeo-
genesis from GP.
Data analysis
Data from fasting subjects and from the two high-dose
cortisol groups were compared by ANOVA. Simple
linear and multiple-step linear regression analysis was
carried out by the method of least squares. Significance
was defined as P 0.05. Data are represented for both
methods for the calculation of gluconeogenesis as
meanspS.E.M.
RESULTS
Plasma cortisol concentrations were increased by at least
3-fold in the cortisol infusion groups (Table 1). Plasma
insulin, glucagon and GH levels were not significantly
different when compared with fasting alone (Table 1).
NEFA concentrations were similar (mean 0.42p
0.03 mmol\l) in all three groups after 12 h of fasting
(baseline). After 16 h of fasting (13.00 hours), the NEFA
concentrations were significantly higher in the
cortisol groups than in the fasting alone group (0.90p0.13
and 0.82p0.08 compared with 0.63p0.09 mmol\l
respectively; P 0.05). NEFA concentrations were
# 2001 The Biochemical Society and the Medical Research Society
742 S. Khani and J. A. Tayek
Table 1 Hormone concentrations during a 16 h fast and at the end of a 4 h P–P clamp cortisol
infusion study
Values are meanspS.E.M. (
n
);*
P
0.05 compared with fasting alone. Results are shown at 16 h and 20 h of fasting. There
were no differences in the 12 h values for all the groups (results not shown).
Group Insulin (pmol/l) Cortisol (nmol/l) Glucagon (ng/l) GH ( µg/l)
16 h fasting alone (6) 40p6 199p27 42p6 1.3p0.3
16 h high cortisol (5) 31p6 660p30* 59p6 3.1p1.9
20 h fasting alone (6) 23p4 124p25 53p10 2.0p0.3
20 h high cortisol (5) 26p7 728p97* 68p7 1.8p0.3
Figure 2 Correlation between percentage gluconeogenesis
and NEFA concentration
The graph shows results from three groups at 16 h of fasting: six fasting alone
subjects, five subjects that had received high-dose cortisol, and five subjects just
before receiving high-dose cortisol. All values were obtained at 13.00 hours. The
figure demonstrates a modest correlation between gluconeogenesis and NEFA
(‘free fatty acid ’) concentration.
modestly correlated with percentage gluconeogenesis at
16 h (r l 0.661, P 0.05 ; Figure 2).
Amino acid profiles were obtained after 16 h and 20 h
of fasting to document the effects of cortisol infusion on
plasma amino acid concentrations (Table 2). Plasma
leucine, isoleucine and phenylalanine were significantly
increased at the end of the 4 h cortisol infusion. Plasma
amino acids were similar in all groups at baseline (12 h
fasting; results not shown).
A 4 h administration of cortisol increased plasma
glucose from 4.6p0.2 to 7.9p0.5 mmol\lat16hof
fasting. There was a similar increase in the 20 h fasting,
high cortisol group (Figure 3). In comparison, fasting
glucose concentrations decreased from 5.1p0.1 to
4.7p0.1 mmol\l(P 0.05) in the fasting alone (no
cortisol) group between 12 and 16 h of fasting.
The isotope enrichment of plasma glucose is listed in
Table 3 for the three groups. Very little enrichment was
detected in M
%
and M
&
, since the probability of re-
combination of two labelled trioses is very low
(2%i2%l 0.04%). Although the enrichments at M
%
Table 2 Plasma concentrations of selected amino acids
during a 16 h fast and during a P–P cortisol infusion study
Values are meanspS.E.M.; *
P
0.05 compared with 16 h fasting alone group.
The amino acids in
bold are considered to be essential amino acids (needed in
the diet) for adults; the ninth essential amino acid, methionine, was not measured
on the Beckman Gold amino acid analyser.
Amino acid
Concentration ( µmol/l)
High cortisol Fasting alone
Leucine 171p16* 137p13
Isoleucine 78p4* 65p7
Valine 224p8 210p9
Aspartic acid 33p11 31p7
Threonine 145p16 126p7
Serine 156p20 146p18
Glutaminejglutamate 392p62 377p65
Glycine 211p11 226p16
Alanine 359p26 340p36
Tyrosine 67p857p5
Phenylalanine 77p6* 66p5
Tryptophan 30p227p2
Ornithine 59p857p7
Lysine 229p25 260p26
Histidine 89p389p6
Arginine 191p42 192p35
Total 2511p117 2406p207
and M
&
were very low, their values were used in the HS
method (reciprocal pool method); however, they were
not used in the TK method. The two methods provided
rates of gluconeogenesis that were similar. As shown in
Table 4, the average value was 61% by the HS method
and 62% by the TK method. These values are expressed
as a percentage of GP.
Baseline (09.00 hours) rates of gluconeogenesis and GP
were similar in the two cortisol groups and the fasting
alone group at 12 h of fasting (results not shown).
Gluconeogenesis as a percentage of total GP was 35p2%
using the HS equation and 40p2 % using the TK
equation (P 0.05). Between 12 and 16 h of fast-
ing, the glucose concentration decreased by 9% (see
above) and GP decreased by 10% (P 0.05). During
# 2001 The Biochemical Society and the Medical Research Society
743Cortisol increases gluconeogenesis in humans
Figure 3 Effects of cortisol administration on blood glucose
Shown are changes in blood glucose over the 7–11 h study period. Both group 1
and group 2, who underwent high-dose cortisol (hydrocortisone) infusion under
P–P conditions, showed greater increases in blood glucose than in the fasting
alone group. Maximum glucose concentrations were similar in groups 1 and 2.
these 4 h of fasting, gluconeogenesis increased signifi-
cantly to 55p5% and 57p5% (or 6.3p0.7 and
6.5p0.6 µmol:min
"
:kg
"
), as calculated using the HS
and TK methods respectively. This was probably due to
mobilization of glycogen in the liver and a slow increase
in gluconeogenesis to maintain euglycaemia.
Table 3 Plasma glucose isotope enrichment at 16 h of fasting with and without a high-dose cortisol infusion
Values are meanspS.E.M. Similar data were obtained at 20 h of fasting (results not shown).
Conditions
Enrichment (% above baseline)
M
1
M
2
M
3
M
4
M
5
M
6
Fasting alone (
n
l 6) 0.268p0.032 0.255p0.026 0.350p0.029 0.061p0.003 0.011p0.004 2.00p0.14
Cortisol (
n
l 5) 0.392p0.091 0.312p0.062 0.425p0.076 0.062p0.003 0.010p0.003 2.10p0.39
Table 4 Comparison of the use of the TK and HS methods for calculation of gluconeogenesis
Values are meanspS.E.M. Significance of differences : *
P
0.05 compared with 16 h fasting alone;
P
0.05 compared
with 20 h fasting alone. At 12 h fasting the HS method calculated a lower percentage of GP compared with the TK method
(
P
0.05). At all other times there were no significant differences between the two methods in estimates of percentage
gluconeogenesis.
