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The Babraham Institute, Cambridge CB2 4AT, United Kingdom
1Correspondence: E-mail: joy.dauncey{at}bbsrc.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: glucose transporter • nutrition • food intake • environmental temperature
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. Current interest in the two major facilitative glucose
transporters in muscle,
GLUT12
(insulin-independent) and GLUT4 (insulin-dependent), reflects their
central relevance to glucose utilization and metabolic disorders such
as diabetes (2
, 3
). Overexpression of GLUT1 in skeletal muscle is
associated with marked increases in lactate and glycogen because of an
increase in basal glucose uptake (4)
, and this increased glucose flux
results in resistance of GLUT4 to activation by insulin and other
stimuli, such as hypoxia and contractile activity (5)
. Studies with
GLUT4 knockout mice demonstrate that GLUT4 is important not only for
maintaining normal insulin-stimulated glucose uptake, but also in
regulating growth and metabolism (6)
. Moreover, because overexpression
of GLUT4 in transgenic animals ameliorates the insulin resistance
associated with obesity or diabetes, there is considerable interest in
identifying mechanisms that up-regulate muscle GLUT4 expression (7)
.
Mild undernutrition postnatally up-regulates muscle growth hormone
receptor gene expression in striking contrast with down-regulation of
hepatic growth hormone receptor (8)
. This suggests that the metabolic
functions of muscle may be particularly important when energy supply is
limited. However, there is virtually no information about the role of
postnatal energy status in regulating muscle GLUTs. Attention has
focused on adult rodents kept under extreme conditions such as
prolonged fasting (9
, 10
), a 40% fat diet compared with one of only
5% (11)
, or severe cold exposure of 4°C (12)
. Some key regulators of
GLUT expression and function are themselves modulated by nutrition.
Energy balance markedly influences thyroid hormone (TH) status and a
reduction in food intake that is not severe enough to prevent growth
reduces thyroid gland activity, plasma TH levels, and nuclear TH
receptor binding capacity of skeletal muscle (1
, 8
, 13
). TH have been
implicated in the neonatal repression of GLUT1 and induction of GLUT4
in cardiac muscle (14)
, and the marked TH-induced increase in basal and
insulin-stimulated glucose uptake in rat skeletal muscle can be
accounted for by induction of GLUT4 protein (15)
. This raises the
hypothesis that the reduction in TH status induced by postnatal
undernutrition is associated with changes in GLUT expression and
function, specifically with reductions in GLUT4 and in
insulin-stimulated glucose transport.
This study was conducted to determine the role of energy status in regulating GLUT gene expression and function in muscle during postnatal development. Energy balance was altered by manipulating food intake and environmental temperature within limits that enabled growth to continue, but at very different rates. Studies were undertaken in the young pig because it provides a good metabolic, hormonal, and developmental model for the human infant. Moreover, its energy status can be manipulated precisely in early postnatal life and its large litter size allows comparisons between closely related individuals. Attention has focused on assessing the abundance of GLUT1 and GLUT4 mRNA in a range of morphologically and functionally distinct muscles, because it is not known whether muscles are differentially affected by energy status. In addition, in vitro insulin-independent and insulin-dependent 2-deoxy-glucose uptake have been measured in a small, isolated skeletal muscle. Results on GLUT gene expression and function are presented in relation to the overall effects of nutrition and thermal environment on growth rate, energy balance, muscle development, and hormonal status.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 16
). Treatments were continued for 4 wk until assessment of
glucose transporter expression and function at 7 wk of age. The food
contained 14 kJ gross energy/g wet weight, 32% carbohydrate, 22.5%
protein, 5.5% fat, 3.5% fiber, and 6% ash, with added vitamins and
minerals. Food was given daily at 9:30 AM and the amount
provided was increased gradually with age. Daily food intakes were
150 g (H) and 75 g (L) at 3 wk, and increased to 700 g
(H) and 350 g (H) at 7 wk, which provided 9.8 and 4.9 MJ,
respectively. Animals were weighed three times per week and growth
efficiencies were calculated as g weight gain/g food. Our previous
studies have shown that these diets have marked effects on thyroid
gland histology, plasma TH concentrations, and nuclear TH binding
capacity of skeletal muscle (1
, 8
, 13
).
