© 1999 American Heart Association, Inc.
Original Contribution |
-Adrenergic Stimulation Mediates Glucose Uptake Through Phosphatidylinositol 3-Kinase in Rat Heart
Presented in part at the 70th Annual Scientific Sessions of the American Heart Association, Orlando, Fla, November 9–12, 1997, and published in abstract form (Circulation. 1997;96[suppl I]:I-691).
From the Department of Medicine, Division of Cardiology, University of Texas-Houston Medical School, Houston, Tex.
Correspondence to Heinrich Taegtmeyer, MD, DPhil, Department of Internal Medicine, Division of Cardiology, University of Texas-Houston Medical School, 6431 Fannin, MSB 1.246, Houston, TX 77030. E-mail ht{at}heart.med.uth.tmc.edu
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Abstract |
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Abstract—We examined whether insulin and catecholamines share common pathways for their stimulating effects on glucose uptake. We perfused isolated working rat hearts with Krebs-Henseleit buffer containing [2-3H]glucose (5 mmol/L, 0.05 µCi/mL) and sodium oleate (0.4 mmol/L). In the absence or presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitor wortmannin (3 µmol/L), we added insulin (1 mU/mL), epinephrine (1 µmol/L), phenylephrine (100 µmol/L) plus propranolol (10 µmol/L, selective
-adrenergic
stimulation), or isoproterenol (1 µmol/L) plus
phentolamine (10 µmol/L, selective ß-adrenergic
stimulation) to the perfusate. Cardiac power was found to be
stable in all groups (between 8.07±0.68 and 10.7±0.88 mW) and
increased (25% to 47%) with addition of epinephrine, but not
with selective - and ß-adrenergic stimulation. Insulin and
epinephrine, as well as selective - and ß-receptor
stimulation, increased glucose uptake (the following values are in
µmol/[min · g dry weight]: basal, 1.19±0.13; insulin,
3.89±0.36; epinephrine, 3.46±0.27; -stimulation,
4.08±0.40; and ß-stimulation, 3.72±0.34). Wortmannin completely
inhibited insulin-stimulated and selective -stimulated glucose
uptake, but it did not affect the epinephrine-stimulated or
selective ß-stimulated glucose uptake. Sequential addition of insulin
and epinephrine or insulin and -selective stimulation showed
additive effects on glucose uptake in both cases. Wortmannin further
blocked the effects of insulin on glycogen synthesis. We conclude that
-adrenergic stimulation mediates glucose uptake in rat heart through
a PI3-K–dependent pathway. However, the additive effects of
-adrenergic stimulation and insulin suggest 2 different isoforms of
PI3-K, compartmentation of PI3-K, potentiation, or inhibition by
wortmannin of another intermediate of the -adrenergic signaling
cascade. The stimulating effects of both the - and the
ß-adrenergic pathways on glucose uptake are independent of changes in
cardiac performance.
Key Words: isolated working rat heart • wortmannin • glucose tracer • signal transduction
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Glucose uptake in heart muscle is stimulated by insulin and catecholamines.1 2 3 It is not known whether the signaling pathways for the hormones are separate or share common intermediates. Stimulation with insulin results in receptor autophosphorylation and subsequent activation of a plethora of mediators, among them insulin receptor substrate 1, which activates phosphatidylinositol 3-kinase (PI3-K). PI3-K has been consistently shown to mediate the membrane-trafficking effects of insulin leading to increased glucose uptake by recruitment of glucose transporters from an intracellular pool.4 5 6 7 The PI3-K family of enzymes is known to be regulated by several different upstream pathways in response to virtually all growth factors and cytokines and can be inhibited by the fungal metabolite wortmannin.8
Several hypotheses have been advanced for the stimulating effects of
catecholamines on glucose uptake. These hypotheses include
the stimulation of glucose transporter recruitment from the same or a
different pool of intracellular transporters by contraction, increases
in intracellular [Ca2+], or the activation of
the -adrenergic pathway.9 10 11 12 Recent evidence suggests
phosphorylation of insulin receptors by components of
the -adrenergic pathway,13 and the involvement of
-adrenergic activation in the mechanism of pressure overload
hypertrophy14 suggests the involvement of the
-adrenergic pathway in growth signaling. Thus, it is conceivable
that the signaling cascades activated by the different
interventions, leading to increased glucose uptake in heart, may
overlap considerably.