Group GP ( µmol:min
1
:kg
1
)
Gluconeogenesis (% of GP)
HS method TK method
12 h fasting alone (
n
l 16) (09.00 hours) 12.5p0.2 35p2 40p2
16 h fasting alone (
n
l 6) (13.00 hours) 11.5p0.6 55p557p5
16 h fastingjhigh cortisol (
n
l 5) 14.8p0.8* 66p6* 65p5*
20 h fasting alone (
n
l 6) (17.00 hours) 10.1p0.6 70p471p4
20 h fastingjhigh cortisol (
n
l 5) 12.5p0.9 80p3 76p1
Overall meanpS.E.M. 61p862p6
Figure 4 Effects of cortisol on gluconeogenesis and GP
The bars represents net GP; the hatched bar denotes gluconeogenesis and the
empty bar denotes glycogen breakdown (GP minus gluconeogenesis, as an estimate
of glycogen breakdown). Data are from the 16 h fasting alone group and from
the 16 h high-cortisol fasting group. High-dose cortisol infusion increased GP and
gluconeogenesis compared with fasting alone. A similar effect was seen at 20 h of
fasting (results not shown).
In the 16 h high-dose cortisol group, GP was in-
creased compared with that in the fasting alone group
(14.8p0.8 and 11.5p0.6 µmol:min
"
:kg
"
respectively;
P 0.05) (Figure 4). Gluconeogenesis as a percent-
age of GP increased from 55–57% to 65–66% at
16 h of fasting (P 0.05) (Table 4). The increase in
GP of 3.3 µmol:min
"
:kg
"
was due mostly to the in-
crease in gluconeogenesis, calculated as 3.5 and
# 2001 The Biochemical Society and the Medical Research Society
744 S. Khani and J. A. Tayek
3.1 µmol:min
"
:kg
"
by the HS and TK methods re-
spectively. To express this as a percentage, gluconeo-
genesis accounted for 95–106% of the observed increase
in GP. These values suggest that all of the increase in
GP is due to an increase in gluconeogenesis. The
plasma cortisol concentration was significantly corre-
lated with fasting blood glucose (r l 0.650; P 0.01)
and with gluconeogenesis (r l 0.430, P 0.05).
After 20 h of fasting, cortisol infusion had again
increased GP to a value greater than that seen
with fasting alone (12.5p0.9 compared with
10.1p0.6 µmol:min
"
:kg
"
; P 0.05). After 20 h of
fasting alone, gluconeogenesis accounted for 70–71%
of GP, whereas when cortisol was administered this per-
centage increased to 76–80% of GP (Table 4). High-dose
cortisol increased the absolute rate of gluconeogenesis,
calculated using the TK equation, when compared
with 20 h of fasting alone (9.5p0.7 compared with
7.2p0.7 µmol:min
"
:kg
"
; P 0.05). Using the HS
equation, the absolute rate of gluconeogenesis was
also increased significantly by cortisol (10.0p0.7 com-
pared with 7.1p0.7 µmol:min
"
:kg
"
; P 0.05). The
calculated 2.3 (TK equation) or 2.9 (HS equation)
µmol:min
"
:kg
"
increase in gluconeogenesis accounted
for the observed increase in GP of 2.4 µmol:min
"
:kg
"
.
The 7 and 11 h [U-
"$
C
'
]glucose infusions provided
similar estimates of gluconeogenesis using the HS and
TK equations (Table 4).
DISCUSSION
Although cortisol administration is known to increase
GP, its effects in humans on gluconeogenesis have been
difficult to verify. Only recently have several methods
become available for the estimation of gluconeogenesis in
humans. The present study involved the acute adminis-
tration of cortisol over a 4 h period under P–P clamp
conditions and determination of the effects on gluconeo-
genesis and GP. Administering high-dose cortisol
increased GP, mostly by increasing gluconeogenesis.
While recent data suggested that cortisol can increase
glycogen breakdown in the liver by mobilization of
lysosomes containing glycogen-hydrolysing glucosidase
and glycogen breakdown activity [19], we did not observe
this effect.
Rats which undergo adrenalectomy show reduced
gluconeogenesis and glycogen breakdown [20]. Patients
with adrenal insufficiency frequently have hypo-
glycaemia, which is probably due to reduced gluconeo-
genesis, glycogenolysis or both. As early as 1 h into the
4 h high-dose cortisol infusion the blood glucose level
was increased. While we did not measure gluconeogenesis
earlier than 3 h, the observed increase in blood glucose
may have been due to a combination of effects, including
an increase in gluconeogenesis, an increase in glycogen
breakdown and\or a decrease in glucose utilization.
Earlier work in chickens demonstrated that cortisol
increases glycogen breakdown as early as 45 min [21], so
that some of the observed increase in blood glucose may
have been due to liver glycogen mobilization [19,21].
Unfortunately, blood samples were not obtained at
1 or 2 h to determine the early effects of cortisol on glyco-
genolysis or gluconeogenesis. However, blood sam-
ples were obtained between 3 and 4 h. Gluconeogenesis
accounted for nearly all of the observed increase in GP.
The long-term effects of cortisol on gluconeogenesis in
humans have not been reported. However, patients with
malaria have persistent elevations in serum cortisol
and glucagon and significantly increased gluconeo-
genesis [22]. We have shown that a similar increase in
glucagon concentration in normal subjects increases the
rate of gluconeogenesis to 8.5 µmol:min
"
:kg
"
[14];
this is not as high as seen in patients with malaria
(14.4 µmol:min
"
:kg
"
[22]). In our present study, cor-
tisol alone increased gluconeogenesis by 10.0 (HS
equation) or 9.6 (TK equation) µmol:min
"
:kg
"
,
depending on the method used. However, the rate of
gluconeogenesis of 14.4 µmol:min
"
:kg
"
observed in
patients with malaria suggests that there is a synergistic
effect of glucagon and cortisol. Earlier work has demon-
strated that the addition of a cortisol infusion can double
the effects of a combined adrenaline and glucagon
infusion on GP [15]. Unfortunately, in the present study,
the combination of high cortisol and high glucagon was
not tested.
Effects of cortisol on glucose metabolism
In the present study, high-dose cortisol increased GP by
increasing gluconeogenesis alone. As expected, the serum
glucose concentration also increased during the 4 h
cortisol infusion (from 4.8 to 8.7 mmol\l). This increase
in blood glucose occurred after 60 min (Figure 3), which
may have been due to a rapid effect of cortisol on
gluconeogenesis [13]. While we did not determine gluco-
neogenesis before 3–4 h, earlier work suggests that,
during recovery from hypoglycaemia, gluconeogenesis
starts to increase within 120 min and reaches a maximum
by 3 h [13]. While cortisol concentrations were doubled
during hypoglycaemia, other hormones were also
increased (glucagon, adrenaline, GH), which may have
also contributed to the early onset of gluconeogenesis
[13]. Synergistic glycaemic actions of counter-regulatory
hormones have been demonstrated with glucagon and
adrenaline when cortisol is added [15]. While synergism
was not investigated in the present study, cortisol did
increase gluconeogenesis and blood glucose.
Limitations of the study
Clearly the increase in serum cortisol of 460–
600 nmol\ml (16–22 µg\dl) is greater than one would
expect to see in patients with the metabolic syndrome.
# 2001 The Biochemical Society and the Medical Research Society
745Cortisol increases gluconeogenesis in humans
The rationale for the high dose was to determine if the
effect on gluconeogenesis was measurable within a 4–8 h
period of a cortisol infusion. The similar results after 4 h
and 8 h suggest that the 4 h infusion period is sufficient to
evaluate effects on gluconeogenesis. Lower concen-
trations of cortisol, such as are seen in the metabolic
syndrome, need to be studied to determine the role of
cortisol in the pathophysiology of the abnormal glucose
metabolism observed in patients with the metabolic
syndrome.