Tissue sampling and measurement of plasma glucose
The specific aim of this study was to determine the long-term
effects of nutritional status and thermal environment rather than the
acute effects of feeding. Therefore, because several hormonal and
metabolic parameters are influenced by the time of the last meal (8
,
17
), tissue sampling was carried out 20–24 h after feeding. At 7 wk,
animals were sedated by an intramuscular injection of ketamine
hydrochloride (1.0 ml Vetalar, 100 mg/ml; Parke-Davis Veterinary,
Pontypool, U.K.) and killed with a 0.7 ml/kg body weight intracardiac
injection of pentobarbitone sodium (20% weight/volume; Duphar).
Muscles selected for analysis of GLUT1 and GLUT4 mRNAs were longissimus
dorsi (l. dorsi; white, dorsal), rhomboideus (red, interscapular),
soleus (red, hind limb), diaphragm, and heart. Details of myofiber type
proportions in these muscles during postnatal development have been
published (18
, 19
). Muscles were dissected rapidly, divided into 5 g portions, frozen in liquid nitrogen, and stored at -70°C. Care was
taken to ensure that muscles were sampled at the same relative point in
relation to depth and distance from origin. Muscle samples for
measurement of glucose uptake were taken simultaneously. Plasma was
stored at -40°C until analysis for glucose concentration by the
glucose oxidase method, using a YSI 2300 Stat Plus Analyser.
Isolation and measurement of total RNA
Total RNA was isolated from 0.5 g portions of frozen tissue
by the guanidinium thiocyanate method (20)
and quantified by absorbance
at 260 nm, where 1 optical density (OD) unit = 40 µg RNA/ml
solution. The integrity of total RNA extracted was routinely checked by
gel electrophoresis, and the 18S and 28S RNA bands indicated excellent
integrity of the preparations.
Construction of riboprobes
GLUT1
Total RNA (20 µg) from porcine liver was used to generate
first-strand cDNA, using an oligo dT (12–18) primer (Sigma O6378) in
combination with an AMV reverse transcriptase (Promega, Madison, Wis.).
Polymerase chain reaction (PCR) was carried out on this cDNA to
generate a GLUT1 DNA fragment, using oligonucleotide primers based on
the published porcine GLUT1 cDNA sequence (21)
. The 5' primer
[5'-GCG(GAATTC)CATGCTGATGA-3'] representing nucleotides 153–169 of
the GLUT1 sequence contained an EcoRI recognition site (in
brackets). The 3' primer [5'-CTT(AAGCTT)GATGCCGACGACGATGC-3'] was the
complement of nucleotides 365–381 and contained a HindIII
recognition site (in brackets). The resulting PCR product was digested
with EcoRI and HindIII to give a 230 bp DNA
fragment, cloned into Bluescript KS (Stratagene Ltd., Cambridge, U.K.),
and the DNA sequence was verified by automated fluorescent
double-stranded DNA sequencing. The plasmid DNA was linearized by
EcoRI digestion and used as a template to generate an
antisense riboprobe in an in vitro transcription system
using T3 RNA polymerase in the presence of
[
32P]UTP. This GLUT1 riboprobe had a full
length of 300 nucleotides, of which 230 were protected.
GLUT4
Total RNA (20 µg) from porcine adipose tissue was used to
generate first-strand cDNA, using a primer that was the complement of
nucleotides 226–246 in the published porcine cDNA sequence (22)
:
[5'-AAGCTT(AAGCTT)CACCTGGGCGATCAGAATGCC-3'], which contained a
HindIII site (in brackets), in combination with an AMV
reverse transcriptase (Promega). PCR was carried out on this cDNA to
generate a GLUT4 DNA fragment, using oligonucleotide primers based on
the published porcine GLUT4 cDNA sequence (22)
. The 5' primer
[5'-AGCT(GAATTC)GCTCCTACGAGATGCTCATT-3'] representing
nucleotides 80–100 of the GLUT4 sequence contained an
EcoRI recognition site (in brackets). The 3' primer
[5'-ACGA(AAGCTT)ATCAGAATGCCAATGACGA-3'] was the complement of
nucleotides 218–236 and contained a HindIII recognition
site (in brackets). The resulting PCR product was digested with
EcoRI and HindIII to give a 156 bp DNA fragment,
cloned into Bluescript KS (Stratagene Ltd.), and the DNA sequence was
verified by automated fluorescent double-stranded sequencing. The
plasmid DNA was linearized by EcoRI digestion and used as a
template to generate an antisense riboprobe in an in vitro
transcription system, using T3 RNA polymerase in the presence of
[32P]UTP. This GLUT4 riboprobe had a full
length of 240 nucleotides, of which 156 were protected.