We examined whether insulin and catecholamines stimulate
glucose uptake in heart muscle by the same or by different mechanisms.
We found that -adrenergic stimulation mediates glucose uptake
through a PI3-K–dependent pathway. Because of the additive effects of
-adrenergic stimulation and insulin, we conclude that there are 2
different isoforms of PI3-K, there is compartmentation of PI3-K, there
is potentiation of the insulin-receptor and the -receptor pathways,
or there is inhibition by wortmannin of another intermediate of the
-adrenergic signaling cascade, possibly protein kinase C.
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Materials and Methods |
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Animals
Male Sprague-Dawley rats (300 to 350 g) were obtained from Harlan (Indianapolis, IN). Animals were fasted overnight (16 to 20 hours) with free access to water. The use of animals and the experimental protocol were approved by the Animal Welfare Committee of the University of Texas-Houston Health Science Center.
Materials
Chemicals were obtained from Fisher Scientific or Sigma. Enzymes
and cofactors for metabolite assays were obtained from
Boehringer Mannheim or Sigma Chemical Co. Regular human insulin
(Humulin R) was purchased from Eli Lilly and Co (Indianapolis, IN).
Wortmannin and the catecholamines were from
Sigma.
Radioisotopes
HPLC-purified [2-3H]glucose was obtained
from Amersham. Before each perfusion we ascertained that
3H radioactivity was in the tracer and not in
3H2O. The tracer was
discarded if the activity from intrinsic tritiated water was >1% of
the total activity. A purity check of the tracer was also performed
using the method described by Cheung et al15 to ascertain
that the tracer was indeed [2-3H]glucose.
Working Heart Preparation
The preparation has been described in detail
earlier.16 Briefly, rats were anesthetized with
sodium pentobarbital (5 mg/100 g body weight IP). After injection of
heparin (200 IU) into the inferior vena cava, the heart was
rapidly removed and placed in ice-cold Krebs-Henseleit buffer. The
aorta was cannulated, and a brief period of retrograde perfusion (<5
minutes) with oxygenated buffer containing glucose (5
mmol/L) was performed to wash out any blood from the heart and to
cannulate the left atrium. Hearts were then perfused as working hearts
at 37°C with recirculating Krebs-Henseleit buffer (200 mL) containing
glucose (5 mmol/L) and sodium oleate (0.4 mmol/L) bound to
1% BSA and Cohn fraction V (fatty acid free; Intergen Co) and
equilibrated with 95% O2-5%
CO2. Perfusate
[Ca2+] was 2.5 mmol/L. All experiments
were carried out with a preload of 15 cm H2O and
an afterload of 100 cm H2O. The hearts were
beating spontaneously at an average rate of 300 bpm. Aortic flow and
coronary flow were measured every 5 minutes, and cardiac output
was calculated as the sum of both values. Heart rate and
systolic and diastolic aortic pressures were
measured continuously with a 3F Millar transducer (Millar Instruments)
and a MacLab physiological recording system
(ADInstruments).
Perfusion Protocol
Hearts were perfused for 60 or 90 minutes in the presence or
absence of wortmannin (3 µmol/L). At a concentration of 3
µmol/L, wortmannin completely inhibited insulin-stimulated glucose
uptake. Wortmannin was dissolved as a 10 mmol/L solution in DMSO
freshly on the day of every experiment.
[2-3H]Glucose (10 µCi) was added to the
perfusate (200 mL) before the beginning of the experiment.