In addition, caution should be used when comparing
the cortisol groups with a separate group of normal
subjects who fasted for the 16–20 h period. During the
study period (09.00 to 17.00 hours), the serum cortisol
concentration decreased. This may have accentuated the
observed effect of cortisol. In this type of experiment,
when gluconeogenesis increases between 12 and 20 h of
fasting [6], the use of a baseline comparison of gluco-
neogenesis at 12 h of fasting would not be appropriate.
Four subjects were administered replacement cortisol,
glucagon and insulin concentrations [14]. The rate of GP
was similar to that seen at 16 h of fasting [14], suggesting
that the use of fasting alone subjects in the present
study may not have overestimated the observed effects.
Clearly, prospective studies of small increases in serum
cortisol concentrations are needed in order to understand
the influence of cortisol in the metabolic syndrome.
Effects of cortisol on NEFA concentrations
Plasma cortisol decreases in the early morning as part of
a normal diurnal fall. While some authors believe that this
fall may be responsible for the parallel fall in GP, Boden
et al. [23] have suggested that changes in GP may instead
be due to changes in NEFA concentrations. In the
present study, serum NEFA concentrations increased
over time in all groups. Both of the cortisol groups
demonstrated a significant increase in NEFA which was
greater than that seen with fasting alone. It is important
to point out that cortisol increases lipolysis and NEFA
concentrations. Of note is the modest correlation of
NEFA concentration with percentage gluconeogenesis
(r l 0.661,P 0.05; Figure 2).Whilethis does notprove a
cause and effect, the association between NEFA and rate
of gluconeogenesis suggests that a relationship exists.
Earlier observations have demonstrated a correlation
between NEFA and gluconeogenesis in normal subjects
(r l 0.665, P 0.05, n l 14) [5,6], subjects with Type 2
diabetes (r l 0.616, P 0.05, n l 9) [24] and cancer
patients (r l 0.599, P 0.05, n l 13) (data from [5]).
Amino acids and cortisol
Essential amino acids are those amino acids that can only
be derived in the plasma compartment by the process of
proteolysis (muscle protein breakdown). Three of the
essential amino acids, leucine, isoleucine and phenyl-
alanine, were increased by cortisol infusion. Since the
subjects were fasting during the study, the only sources
of these three amino acids were intracellular, which
suggests that the elevated concentrations of leucine,
isoleucine and phenylalanine were derived from muscle
proteolysis.
Previous evidence suggests that cortisol increases the
concentrations of hepatic gluconeogenic precursors, as
well as improving gluconeogenic efficiency [25]. High-
dose cortisol administration increases leucine and phenyl-
alanine levels after 9–12 h [26]. These plasma levels are
increased due to an increase in the plasma rate of
appearance, which is an index of proteolysis [26]. While
the rate of appearance of leucine and phenylalanine was
not measured in the present study, the observed increase
in the plasma concentrations of these amino acids is
probably due to the proteolytic effect of cortisol.
Comparison of the HS and TK methods for
calculation of gluconeogenesis
The data in Table 4 demonstrate that, at 12 h of fasting,
the HS method underestimated the TK method by five
absolute percentage points (P 0.05). A recent pub-
lication by Haymond and Sunehag [9] demonstrated that
their method gave a value that was three absolute
percentage points below that obtained using the TK
method (50p7% compared with 53p7%). The present
paper describes results in a total of three groups (Table 4),
with a mean average (when including results from all
conditions) that is one percentage point lower with the
HS method compared with the TK method (61p8%
compared with 62p6%). Thus use of the reciprocal
model (HS method) provides similar estimates of gluco-
neogenesis as the TK method, and eliminates the need to
determine lactate enrichment.
The lower values obtained in the 12-h fasted subjects
by the HS method may have been due to the low
enrichment. A low enrichment in M
"
M
&
may under-
estimate the rate of gluconeogenesis when one uses
the reciprocal pool model (HS method). However, the
difference was modest (5 %) and within the expected
range determined by other methods. The low plasma
enrichment of glucose in M
"
M
&
was due in part to the
high costs of using the [
"$
C
'
]glucose isotope.
Criticism of the method
Landau [7] argued that the determination of gluco-
neogenesis has an error of a factor of 2, due to the number
2 used in the estimate of the dilution of hepatic
lactate\pyruvate. A rebuttal to these arguments has been
published [27]. Measurement of overall GP is agreed to
be accurate. It is the absolute rate of gluconeogenesis that
has been criticized to be overestimated by a factor of 2
when we use the TK equation. To adjust for this, readers
can divide the gluconeogenesis value from the TK method
by 2. However, this argument does not apply to the
assumptions in the newer reciprocal pool model (HS
# 2001 The Biochemical Society and the Medical Research Society
746 S. Khani and J. A. Tayek
method) [9]. Even with the correction factor of 2 in
the TK equation, the increase in gluconeogenesis in the
high-dose cortisol group in the present study would
still be significantly greater than that seen in the
16 h fasting alone group (4.8p0.1 compared with
3.2p0.1 µmol:min
"
:kg
"
; P 0.05). However, we be-
lieve that this adjustment is wrong, because Landau et al.
[7,28] based their claim upon a graphic model in which
the glucose pool was divided into two arbitrary subpools:
a large one with as much as 80% in brain’, etc. that is
oxidized to CO
#
and not recycled ’, and a small one
(20%) in which recycling occurs. However, recycling of
the glucose molecule has no borders, and recycling affects
the whole-body glucose pool, not just 20% of the glucose
pool. The isotopomer pattern in glucose taken from
different parts of the systemic blood will be the same,
irrespective of the site from which the blood is sampled.
The models of Landau et al. [28] are untenable, and
provide no support for their criticism of our equation to
estimate gluconeogenesis. Furthermore, the reciprocal
pool model provides similar results to our method and to
the MIDA method in infants and in many other
conditions, as reported recently [8]. Finally, the present
study demonstrates that the reciprocal pool model
provides realistic estimates of gluconeogenesis in humans,
and that the values obtained are very similar to those
obtained by the TK method.
Conclusion
Using a P–P clamp infusion protocol, high-dose cortisol
infusion increased blood glucose and GP by stimulating
gluconeogenesis. The effect of cortisol on gluconeo-
genesis was similar if the subject had fasted for 16 or 20 h.
This is the first study in humans that demonstrates the
ability of cortisol to increase gluconeogenesis. These data
demonstrate that cortisol increases GP by stimulating
gluconeogenesis within 3–4 h. Thus the elevation of
cortisol noted to occur in the metabolic syndrome may
contribute to hepatic gluconeogenesis and abnormal
glucose metabolism.
ACKNOWLEDGMENTS
This work was supported by NIH Clinical Investigator
Award KO8DK02083 and MO1-RR-00425.
REFERENCES
1 Bjorntorp, P. (2000) Metabolic difference between
visceral fat and subcutaneous abdominal fat. Diabetes
Metab. 26, S10–S12
2 Levitt, N. S., Lambert, E. V., Woods, D., Hales, C. N.,
Andrew, R. and Seckel, J. R. (2000) Impaired glucose
tolerance and elevated blood pressure in low birth
weight, non-obese, young South African adults: early
programming of cortisol axis. J. Clin. Endocrinol. Metab.