RNase protection assay
Assays were carried out using 50 µg samples of total RNA
extracted from the different skeletal and cardiac muscles. Methods were
similar to those described previously (8)
. In brief, samples were
hybridized with a small molar excess of the radiolabeled GLUT riboprobe
to ensure linearity of the assay with respect to RNA. After 16 h
hybridization at 45°C, excess nonprotected RNA was digested with
RNase A (50 µg/ml, ~1 U/sample) and RNase T1 (300 U/ml, ~80
U/sample). The protected hybridization products were purified by
extraction in phenol:chloroform:isoamyl alcohol (25:24:1) and separated
on 6% polyacrylamide sequencing gels. The dried gels were exposed to
X-ray film (X-OMAT AR, Kodak, Cambridge, U.K.) at -70°C, and
relative intensities of the protected bands were quantified by image
analysis (Seescan, Cambridge U.K.). The system was linear over the
range of OD values measured. Loading of a standard sample on different
gels was used to normalize values from different assays. Riboprobes for
the two glucose transporters were used in the same assay, and results
for GLUT1 and GLUT4 mRNAs are presented as OD units.
Determination of 2-deoxy-glucose uptake in skeletal muscle
For in vitro measurement of glucose uptake, it was
essential to use a small muscle in order to enable adequate oxygenation
during the procedure. Our extensive preliminary studies indicated the
muscle of choice to be flexor carpi radialis. Detailed studies were
undertaken in four litters of four animals each kept under the
different conditions of diet and temperature. The mean
(±SE) weight of muscle samples used in the study
was 153 ± 7 mg. Two pieces of this muscle, with tendons attached
at both ends, were dissected from each forelimb, giving four samples
per animal. For each limb, one sample was used for basal glucose uptake
and the other for treatment with insulin. Muscles were fixed on cork
holders using threads tied to each tendon.
Glucose uptake by the isolated muscles was measured by a modification
of a previously published method (23)
. To allow muscles to recover from
the dissection procedure, they were incubated initially for 60 min at
35°C in 8 ml oxygenated Krebs-Henseleit bicarbonate buffer (KHB)
containing 8 mM glucose, 32 mM sucrose, and 0.1% bovine serum albumin.
This was followed by 30 min incubation at 35°C in identical medium in
the absence or presence of 20 mU/ml porcine insulin (Sigma, I-5523).
Preliminary studies using a range of insulin concentrations had shown
20 mU/ml to yield the optimal rate of reaction. Glucose uptake activity
was measured by use of the glucose analog 2-deoxy-D-glucose (2-DG).
After the two periods of incubation, muscles were rinsed in the absence
or presence of glucose for 20 min at 29°C in 8 ml oxygenated KHB
containing 40 mM sucrose and insulin, if present during the previous
incubation period. The muscles were then incubated for 20 min at 29°C
in 8 ml of KHB containing 1 mM 2-DG and 39 mM sucrose in the absence or
presence of insulin. To this medium were added 4 µCi
2-deoxy-D-[1-3H]glucose (15.4 Ci/mmol; Amersham
International Plc, Buckinghamshire, U.K.) and 0.8 µCi
[U-14C]sucrose (615 mCi/mmol; Amersham).
Concentrations of 2-deoxy-D-[1-3H]glucose and
[U-14C]sucrose in the medium were 32.5 and 160
nM, respectively. The medium was oxygenated with 95%
O2-5% CO2 throughout the
incubation, to prevent hypoxia, and an aliquot of silicone antifoaming
agent (30% emulsion; BDH, U.K.) was added to the medium. After
incubation the muscles were blotted briefly on filter paper dampened
with KHB, weighed immediately, and solubilized in 2 ml 0.5 M NaOH at
65°C overnight. Perchloric acid (172 µl, 70%) was then added to
the solution, which was then centrifuged. The 3H
and 14C radioactivity in 400 µl supernatant was
measured using 5 ml liquid scintillation solution and a liquid
scintillation analyser (Packard 2500TR, Meriden, Conn.). The
radioactivity of [U-14C]sucrose was used to
calculate to extracellular space; the mean (±SE) content
of [U-14C]sucrose in the muscles was 13.7 ± 0.3 dpm/mg tissue. Results for glucose uptake activity are expressed
as pmol 2-DG/ml extracellular space/20 min.