Table 1
shows the different experimental
groups and the interventions, which were performed at t=30
minutes (and t=60 minutes in 2 groups). The concentrations
of insulin (1 mU/mL), epinephrine (1 µmol/L),
isoproterenol (1 µmolL), and phenylephrine (100
µmol/L) were chosen to achieve maximal stimulatory effects. The
concentrations of propranolol (10 µmol/L) and
phentolamine (10 µmol/L) were chosen because they fully
inhibited the effects of isoproterenol and phenylephrine,
respectively (data not shown). Hearts in the Alpha and Alpha-WM groups
and Beta and Beta-WM groups were stimulated with an -adrenergic
agonist plus a ß-adrenergic antagonist and a
ß-adrenergic agonist plus an -adrenergic antagonist,
respectively (hearts in the Alpha-WM and Beta-WM groups were treated
with wortmannin). This approach was chosen for the following 2
reasons. First, the presence of an inhibitor of the
receptor type not to be stimulated eliminates any cross-stimulation by
endogenous catecholamines. Secondly, the
negative inotropic effects of - and ß-blockers blunted the
positive inotropic effects of the - and ß-adrenergic agonists
(data not shown). At the end of all perfusions, hearts were
freeze-clamped with aluminum tongs cooled to the temperature of liquid
nitrogen.
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Assessment of Contractile Performance
Mean aortic pressure (cm H2O) was
calculated as (systolic+diastolic pressurex2)/3.
Heart rate was measured as bpm and cardiac output as mL/min. Cardiac
power was determined from the product of cardiac output and mean
aortic pressure as described earlier.17
Measurement of Glucose Uptake
Glucose uptake was determined by the rate of
3H2O production
from [2-3H]glucose.18 Counting of
the isotope was performed on a Packard 1900 TR liquid scintillation
analyzer by the method of spectral index analysis as
described by the manufacturer (Packard Instruments). Release of
3H2O into the
perfusate was analyzed in 5-minute intervals.
3H2O was separated from
[2-3H]glucose in the perfusate by anion
exchange chromatography on AG-1X8 resin (Bio-Rad
Laboratories).19 The amount of
3H2O in the
perfusate was plotted against time, and the slopes of the
desired intervals were used to calculate glucose uptake rates, which
were expressed as µmol/(min · g dry weight).
Tissue Analysis
The frozen tissue, ground under liquid nitrogen, was extracted
with 6% perchloric acid. The tissue extracts were neutralized with 3
mol/L KOH. A small portion of the pulverized tissue was dried in an
oven (70°C) to constant weight and the wet-to-dry ratio was
calculated. The tissue extracts were analyzed for glycogen as
reported by Walaas and Walaas20 and for
glucose-6-phosphate (G6P) and lactate content according to standard
biochemical methods.
Perfusate Samples
Samples of the coronary effluent (1 mL) were withdrawn
every 5 minutes and were stored on ice until assayed for glucose and
lactate by a glucose/lactate analyzer (2300 STAT, YSI Inc). The
samples were analyzed for the specific activity
([2-3H]glucose) and for
3H2O content.
Statistical Analysis
All data are presented as mean±SEM. Statistical
comparison was by 1-way repeated-measures analysis or unpaired
ANOVA with post hoc comparison by Newman-Keuls test as
appropriate.21 Differences were considered statistically
significant when P<0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cardiac Performance
Cardiac power was stable in all groups before and after the interventions (Table 2
). Cardiac power in
the first 30 minutes ranged from 8 to 11 mW. Except for
epinephrine, which caused a 25% to 47% sustained increase in
cardiac power, none of the interventions changed contractile
performance, and cardiac power remained stable for the entire
duration of the experiments. Although the response to
epinephrine was less pronounced in the presence of wortmannin,
the differences were not statistically significant. In preliminary
experiments, it was established that the positive inotropic responses
of the - and the ß-adrenergic agonists were blocked by the -
and ß-adrenergic antagonists, respectively (data not
shown).
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Glucose Uptake
Figure 1 shows rates of myocardial
glucose uptake before and after the addition of insulin without or with
wortmannin. Insulin addition caused a 3-fold increase in glucose uptake
that was completely inhibited by wortmannin (shaded bars).
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) or absence
(
) of wortmannin (3 µmol/L). Hearts were
perfused at physiological workload with
Krebs-Henseleit buffer containing glucose (5 mmol/L) and oleate
(0.4 mmol/L) as substrates. Values are mean±SEM.
**P<0.01 compared with no insulin.
Figure 2 shows rates of myocardial
glucose uptake before and after the addition of epinephrine in
the presence or absence of wortmannin. Epinephrine, as insulin,
caused a significant increase in glucose uptake, but this increase was
not inhibited by wortmannin.