85, 4611–4618
3 Lee, Z. S., Chan, J. C., Yeung, V. T., et al. (1999) Plasma
insulin, growth hormone, cortisol, and central obesity
among young Chinese type 2 diabetic patients. Diabetes
Care 22, 1450–1457
4 Clerc, D., Wick, H. and Keller, U. (1986) Acute cortisol
excess results in unimpaired insulin action on lipolysis
and branched chain amino acids, but not on glucose
kinetics and c-peptide concentrations in man. Metab.
Clin. Exp. 35, 404–410
5 Tayek, J. A. and Katz, J. (1997) Glucose production,
recycling, Cori cycle and gluconeogenesis in humans:
relationship to serum cortisol concentrations. Am. J.
Physiol. 272, E476–E484
6 Katz, J. and Tayek, J. (1998) Gluconeogenesis and Cori
cycle in 12, 20 and 40-h fasted humans. Am. J. Physiol.
275, E537–E542
7 Landau, B. R. (1999) Limitations in the use of [U-
"$
C]
glucose to estimate gluconeogenesis. Am. J. Physiol. 277,
E408–E413
8 Sunehag, A. L., Haymond, M. W., Schanler, R. J., Reeds,
P. J. and Bier, D. M. (1999) Gluconeogenesis in very low
birth weight infants receiving total parenteral nutrition.
Diabetes 48, 791–800
9 Haymond, M. W. and Sunehag, A. L. (2000) The
reciprocal pool model for the measurement of
gluconeogenesis by use of [U-
"$
C] glucose; Am. J.
Physiol. 278, E140–E145
10 Goldstein, R. E., Wasserman, D. H., McGuinness, O. P.,
Brooks, D., Lacy, D. B. and Cherrington, A. D. (1993)
Effects of chronic elevation in plasma cortisol on hepatic
carbohydrate metabolism. Am. J. Physiol. 264,
E119–E127
11 Goldstein, R. E., Reed, G. W., Wasserman, D. H., et al.
(1992) The effects of acute elevation in plasma cortisol
levels on alanine metabolism in the conscious dog.
Metab. Clin. Exp. 41, 1295–1303
12 Goldstein, R. E., Abumrad, N. N., Lacy, D. B.,
Wasserman, D. H. and Cherrington, A. D. (1995) Effects
of an acute increase in epinephrine and cortisol on
carbohydrate metabolism during insulin deficiency.
Diabetes 44, 672–681
13 Lecavalier, L., Bolli, G., Cryer, P. and Gerich, J. (1989)
Contribution of gluconeogenesis and glycogenolysis
during glucose counterregulation in normal humans.
Am. J. Physiol. 256, E844–E851
14 Chhibber, V. L., Soriano, C. and Tayek, J. A. (2000)
Effects of low-dose and high-dose glucagon on glucose
production and gluconeogenesis in humans. Metab. Clin.
Exp. 49, 39–46
15 Shamoon, H., Hendler, R. and Sherwin, R. S. (1981)
Synergistic interactions among anti-insulin hormones
in the pathogenesis of stress hyperglycemia in humans.
J. Clin. Endocrinol. Metab. 52, 1235–1241
16 de Feo, P., Perriello, G., Torlone, E. et al. (1989)
Contribution of cortisol to glucose counterregulation
in humans. Am. J. Physiol. 257, E35–E42
17 Metskevich, M. S. and Rumiantseva, O. N. (1976) Effect
of metopirone and glucocorticoids on the glycogen
content in the adrenal of rat fetuses. Ontogenez 7,
638–642
18 Tayek, J. A. (1994) Growth hormone and glucose
metabolism in lung cancer. Endocrine 2, 1055–1059
19 Kalamidas, S. A. and Kotoulas, O. B. (2000) Studies on
the breakdown of glycogen in the lysosomes: the effect
of hydrocortisone. Histol. Histopathol. 1, 29–35
20 Cipres, G., Butta, N., Urcelay, E., Parrilla, R. and
Martin-Requero, A. (1995) Impaired protein kinase C
activation is associated with decreased hepatic alpha1-
adrenoreceptor responsiveness in adrenalectomized rats.
Endocrinology 136, 468–475
21 Egana, M., Sancho, M. J. and Macarulla, J. M. (1981) An
early effect of cortisol, previous to its glycogenogenic
action. Horm. Metab. Res. 13, 609–611
22 Dekker, E., Romijn, J. A., Ekberg, K. et al. (1997)
Glucose production and gluconeogenesis in adults with
uncomplicated falciparum malaria. Am. J. Physiol. 272,
E1059–E1064
# 2001 The Biochemical Society and the Medical Research Society
747Cortisol increases gluconeogenesis in humans
23 Boden, G., Chen, X. and Urbain, J. L. (1996) Evidence
for a circadian rhythm of insulin sensitivity in patients
with NIDDM caused by cyclic changes in hepatic glucose
production. Diabetes 45, 1044–1050
24 Tayek, J. A. and Katz, J. (1996) Glucose production,
recycling, and gluconeogenesis in normals and diabetics, a
mass isotopomer [U-
"$
C] glucose study. Am. J. Physiol.
270, E709–E717
25 Fujiwara, T., Cherrington, A. D., Neal, D. N. and
McGuinness, O. P. (1996) Role of cortisol in the
metabolic response to stress hormone infusions in the
conscious dog. Metab. Clin. Exp. 45, 571–578
Received 5 June 2001/30 July 2001; accepted 19 September 2001
26 Brillon, D. J., Zheng, B., Campbell, R. G. and Matthews,
D. E. (1995) Effect of cortisol on energy expenditure and
amino acid metabolism in humans. Am. J. Physiol. 268,
E501–E513
27 Katz, J. and Tayek, J. A. (1999) Recycling of glucose and
the determination of the Cori cycle and gluconeogenesis.
Am. J. Physiol. 277, E401–E407
28 Landau, B. R., Wahren, J., Egberg, K., Previs, S. F., Yang,
D. and Brunengraber, H. (1998) Limitations in estimating
gluconeogenesis and Cori cycling from mass isotopomer
distributions using [U-
"$
C
'
] glucose. Am. J. Physiol. 274,
E954–E961
# 2001 The Biochemical Society and the Medical Research Society
... The hyperglycaemic effect has been reported in frogs (Hanke, 1974(Hanke, , 1978Broughton and Deroos, 1984) and other animal species (Chan and Woo, 1978a;Leach and Taylor, 1982;Pretty et al., 2009). Its hyperglycaemic action is due to activation of gluconeogenesis (Baxter, 1979;Renaud and Moon, 1980;Khani and Tayek, 2001). The hyperglycaemic response to cortisol involves metabolic actions such as glucose release from the liver as a product of glycogenolysis, increase in gluconeogenesis and decrease in peripheral glucose utilisation. ...
... The rise in blood glucose following cortisol injection in this study confirms its hyperglycaemic effect. The results agree with findings in frogs (Hanke, 1974(Hanke, , 1978Broughton and DeRoos, 1984;Tavoni et al., 2013) and other animal species (Chan and Woo, 1978a;Khani and Tayek, 2001). The significantly higher levels of blood glucose following cortisol injection in the toad are probably due to an enhanced liver gluconeogenesis. ...