Statistical analysis
The data were subjected to analysis of variance for randomized
block design, where litters were blocks and diet and temperature were
the main effects, using the statistical package Genstat. When
interactions between diet and temperature were significant, further
comparisons between means were made by the least significant difference
method. Probabilities were considered significant at the 5%, 1%, and
0.1% levels. Results are expressed as mean values ±
SE.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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presents growth rates (g/d) and efficiencies of growth over the 4 wk of
treatment (g weight gain/g food intake) for animals in the four
treatment groups. Food intake and temperature affected both these
parameters, and there were statistically significant interactions
between the two environmental variables, with the effect of diet being
greater at 26°C than at 35°C. All animals gained weight during the
period of investigation, but animals at 26°C on the low food intake
had a suboptimal energy balance and lower growth efficiencies than the
three other groups (P<0.05). Plasma glucose levels,
measured 20–24 h after the last meal, in the 35H, 35L, 26H, and 26L
groups, respectively (mean values ±SE), were
7.98 ± 0.31, 7.22 ± 0.27, 7.92 ± 0.23, and 7.51 ± 0.38 mmol/l. The effects of treatment were not statistically
significant, although animals on the low food intake tended to have
lower plasma glucose levels than those on the high food intake
(P=0.06). The finding of only a small difference in plasma
glucose level between animals on the two levels of food intake suggests
that at the time of measurement, 20–24 h after feeding, blood glucose
homeostasis must have been close to the steady state.
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GLUT gene expression
Tissue-specific distribution of GLUT1 and GLUT4
Figure 2
presents a typical autoradiograph obtained using the newly constructed
riboprobes, showing protected bands of 230 and 156 bp for GLUT1 and
GLUT4, respectively. It is not possible to make a detailed quantitative
assessment of the relative abundance of GLUT4 compared with GLUT1
because of differences in labeling incorporation and efficiency. In
general, however, GLUT4 mRNA levels were greater than those for GLUT1
mRNA, as indicated by the need to expose the gels to X-ray film for
~18 h for GLUT4 and 120 h for GLUT1. Moreover, the ratio of
GLUT4:GLUT1 was much greater in skeletal muscles than in cardiac
muscle.
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To assess the relative distribution of the two glucose
transporters in the different muscles examined, a detailed analysis of
GLUT1 and GLUT4 mRNAs was made in the 26H group. Table 1
shows that the abundance of GLUT1 mRNA was similar in l. dorsi,
rhomboideus, soleus, and diaphragm, and ~eightfold greater in heart
than in these four skeletal muscles. For GLUT4, by contrast, mRNA
levels increased in the order l. dorsi < rhomboideus <
soleus, and levels in heart and diaphragm were similar and
approximately twice those in soleus.
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Regulation of GLUT1 and GLUT4 mRNA by energy status
Results for the effects of nutrition and thermal environment
on glucose transporter mRNA abundance in different muscles are
presented in Table 2
for GLUT1 and Fig. 3
for GLUT4. There were striking muscle-specific effects of food intake
on the mRNA levels of both glucose transporters. In l. dorsi and
rhomboideus, the low food intake was associated with marked
up-regulation in expression of both genes; the effect on GLUT4 was
particularly striking: GLUT4, P < 0.001; GLUT1,
P < 0.05. The overall effect of temperature on GLUT1 mRNA
was also significant: 35°C > 26°C; P < 0.01 and
P < 0.05 for l. dorsi and rhomboideus, respectively. By
contrast, in diaphragm and heart there was no significant effect of
diet or temperature on either GLUT1 or GLUT4 gene expression.