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) of wortmannin (3 µmol/L). See Figure 1
To distinguish between the - and ß-receptor–mediated effects of
epinephrine, we stimulated hearts in the presence or absence of
wortmannin with either phenylephrine or isoproterenol. To
eliminate interference from endogenous
catecholamines from cardiac nerve termini, we inhibited the
ß-receptor with propranolol in hearts in which
phenylephrine was added and, conversely, we inhibited the
-receptor with phentolamine in hearts in which isoproterenol
was added. Figures 3A and 3B demonstrate
that the selective stimulation of either - or ß-adrenergic
receptors increased glucose uptake to the same degree as
epinephrine. However, whereas wortmannin did not affect
ß-stimulated glucose uptake, the -stimulated uptake was completely
inhibited. The changes in glucose uptake observed with selective -
and ß-adrenergic stimulation were similar to the effects of
epinephrine, although contractile function was unchanged in
these protocols.
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Figure 4 shows glucose uptake of those
hearts in which the stimulation with insulin was followed by either
epinephrine (Figure 4A) or -selective stimulation
(Figure 4B). In both groups the effects of the second
intervention were additive to the effects of insulin on glucose uptake,
but epinephrine caused a greater increase than selective
-receptor stimulation or epinephrine in the absence of
insulin (see Figure 2
).
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It is of note that wortmannin did not inhibit unstimulated glucose
uptake in any of the groups (ie, glucose uptake measured in the absence
of insulin or catecholamines [Figures 1 through 3, before intervention]).
Glycogen and Metabolites
Figure 5 shows the change in tissue
content of glycogen caused by the different interventions. The total
glycogen content before the interventions was 71.0±3.04 µmol/g
dry weight. The total glycogen content at the end of the experiments is
shown at the bottom of Figure 5 for each group. Addition of
insulin increased myocardial glycogen content significantly. This
increase was completely inhibited by wortmannin. Addition of
epinephrine resulted in significant net glycogen breakdown,
which was unaffected by wortmannin. Selective ß-receptor stimulation
caused glycogen breakdown similar to epinephrine, whereas
-receptor stimulation only caused an insignificant amount of
glycogen breakdown. Wortmannin did not affect these changes
significantly. Insulin blunted the net breakdown of glycogen induced by
epinephrine or -adrenergic stimulation.
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We also measured G6P, which is a regulator of glycogen synthesis. The tissue content of G6P was highest after the addition of insulin (0.91±0.24 µmol/[min · g dry weight]) and lowest after the addition of epinephrine (0.23±0.24 µmol/[min · g dry weight]). Statistical comparison of all 10 groups did not reveal any significant differences.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study provides evidence that
-adrenergic stimulation
mediates glucose uptake in rat heart through a PI3-K–dependent
pathway. The observed additive effects of -adrenergic stimulation
and insulin suggest the following possibilities: there are 2 different
isoforms of PI3-K, there is compartmentation of PI3-K, there is
potentiation of the insulin and the -receptor pathways, or there is
inhibition by wortmannin of another intermediate of the -adrenergic
signaling cascade. The study further demonstrates that the stimulating
effects of both the - and the ß-adrenergic pathways on glucose
uptake are independent of changes in cardiac performance.
Finally, it could be demonstrated that the effects of insulin on
glycogen synthesis are also mediated through PI3-K and that the effects
of epinephrine on glycogen breakdown are mediated through the
ß-adrenergic pathway.
Experimental Models
Our finding of increased glucose uptake on epinephrine
addition is in agreement with other investigations performed in the
isolated heart3 9 22 but is in contrast to results
obtained by addition of epinephrine in vivo.23 24
The observed decrease in glucose uptake on catecholamine
addition in vivo may be due to catecholamine effects on
other metabolically active tissues. It is conceivable that
the increase in lactate production and release of fatty acids
by skeletal muscle on epinephrine addition increases the
availability of these substrates to the heart. The preference of the
heart for the oxidation of lactate and fatty acids under normoxic
conditions22 may then overcome the stimulatory effects of
epinephrine on glucose metabolism and result in a
net decrease of glucose uptake. These discrepancies of the
epinephrine effects in vivo and in vitro demonstrate the
importance of isolated systems for the investigation of mechanisms by
which hormones elicit their effects on myocardial
metabolism. We used the isolated working rat heart
preparation for our studies, because the model allows us to eliminate
the interference from peripheral tissues in vivo and
provides control of the metabolic and hormonal environment,
while contractile function is similar to contractile function in vivo.