... The results of the present study in which cortisol caused reduction in liver and muscle glycogen agrees with the findings in fishes (Foster and Moon, 1986;Vijayan and Leatherland, 1989) and in rats (Tavoni et al., 2013). Cortisol, a major glucocorticoid exerts its hyperglycaemic effect through activation of gluconeogenesis (Baxter, 1979;Renaud and Moon, 1980;Khani and Tayek, 2001). Since 0.7% amphibian saline injection had no effect on blood glucose, the hyperglycaemic effect of cortisol could not be ascribed to the stress of the injections. ...
Article
Full-text available
The role of adrenergic receptors in cortisol-induced hyperglycaemia is not well known. The present study investigates the effects of adrenergic receptor blockers in cortisol-induced hyperglycaemia in the common African toad (Bufo regularis). Each toad was fasted and anesthetized with sodium pentobarbitone (3 mg/100 g i.p). The animals (control) received intravenous (i.v) injection of 0.7% amphibian saline while animals (untreated) were given cortisol (20 µg/kg). In pre-treatment groups, animals received prazosin (0.2 mg/kg i.v), propranolol 0.5 mg/kg or combination of prazosin (0.2 mg/kg i.v) and propranolol (0.5 mg/kg i.v) before i.v injection of cortisol (20 µg/kg). Thereafter, blood samples were collected for estimation of blood glucose level using the modified glucose oxidase method. Cortisol caused significant increase in blood glucose level from 44.4±3.8 to 71.7±9.7 mg/dl. Pre-treatment of the toads with propranolol (0.5 mg/kg i.v) caused significant reduction (p≤ 0.01) in cortisol-induced hyperglycaemia while pre-treatment with prazosin (0.2 mg/kg i.v) produced no significant effect on hyperglycaemia induced by cortisol. The combination of both prazosin and propranolol completely abolished the effects of cortisol on blood glucose level. The results suggest that cortisol-induced hyperglycaemia in the toad (B. regularis) is mediated probably by both the α-and β-adrenergic receptors with the beta adrenergic receptors playing dominant role.
... The hyperglycaemic effect has been reported in frogs (Hanke, 1974(Hanke, , 1978Broughton and Deroos, 1984) and other animal species (Chan and Woo, 1978a;Leach and Taylor, 1982;Pretty et al., 2009). Its hyperglycaemic action is due to activation of gluconeogenesis (Baxter, 1979;Renaud and Moon, 1980;Khani and Tayek, 2001). The hyperglycaemic response to cortisol involves metabolic actions such as glucose release from the liver as a product of glycogenolysis, increase in gluconeogenesis and decrease in peripheral glucose utilisation. ...
... The rise in blood glucose following cortisol injection in this study confirms its hyperglycaemic effect. The results agree with findings in frogs (Hanke, 1974(Hanke, , 1978Broughton and DeRoos, 1984;Tavoni et al., 2013) and other animal species (Chan and Woo, 1978a;Khani and Tayek, 2001). The significantly higher levels of blood glucose following cortisol injection in the toad are probably due to an enhanced liver gluconeogenesis. ...
... The results of the present study in which cortisol caused reduction in liver and muscle glycogen agrees with the findings in fishes (Foster and Moon, 1986;Vijayan and Leatherland, 1989) and in rats (Tavoni et al., 2013). Cortisol, a major glucocorticoid exerts its hyperglycaemic effect through activation of gluconeogenesis (Baxter, 1979;Renaud and Moon, 1980;Khani and Tayek, 2001). Since 0.7% amphibian saline injection had no effect on blood glucose, the hyperglycaemic effect of cortisol could not be ascribed to the stress of the injections. ...
Article
Full-text available
The role of adrenergic receptors in cortisol-induced hyperglycaemia is not well known. The present study investigates the effects of adrenergic receptor blockers in cortisol-induced hyperglycaemia in the common African toad (Bufo regularis). Each toad was fasted and anesthetized with sodium pentobarbitone (3 mg/100 g i.p). The animals (control) received intravenous (i.v) injection of 0.7% amphibian saline while animals (untreated) were given cortisol (20 µg/kg). In pre-treatment groups, animals received prazosin (0.2 mg/kg i.v), propranolol 0.5 mg/kg or combination of prazosin (0.2 mg/kg i.v) and propranolol (0.5 mg/kg i.v) before i.v injection of cortisol (20 µg/kg). Thereafter, blood samples were collected for estimation of blood glucose level using the modified glucose oxidase method. Cortisol caused significant increase in blood glucose level from 44.4±3.8 to 71.7±9.7 mg/dl. Pre-treatment of the toads with propranolol (0.5 mg/kg i.v) caused significant reduction (p≤ 0.01) in cortisol-induced hyperglycaemia while pre-treatment with prazosin (0.2 mg/kg i.v) produced no significant effect on hyperglycaemia induced by cortisol. The combination of both prazosin and propranolol completely abolished the effects of cortisol on blood glucose level. The results suggest that cortisol-induced hyperglycaemia in the toad (B. regularis) is mediated probably by both the α-and β-adrenergic receptors with the beta adrenergic receptors playing dominant role.
... Cortisol is a hormone relevant to metabolic risk for several reasons. Since cortisol stimulates gluconeogenesis (i.e., the creation of glucose from non-glucose stores in the body), it is theorized to contribute directly to negative metabolic states like the metabolic syndrome (Khani & Tayek, 2001). Related to this, cortisol has been associated with HbA1c (an index of average blood sugar levels) across three months, (Lehrer et al., 2016) and a study of 1258 participants found that higher concentrations of cortisol in hair was related to greater odds of having metabolic syndrome and higher HbA1c (Stalder et al., 2013). ...
... Higher cortisol being linked with higher glucose is supported by mechanisms such as gluconeogenesis, where increased cortisol levels stimulate the production of glucose from precursors other than glycogen (Melkonian et al., 2023). Continued excess production of glucose from this process can lead to an increased risk of poorer metabolic outcomes (Khani & Tayek, 2001). These physiological connections may have particular relevance for food insecure populations. ...
Article
Full-text available
Food insecurity is highly prevalent and linked to poorer diet and worse metabolic outcomes. Food insecurity can be stressful, and could elicit chronic psychological and physiological stress. In this study, we tested whether stress could be used to identify those at highest risk for worse diet and metabolic measures from food insecurity. Specifically, we hypothesized that cortisol (a physiological marker of stress) and perceived psychological stress would amplify the link between food insecurity and hyperpalatable food intake as well as metabolic measures. In a sample of 624 Black and White women aged 36–43 who participated in the NHLBI Growth and Health Study’s midlife assessment, we assessed associations between food insecurity with hyperpalatable food intake (high fat + high sodium foods; high fat + high sugar foods; and high carbohydrate + high sodium foods), and metabolic measures (fasting glucose, insulin resistance, and waist circumference). We found that food insecurity was associated with higher levels of perceived stress (R² = 0.09), and greater intake of high fat + high sugar (hyperpalatable) foods (R² = 0.03). In those with higher cumulative cortisol (as indexed by hair cortisol), food insecurity was associated with higher levels of fasting glucose. Neither cortisol nor perceived stress moderated any other relationships, and neither variable functioned as a mediator in sensitivity analyses. Given these largely null findings, further research is needed to understand the role stress plays in the chronic health burdens of food insecurity.