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Glucose uptake
Table 3
presents the results for basal (insulin-independent) and
insulin-stimulated 2-deoxy-glucose uptake in isolated muscle from the
four treatment groups. Basal uptake (pmol/ml/20 min) was almost
identical in the 35H, 35L, and 26H groups, whereas in the 26L group it
was ~50% greater. Values for insulin-stimulated glucose uptake
(pmol/ml/20 min) showed a trend similar to that for GLUT4 mRNA, with
the L intake resulting in higher values than the H intake at both
environmental temperatures. Moreover, results for the percentage
increment in 2-deoxy-glucose uptake suggested that there was an
interaction between diet and temperature (P=0.07). Overall,
the 26L group had the lowest percentage increment in 2-deoxy-glucose
uptake due to insulin (Fig. 4
); it was ~20% compared with 70% in the three other groups.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Muscle-specific regulation of GLUT1 and GLUT4 gene expression
A major finding of the present study was that food intake
affected postnatal GLUT gene expression in l. dorsi and rhomboideus,
but not in diaphragm and heart. This muscle-specific response was not
related simply to contractile activity and oxidative capacity, because
proportions of slow oxidative and fast glycolytic fibers are very
different in l. dorsi and rhomboideus but similar in rhomboideus and
diaphragm (18
, 19
). The lack of response in diaphragm and heart may be
explained in part by the finding that within a treatment group, GLUT4
mRNA levels in these tissues were three- to fourfold higher than in l.
dorsi and rhomboideus. If mRNA levels are already high, the tissue may
be unable to further up-regulate gene expression significantly when
food intake is reduced. However, such an argument cannot be used for
GLUT1. Although levels of GLUT1 mRNA were similar in l. dorsi,
rhomboideus, and diaphragm within a treatment group, a low food intake
markedly increased GLUT1 in l. dorsi and rhomboideus, but had no effect
in diaphragm. Thus, the ability of nutrition to affect GLUT gene
expression postnatally may be dependent not only on the potential
capacity for gene expression to be altered by extrinsic factors, but
also on the specific functions of different muscles within the whole
body. Diaphragm and heart play essential roles in respiratory and
cardiovascular function; since GLUT expression was unaffected, these
functions will not be compromised by defective glucose transport due to
external factors. By contrast, l. dorsi and rhomboideus have important
roles in glucose, glycogen, and whole-body energy metabolism, and the
altered GLUT expression that occurs in response to nutrition will
enable modification of metabolic fuel utilization.
Role of energy balance in regulation of GLUT gene expression and in
subcellular localization and activity of GLUT4
Because overexpression of muscle GLUT4 in transgenic animals
ameliorates the insulin resistance associated with obesity and
diabetes, there is considerable interest in identifying mechanisms that
up-regulate GLUT4 expression (7)
. Our results, however, highlight the
important point that up-regulation of GLUT4 expression is not
necessarily associated with an increase in insulin-dependent glucose
uptake. The marked physiological up-regulation of GLUT1, and
particularly GLUT4 mRNA abundance in l. dorsi and rhomboideus induced
by mild undernutrition, concurs with the increases that occur in some
adult rat muscles after the more pathological condition of several
days' fasting (9
, 10
). The present study showed that the highest GLUT4
mRNA levels in l. dorsi and rhomboideus occurred in animals living at
26°C on a low food intake (26L). Since thermal neutrality is
dependent on energy intake and varies over 24 h in relation to
feeding, 26°C may sometimes have been below the critical temperature
of the 26L animals. During these times, thermoregulatory demand will
have increased; consequently, there was a suboptimal energy balance and
the lowest growth efficiency. Thus, GLUT4 gene expression is regulated
not simply by food intake, but also by energy status, with
up-regulation occurring when energy intake is limiting in relation to
energy demand.
Assessment of basal and insulin-dependent 2-deoxy-glucose uptake in an isolated muscle showed that although basal uptake was greatest in the 26L group, they had the smallest increase in glucose uptake due to insulin and hence a reduction in insulin sensitivity. This suggests that when energy balance is suboptimal, the population of GLUTs, i.e., both GLUT1 and GLUT4, on the plasma membrane of muscle cells in the basal state is already high. By contrast, the intracellular population of insulin-responsive GLUTs, i.e., mainly GLUT4, is inadequate and there will be only a small increase in glucose uptake in response to insulin.