Despite the differences in the effects of catecholamines in
vivo and in vitro, it is reasonable to assume that the
signal-transduction cascades elucidated in this study are also
activated by epinephrine in vivo, in which the effects
may be blunted by other regulatory mechanisms.
Inhibition of PI3-K by Wortmannin
The fungal metabolite wortmannin is a potent inhibitor
of PI3-K. Wortmannin is thought to be specific at low
concentrations.25 26 At a concentration of 3
µmol/L, we found complete inhibition of insulin-induced glucose
uptake. This concentration is 30 times the
Ki for PI3-K in soleus
muscle25 (ie, inhibition of PI3-K can be expected to
be near 100%) and is consistent with those used in skeletal
muscle, adipocytes, and heart muscle (0.1 to 5
µmol/L).6 7 27 28
Wortmannin has also been shown to inhibit other cellular enzymes
such as protein kinase C and myosin light chain kinase, but the
concentrations required for these effects were 100- to 1000-fold higher
than those necessary to inhibit glucose uptake.25 26 It
appears therefore reasonable to assume that the concentration of 3
µmol/L, which we chose for the present study, renders wortmannin
a specific inhibitor of PI3-K. This conclusion is
consistent with the one drawn from studies in brown
adipocytes.29 However, significant inhibition of protein
kinase C by wortmannin may be an alternative explanation for the
inhibition of -adrenergically stimulated glucose uptake by
wortmannin.
Mechanism of Myocardial Glucose Uptake
Because of their importance for the understanding of type 2
diabetes mellitus, the mechanisms underlying the regulation of glucose
uptake by insulin have been intensely investigated and are largely
understood.4 30 Activation of the insulin receptor leads
to autophosphorylation of the receptor followed by the
activation of insulin-receptor substrate 1, which forms a complex with
and activates PI3-K, the key mediator for the acute effects of
insulin on metabolism.4 5 25 Our findings of
the inhibition of insulin-induced glucose uptake and the inhibition of
insulin-induced glycogen synthesis are in support of this concept.
In contrast, only little is known about the mechanism responsible
for the effects of catecholamines on glucose uptake. It has
been suggested that the effects of catecholamines on
glucose uptake in skeletal31 32 and in heart
muscle9 are contraction mediated (ie, mediated through an
increase in cytosolic [Ca2+]). Another
hypothesis on the effects of catecholamines on glucose
uptake has arisen from observations in cardiac myocytes. In contrast to
the contraction-mediated induction of glucose uptake, it has been
suggested that -receptor–coupled G proteins are responsible for the
effect, whereas the stimulation of ß-receptors does not increase
glucose uptake.11 We demonstrate in the isolated working
rat heart that specific stimulation of ß-receptors increases glucose
uptake to the same degree as stimulation of -receptors. In light of
the lack of ß-receptor effects in noncontracting cardiac myocytes, it
is conceivable that - and ß-receptors stimulate different
signaling pathways to increase glucose uptake, in which contraction is
required for the effects of the ß-receptor pathway. Our results
support the concept of different pathways for the stimulation of
glucose uptake through - or ß-receptors. The lack of an increase
in contractile performance in our protocol of selective -
and ß-stimulation demonstrates that an increase in contractile
function is not necessary to elicit the stimulatory effects on glucose
uptake. However, we did not measure the intracellular concentration of
Ca2+.
We demonstrate that a PI3-K inhibitor is able to
block a pathway activated by -adrenergic receptor
stimulation. However, despite the complete inhibition of the
-adrenergically stimulated glucose uptake, the effects of selective
-adrenergic stimulation were still additive to the effects of
insulin on glucose uptake. There are 4 possible explanations for these
observations. First, -receptor stimulation leads to the activation
of a different isoform or a subfraction of PI3-K, which is also
inhibited by wortmannin but not involved in the insulin signaling
pathway. The existence of different subfractions of PI3-K has already
been suggested in skeletal muscle.27 Second, the signaling
pathways may be compartmentalized. Third, it is conceivable that the
effects of insulin and -receptor stimulation potentiate each other.