... Adrenal insufciency, SGLT2 inhibitors, and carbohydrate intake shortage might keep blood glucose levels lower. Cortisol plays a role in stimulating gluconeogenesis and inhibiting glycogenesis to prevent hypoglycemia [12,13]. Tus, adrenal insufciency leads to hypoglycemia [12]. ...
... Cortisol plays a role in stimulating gluconeogenesis and inhibiting glycogenesis to prevent hypoglycemia [12,13]. Tus, adrenal insufciency leads to hypoglycemia [12]. SGLT2 inhibitors lower blood glucose levels by inhibiting the reabsorption of glucose in proximal tubules and by promoting urinary glucose excretion [3]. ...
Article
Full-text available
A 74-year-old patient with type 2 diabetes mellitus received basal-bolus insulin, insulin secretagogues, and sodium glucose transporter 2 (SGLT2) inhibitors. After immune checkpoint inhibitor treatment for lung cancer, he suffered from depressed consciousness with a urinary ketone body (3+). When all hypoglycemic treatments were discontinued, his serum blood glucose remained at 121 mg/dL. He was diagnosed with euglycemic diabetic ketosis. Endocrine loading tests revealed isolated adrenocorticotropic hormone (ACTH) deficiency as an immune-related adverse event. It was suggested that euglycemic diabetic ketosis was induced by the self-suspension of insulin and insulin secretagogues, adrenal insufficiency, SGLT2 inhibitors, and carbohydrate intake shortage.
... Through several processes, including decreased glucose uptake in fat cells and muscles, inhibition of protein synthesis, promotion of lipolysis (the breakdown of fats into fatty acids), and the release of amino acids from muscles to assist gluconeogenesis, cortisol elevates blood glucose levels. These processes work together to raise blood glucose levels, which are essential for giving the brain and other tissues the energy they need during stressful reactions such as the fight-or-flight response ( Figure 2) [16]. ...
Article
Full-text available
The hypothalamic-pituitary-adrenal (HPA) axis plays a pivotal role in the body's response to stress, orchestrating the release of glucocorticoids. In chronic scenarios, these glucocorticoids contribute to various neurological disorders, including Alzheimer's disease (AD) and depression. This abstract explores the potential mechanisms through which HPA axis dysregulation links stress-induced pathways to the pathogenesis of AD and subsequent depression. Chronic stress triggers prolonged HPA axis activation, resulting in elevated cortisol levels, which can lead to hippocampal atrophy, synaptic dysfunction, and neuroinflammation, recognized as key pathological features of AD. These alterations impair cognitive function and may exacerbate amyloid-beta plaque formation and tau hyperphosphorylation, hallmarks of AD. Concurrently, persistent cortisol elevation affects the prefrontal cortex and limbic structures, contributing to depressive symptoms. The interplay between chronic stress, HPA axis dysregulation, and neuroinflammation is crucial in understanding the comorbidity of AD and depression. Unveiling these mechanisms provides insights into potential therapeutic targets aimed at modulating the HPA axis and reducing stress-induced neurodegeneration, offering a dual benefit in managing both AD and depression. Further research is essential to elucidate the precise molecular pathways and develop effective interventions to mitigate the impact of chronic stress on brain health.
... Glucocorticoids play a key role in regulating fetal intrauterine growth, affecting fetal metabolism and homeostasis (Braun et al., 2013). It is also known that glucocorticoids lead to increased gluconeogenesis and energy metabolism (Khani & Tayek, 2001), and that cord blood cortisol is a marker for placental-fetal hypothalamic-pituitary-adrenal (HPA) axis activation (Gravett et al., 2000). Elevated inutero cortisol levels were previously reported in Zika virus animal models (Trus et al., 2018). ...
Article
Full-text available
Introduction The impact of maternal coronavirus disease 2019 (COVID-19) infection on fetal health remains to be precisely characterized. Objectives Using metabolomic profiling of newborn umbilical cord blood, we aimed to investigate the potential fetal biological consequences of maternal COVID-19 infection. Methods Cord blood plasma samples from 23 mild COVID-19 cases (mother infected/newborn negative) and 23 gestational age-matched controls were analyzed using nuclear magnetic spectroscopy and liquid chromatography coupled with mass spectrometry. Metabolite set enrichment analysis (MSEA) was used to evaluate altered biochemical pathways due to COVID-19 intrauterine exposure. Logistic regression models were developed using metabolites to predict intrauterine exposure. Results Significant concentration differences between groups (p-value < 0.05) were observed in 19 metabolites. Elevated levels of glucocorticoids, pyruvate, lactate, purine metabolites, phenylalanine, and branched-chain amino acids of valine and isoleucine were discovered in cases while ceramide subclasses were decreased. The top metabolite model including cortisol and ceramide (d18:1/23:0) achieved an Area under the Receiver Operating Characteristics curve (95% CI) = 0.841 (0.725–0.957) for detecting fetal exposure to maternal COVID-19 infection. MSEA highlighted steroidogenesis, pyruvate metabolism, gluconeogenesis, and the Warburg effect as the major perturbed metabolic pathways (p-value < 0.05). These changes indicate fetal increased oxidative metabolism, hyperinsulinemia, and inflammatory response. Conclusion We present fetal biochemical changes related to intrauterine inflammation and altered energy metabolism in cases of mild maternal COVID-19 infection despite the absence of viral infection. Elucidation of the long-term consequences of these findings is imperative considering the large number of exposures in the population.
... The hypothalamic-pituitary-adrenal axis (HPA) is a major regulator of the neuroendocrine response to exercise-induced physical and psychological stress and is responsible for the release of cortisol, the main hormone related to the stress response (Dedovic et al., 2009). Cortisol mediates wide physiological processes denoted by immunosuppression (Shinkai et al., 1996), enhanced gluconeogenesis (Khani and Tayek, 2001), and increased catabolism [i.e., increased protein breakdown (Brillon et al., 1995), and lipolysis (Divertie et al., 1991)]. Therefore, elevated cortisol levels have been proposed to decrease sport performance due to the impairment of muscle strength derived from an increased catabolic state (Ispirlidis et al., 2008). ...
Article
Full-text available
High-level football (soccer) players face intense physical demands that result in acute and residual fatigue, impairing their physical performance in subsequent matches. Further, top-class players are frequently exposed to match-congested periods where sufficient recovery times are not achievable. To evaluate training and recovery strategies, the monitoring of players’ recovery profiles is crucial. Along with performance and neuro-mechanical impairments, match-induced fatigue causes metabolic disturbances denoted by changes in chemical analytes that can be quantified in different body fluids such as blood, saliva, and urine, thus acting as biomarkers. The monitoring of these molecules might supplement performance, neuromuscular and cognitive measurements to guide coaches and trainers during the recovery period. The present narrative review aims to comprehensively review the scientific literature on biomarkers of post-match recovery in semi-professional and professional football players as well as provide an outlook on the role that metabolomic studies might play in this field of research. Overall, no single gold-standard biomarker of match-induced fatigue exists, and a range of metabolites are available to assess different aspects of post-match recovery. The use of biomarker panels might be suitable to simultaneously monitoring these broad physiological processes, yet further research on fluctuations of different analytes throughout post-match recovery is warranted. Although important efforts have been made to address the high interindividual heterogeneity of available markers, limitations inherent to these markers might compromise the information they provide to guide recovery protocols. Further research on metabolomics might benefit from evaluating the long-term recovery period from a high-level football match to shed light upon new biomarkers of post-match recovery.