These findings clearly demonstrate that postnatal GLUT expression and
function are exquisitely sensitive to small changes in nutritional
status, and are therefore relevant to immediate and long-term health
and to the development of preventative and ameliorative approaches to
infant and adult diabetes (24
, 25
). Much current research on GLUTs
focuses on mechanisms of insulin-dependent trafficking, from the
intracellular pool to the plasma membrane. Our novel findings indicate
that energy balance affects the subcellular distribution and/or
activity of GLUTs in muscle, independently of insulin. This suggests
the presence of important insulin-independent GLUT trafficking
pathways, at least in myocytes. It has recently been hypothesized that
insulin-independent glucose transport regulates insulin sensitivity
(26)
. This hypothesis suggests that insulin resistance is dependent on
whether glucose is entering the myocyte through GLUT1 or GLUT4;
increased glucose transport through GLUT1 will reduce GLUT4 activity by
negative feedback of hexosamines leading to insulin resistance. Of
particular importance, therefore, is the support our findings lend to
this hypothesis.
Mechanisms mediating nutritionally induced changes in GLUT
expression and function
A number of mechanisms can be postulated to have mediated the
responses to reduced energy status. Evidence from cultured L6 muscle
cells suggests that glucose itself regulates GLUT1 gene expression, but
although glucose deprivation causes a sustained increase in GLUT1,
there is no change in GLUT4 mRNA (27
, 28
). Adding glucose to
glucose-starved cells also markedly reduces GLUT1 without major changes
in GLUT4 mRNA (28)
. In the present study, animals on the low food
intake tended to have slightly lower plasma glucose levels than those
on the high intake, and the higher GLUT1 mRNA in l. dorsi and
rhomboideus on the low intake may therefore have been due in part to
lower plasma glucose levels. However, by contrast with GLUT1, there is
little evidence to demonstrate that glucose was directly involved in
regulation of muscle GLUT4 gene expression. Instead, changes in the
metabolic pathways of glucose or glycogen may have been involved.
Nutrition has a marked effect on the glycogen content of muscle: the
starved-to-fed transition is accompanied by rapid glycogen deposition
(29)
, and muscle glycogen content increases with an increase in food
intake (30)
. In this study, muscle glycogen levels were probably
greater in the high than the low food intake groups. Because animals on
the low intake also tended to have lower plasma glucose levels, the
elevated GLUT4 mRNA in l. dorsi and rhomboideus may be explained in
part by alterations in glycemia and glycogen metabolism. Hind limb
weight bearing after 3 days of hind limb suspension markedly elevates
muscle glycogen content, and this is partly due to increased glucose
flux associated with elevated GLUT4 protein (31)
. The possibility is
that muscle has a glycogen compensating mechanism that functions when
its glycogen level is suppressed by factors such as a low food intake,
and this mechanism could involve changes in GLUT gene expression.
In relation to hormonal factors, although TH are key regulators of
muscle GLUT gene expression and function, the mechanism inducing
up-regulation of GLUT4 is unlikely to have involved these hormones. The
reduced thyroid status associated with postnatal undernutrition (1
, 13
)
would be predicted to result in a decrease in GLUT4 and an increase in
GLUT1 mRNAs (14
, 15
). Therefore, although changes in thyroid status may
have been involved in the response of GLUT1, the effects of
nutritionally induced hypothyroidism on GLUT4 were overridden by other
regulatory factors. An alternative candidate that may explain the
muscle-specific increase in GLUT4 gene expression on a low food intake
is glucocorticoids. Studies in young and adult individuals indicate
that fasting, or a low food intake, induces an increase in plasma
cortisol levels and alters the patterns of pulsatile, circadian, and
ultradian cortisol release (32
33
34
35)
, whereas overfeeding results in
lower cortisol levels (36)
. Cortisol induces GLUT4 gene expression in
ovine fetal skeletal muscle (37)
; not only does dexamethasone increase
GLUT4 expression in rat skeletal muscle, but it has no effect in heart
(38)
. Evidence from rats given dexamethasone suggests that
glucocorticoid excess may also cause inhibition of glucose transport
and insulin resistance in skeletal muscle by inhibiting translocation
of GLUT4 to the plasma membrane. These findings accord closely with our
results for the 26L group, which had the lowest growth rate and
suboptimal energy balance, suggesting that the
hypothalamic-pituitary-adrenal axis may play a key role in regulating
the postnatal response of muscle GLUT gene expression and function to
changes in nutrition and energy balance.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Received for publication January 21, 1999.
Revision received February 25, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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