It could be speculated that the common link is protein kinase C, which
has been shown to increase glucose uptake when stimulated with phorbol
esters33 and which is able to phosphorylate
the insulin receptor.13 Fourth, wortmannin may not be
selective for PI3-K and inhibit a component of the -adrenergic
signaling pathway. However, the specificity of wortmannin has been
documented in many studies. Despite the possibility of nonspecific
interference of wortmannin with the -adrenergic pathway, the data
strongly support the concept of 2 distinct mechanisms for - and
ß-adrenergically stimulated glucose uptake.
The presence of different pools of glucose transporters in the
cytosol has been suggested that are thought to be recruited by
different mechanisms.34 35 The additive effects of the
insulin and epinephrine and insulin and selective
-adrenergic stimulation support this hypothesis. This hypothesis is
further supported by our findings that the additive effects of
epinephrine and insulin are greater than the additive effects
of selective -stimulation and insulin. Because selective - or
ß-receptor stimulation alone reached the same magnitude of glucose
uptake as maximal stimulation with epinephrine, one may
speculate that the -receptor and the insulin pathways potentiate
each other. This hypothesis would explain the greater response of
glucose uptake to epinephrine than to selective -stimulation
in the presence of insulin or to epinephrine alone, because the
-adrenergic component of epinephrine would be amplified by
the presence of insulin.
The possibility exists that the additive effects of insulin and epinephrine could be due to an underestimation of insulin-stimulated glucose transport. We have shown before that insulin causes a shift of the rate-limiting step for glucose uptake from transport to phosphorylation36 (ie, insulin stimulates glucose transport more than phosphorylation), and, thus, glucose uptake underestimates glucose transport at this point. If this were the case in the present experiments, then the error would be a systematic error, which would not affect the interpretation of our results. The work of Cheung et al15 showed that glucose uptake as measured by glucose disappearance may be up to 13% higher than uptake measured by 3H2O production from [2-3H]glucose under conditions of high glucose and high insulin concentrations and in the absence of fatty acids. The discrepancy may be due to the same shift of the rate-limiting step of glucose uptake as described above. Even with some underestimation of insulin-stimulated glucose transport by the [2-3H]glucose method, the overall interpretation of our results would be the same.
Myocardial Glycogen Synthesis and Degradation
The involvement of PI3-K in the effects of insulin on glycogen
synthesis has been documented in skeletal muscle and
adipocytes.25 37 Recently, it has been doubted whether
this pathway is dependent on PI3-K.38 If wortmannin is a
specific inhibitor of PI3-K, then stimulation of glycogen
synthesis in rat heart must be PI3-K dependent.
The key enzyme for glycogen breakdown is glycogen
phosphorylase, which is activated by
phosphorylase b kinase, a reaction activated by
[Ca2+]. cAMP activates
phosphorylase b kinase through activation of cAMP-dependent
protein kinase. The stronger effect of ß-receptor activation compared
with the effect of -receptor activation on glycogen breakdown found
in this study suggests that the described mechanism is much more
sensitive to cAMP than to [Ca2+] in heart
muscle.
Conclusions
We have shown that -adrenergic stimulation mediates glucose
uptake in rat heart through a PI3-K–dependent pathway. The observed
additive effects of -adrenergic stimulation and insulin suggest 2
different isoforms of PI3-K, compartmentation of PI3-K, or inhibition
by wortmannin of another intermediate of the -adrenergic signaling
cascade. The study further demonstrates that the stimulating effects of
both the - and the ß-adrenergic pathways on glucose uptake are
independent of changes in cardiac performance. Finally, we
demonstrated that the effects of insulin on glycogen synthesis are also
mediated through PI3-K and that the effects of epinephrine on
glycogen breakdown are mediated through the ß-adrenergic pathway.
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Acknowledgments |
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This study was supported in part by a grant from the United States Public Health Service (RO1-HL43133). T.D. was the recipient of a research fellowship from the German Research Foundation (Deutsche Forschungsgemeinschaft). We thank Patrick Guthrie for technical assistance, Prof Dr F. Beyersdorf for encouragement, and Drs Gary W. Goodwin and Christophe Depre for helpful discussions.
Received July 27, 1998; accepted December 11, 1998.
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