... Основная функция кортизола заключается в мобилизации энергетических ресурсов в условиях их нехватки, например при стрессе или гипогликемии [45]. Он индуцирует глюконеогенез, снижает утилизацию глюкозы в периферических тканях, тем самым способствуя развитию инсулинорезистентности и повышению глюкозы в крови [46]. И поскольку одна из его функцийобеспечение пробуждающегося мозга глюкозой после 8 ч ночного воздержания от приема пищи, изменения секреции кортизола в сторону как его повышения, так и снижения способны оказывать влияние на функциональное состояние мозга и в итоге на РП [45,47]. ...
Article
Full-text available
We previously reported that the protein-tyrosine phosphatase SHP-1 (PTPN6) negatively regulates insulin signaling, but its impact on hepatic glucose metabolism and systemic glucose control remains poorly understood. Here, we use co-immunoprecipitation assays, chromatin immunoprecipitation sequencing, in silico methods, and gluconeogenesis assay, and found a new mechanism whereby SHP-1 acts as a co-activator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene to increase liver gluconeogenesis. SHP-1 is recruited to the regulatory regions of the PCK1 gene and interacts with RNA polymerase II. The recruitment of SHP-1 to chromatin is dependent on its association with the transcription factor signal transducer and activator of transcription 5 (STAT5). Loss of SHP-1 as well as STAT5 decrease RNA polymerase II recruitment to the PCK1 promoter and consequently PCK1 mRNA levels leading to blunted gluconeogenesis. This work highlights a novel nuclear role of SHP-1 as a key transcriptional regulator of hepatic gluconeogenesis adding a new mechanism to the repertoire of SHP-1 functions in metabolic control.
Article
Full-text available
To assess whether acute cortisol excess impairs insulin action on lipolysis, plasma amino acids, endogenous insulin secretion, and glucose kinetics, nine normal subjects were studied after acute cortisol excess (80 mg hydrocortisone by mouth) and after placebo. Insulin sensitivity was assessed 6 hours after hydrocortisone using the glucose clamp technique (insulin infusion of 20 mU/m2 X minute for 120 minutes, plasma insulin levels of approximately equal to 50 mU/L). Hyperinsulinemia suppressed plasma free fatty acids (FFA) similarly by 75 and 76%, respectively. Most plasma amino acid concentrations were increased after hydrocortisone; however, the insulin-induced decrease of branched chain amino acids, serine, threonine, and tyrosine was unimpaired after hydrocortisone. Plasma C-peptide concentrations were less suppressed during hyperinsulinemia after hydrocortisone than after placebo (by 0.15 +/- 0.03 v 0.25 +/- 0.02 nmol/L, P less than 0.01), suggesting diminished insulin-induced suppression of insulin secretion. The glucose infusion rates required to maintain euglycemia were 35% lower (P less than 0.01) after hydrocortisone due to decreased insulin effects on metabolic clearance rate of glucose and diminished suppression of hepatic glucose production (0.4 +/- 0.1 v -0.1 +/- 0.1 mg/kg X minute, p less than 0.05, 3-3H-glucose infusion method). The data demonstrate that acute elevation of plasma cortisol to levels near those observed in severe stress results in insulin resistance of peripheral and hepatic glucose metabolism but in unimpaired insulin effects on plasma FFA and branched chain amino acids, suggesting that cortisol's lipolytic and proteolytic effects are antagonized by elevated plasma insulin levels.
Conference Paper
Obesity stands as a public health issue. Obesity prevalence is increasing throughout every industrialized country. Android obesity is linked with an increased cardiovascular mortality and with type 2 diabetes mellitis, thus calling for an early management of this disease. Several studies showed a significant association between an android fat distribution and an increased cortisol secretion, raising the still debated question of a causal relationship between the development of android obesity and hypercorticism. Morevoer, android obese subjects exhibit reduced plasma testosterone and growth hormone levels, meaning complex hormonal abnormalities in these subjects. Current hypotheses suggest that android fat distribution depends on the association of these hormonal abnormalities. Android obese patients have supranormal free fatty acid plasma concentrations. Visceral fat tissue, through its portal drainage, could be an important source for free fatty acids that may exert complex metabolic effects: involvement in hepatic lipogenesis, increase in hepatic neoglucogenic flux, reduction in insulin metabolic clearance and involvement in peripheral insulin resistance through a competition mechanism described by Randle. Technics in vitro (isolated adipocytes) and in vivo in human (labelled fatty acid flux) showed that visceral fatty acid flux was increased in obese patients and subcutaneous adipose tissue, as opposed to common opinion, was also involved in free fatty acid pool in obese patients. Thus, visceral obesity and diabetes could be linked through an enhanced fatty acid availability from adipose tissues (visceral and subcutaneous) in otherwise genetically type 2 diabetes-prone individuals.
Article
Metopiron, hydrocortisone and dexamethazone are able to influence different links of the hypothalamo-hypohysial-adrenal system and induce the inhibition of glucocorticoid function. Changes in glycogen content in the adrenal gland and liver of rat foetuses under the effect of the drugs in question were studied. It was shown that metopiron exerted no marked influence on the level of glycogen in the adrenal gland and decreased 2.5 times that in the liver. On the contrary, hydrocortisone and dexamethazone increased the glycogen content 2 times in the adrenal gland and did not change that in the liver. The results obtained agree with the hypothesis on the relation between the glycogen level in the adrenal gland and the level of its hormonal activity and are considered as an additional proof of the functioning of hypothalamo-hypophysial-adrenal system during the last days of the rat prenatal development.
Article
The present study was undertaken to determine whether an acute physiological increase in plasma cortisol level had significant effects on alanine metabolism and gluconeogenesis within 3 hours in conscious, overnight-fasted dogs. Each experiment consisted of an 80-minute tracer and dye equilibration period, a 40-minute basal period, and a 3-hour experimental period. A primed, continuous infusion of [3-3H]glucose and continuous infusions of [U-14C]alanine and indocyanine green dye were initiated at the start of the equilibration period and continued throughout the experiment. Dogs were studied with (1) a hydrocortisone infusion ([CORT] 3.0 micrograms.kg-1.min-1, n = 5), (2) hydrocortisone infused as in CORT, but with pancreatic hormones clamped using somatostatin and basal intraportal replacement of insulin and glucagon (CLAMP+CORT, n = 5), or (3) saline infusion during a pancreatic clamp (CLAMP, n = 5). Glucose production and gluconeogenesis were determined using tracer and arteriovenous difference techniques. During CLAMP, all parameters were stable except for a modest 67% +/- 6% increase in gluconeogenic conversion of alanine to glucose and a 53% +/- 26% increase in gluconeogenic efficiency. When plasma cortisol levels were increased fourfold during CLAMP+CORT, there was no change in the concentration, production, or clearance of glucose. Gluconeogenic conversion of alanine to glucose increased 10% +/- 34% and gluconeogenic efficiency increased 65% +/- 43%, while net hepatic alanine uptake (NHAU) increased 60% +/- 19% and hepatic fractional extraction of alanine increased 38% +/- 12%. Cortisol did not cause an increase in the arterial glycerol level or net hepatic glycerol uptake.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
To test the hypothesis that growth hormone secretion plays a counterregulatory role in prolonged hypoglycemia in humans, four studies were performed in nine normal subjects. Insulin (15 mU.M-2.min-1) was infused subcutaneously (plasma insulin 27 +/- 2 microU/ml), and plasma glucose decreased from 88 +/- 2 to 53 +/- 1 mg/dl for 12 h. In study 1, plasma glucose, glucose fluxes (D-[3-3H]glucose), substrate, and counterregulatory hormone concentrations were simply monitored. In study 2 (pituitary-adrenal-pancreatic clamp), insulin and counterregulatory hormone secretions (except for catecholamines) were prevented by somatostatin (0.5 mg/h iv) and metyrapone (0.5 g/4 h po), and glucagon, cortisol, and growth hormone were reinfused to reproduce the concentrations of study 1. In study 3 (lack of growth hormone increase), the pituitary-adrenal-pancreatic clamp was performed with maintenance of plasma growth hormone at basal levels, and glucose was infused whenever needed to reproduce plasma glucose concentration of study 2. Study 4 was identical to study 3, but exogenous glucose was not infused. Isolated lack of a growth hormone response caused a decrease in hepatic glucose production and an increase in glucose utilization that resulted in an approximately 25% greater hypoglycemia despite compensatory increases in plasma catecholamines. Plasma free fatty acid, 3-beta-hydroxybutyrate, and glycerol concentrations were reduced approximately 50%. It is concluded that growth hormone normally plays an important counterregulatory role during hypoglycemia by augmenting glucose production, decreasing glucose utilization, and accelerating lipolysis.
Article
To estimate the relative contributions of gluconeogenesis and glycogenolysis to the increase in hepatic glucose output (HGO) during glucose counterregulation under conditions simulating clinical insulin hypoglycemia, we induced moderate hypoglycemia (approximately 55 mg/dl) with a continuous infusion of insulin that resulted in physiological hyperinsulinemia (approximately 20 microU/ml) in eight normal volunteers and estimated gluconeogenesis by two methods: an isotopic approach in which appearance of plasma glucose derived from lactate was determined and another approach in which we infused alcohol along with insulin to block gluconeogenesis and used the exogenous glucose required to prevent greater hypoglycemia as an index of gluconeogenesis. Both methods gave similar results. Initially glycogenolysis accounted for approximately 85% of HGO; however, once hypoglycemia became established, the contribution of gluconeogenesis increased progressively to 77 +/- 10 (isotopic method) and 94 +/- 10% (alcohol method) of overall HGO. We conclude that in normal humans during moderate protracted hypoglycemia induced by physiological hyperinsulinemia, gluconeogenesis is the predominant factor responsible for the counterregulatory increase in HGO and that increased gluconeogenesis rather than increased glycogenolysis is the primary mechanism preventing development of greater hypoglycemia.
Article
Cortisol produces a glycogenogenic effect 5 hours after intraperitoneal injection to 3 day old chicks. This effect is dependent on protein synthesis because it can be blocked by antibiotics such as actinomycin D. On the other hand, there is a previous glycogenolytic effect 45 minutes after cortisol administration which is independent of protein synthesis. Thyroid hormones produce a similar early effect as has been previously shown. However, the observed glycogenolysis after cortisol injection is not correlated with an enhancement in the liver cAMP levels.
Article
We infused epinephrine, glucagon, and cortisol in combination into health overnight-fasted subjects in doses designed to simulate changes in severe stress. When all three hormones were infused simultaneously, glucose levels rose above 200 mg/dl in spite of a 100-200% increase in plasma insulin. In contrast, infusion of each hormone individually produced either a mild (less than 120 mg/dl) or a transient elevation in the plasma glucose concentration. With the combined hormone infusion, the increment in plasma glucose was 3-fold greater than the sum of the responses to the individual hormones (P less than 0.001). The marked hyperglycemia in this setting is a result of ongoing glucose overproduction which is stimulated by epinephrine and glucagon and sustained by cortisol. Furthermore, epinephrine (and possibly cortisol) inhibited glucose disposal despite concomitant hyperinsulinemia. In contrast to their effects on glucose regulation, the simultaneous infusion of epinephrine, glucagon, and cortisol failed to cause hyperketonemia. We conclude that the combined infusion of epinephrine, glucagon, and cortisol produces a greater than additive hyperglycemic response in normal humans. These data suggest that the clinical occurrence of fasting hyperglycemia in a setting of hypersecretion of multiple antiinsulin hormones (stress hyperglycemia) may result, at least in part, from synergistic interactions among these hormones.
Article
This study was undertaken to investigate the effects of an acute increase in the plasma epinephrine level, with or without an accompanying increase in the plasma cortisol level, during selective insulin deficiency on glycogenolysis and gluconeogenesis in conscious overnight-fasted dogs. Experiments consisted of an 80-min tracer and dye equilibration period, a 40-min basal period, and a 180-min experimental period. In all protocols, selective insulin deficiency was created during the experimental period by infusing somatostatin peripherally (0.8 micrograms.kg-1.min-1) with basal replacement of glucagon intraportally (0.65 ng.kg-1.min-1). In EPI+SAL (n = 6), an additional infusion of epinephrine (0.04 micrograms.kg-1.min-1) was infused during the experimental period along with saline. In EPI+CORT (n = 6), hydrocortisone (3.0 microgram.kg-1.min-1) was infused in addition to epinephrine during the experimental period. In SAL+CORT (n = 5), hydrocortisone was infused during the experimental period. In SALINE (n = 5), neither epinephrine nor cortisol was infused. [3-3H]glucose, [U-14C]alanine, and indocyanine green dye were used to assess glucose production (rate of appearance [Ra]) and gluconeogenesis using tracer and arteriovenous difference techniques. During selective insulin deficiency in SALINE, the arterial plasma glucose level increased from 6.0 +/- 0.1 to 15.8 +/- 1.1 mmol/l; Ra increased from 14.7 +/- 0.7 to 24.9 +/- 1.7 mumol.kg-1.min-1. Gluconeogenic efficiency and the conversion of alanine and lactate to glucose increased to 300 +/- 55 and 355 +/- 67% of basal. In EPI+SAL and EPI+CORT, plasma glucose increased from 6.2 +/- 0.1 to 19.8 +/- 0.9 mmol/l and from 6.3 +/- 0.1 to 19.5 +/- 0.9 mmol/l. In EPI+SAL and EPI+CORT, Ra increased from 16.5 +/- 1.1 to 29.3 +/- 3.2 mumol.kg-1.min-1 and from 15.4 +/- 1.3 to 28.3 +/- 2.5 mumol.kg-1.min-1. The rise in gluconeogenic efficiency was similar to the rise that occurred in SALINE, but gluconeogenic conversion increased 17-fold in each of the two epinephrine groups. During the epinephrine infusion, gluconeogenesis accounted for a maximum of 55% of total glucose production as opposed to 31% during insulin deficiency alone. An increase in cortisol alone during insulin deficiency (SAL+CORT) had no effect on glucose level, glucose production, or gluconeogenesis. These results suggest that small increases in the plasma epinephrine level during insulin deficiency can significantly worsen the resulting hyperglycemia through stimulation of both glycogenolysis and gluconeogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)