Metabolic
effects of glucose-insulin-potassium on the heart
Dr Michael F. Allard1, Dr William
A. Stanley2, Professor Gary D. Lopaschuk3
1Department of Pathology and Laboratory Medicine,
University of British Columbia,
St Paul’s Hospital, Vancouver, Canada;
2Department of Physiology and Biophysics, Case Western University,
Cleveland, OH, USA;
3Cardiovascular Research Group, University of
Alberta, Edmonton, Canada
Glucose-insulin-potassium (GIK) was first proposed
as a metabolic intervention to treat acute myocardial infarctions
almost 40 years ago by Sodi-Pallares et al.[1] In
the last 3 years there has been a marked resurgence of interest
in the use of GIK to treat ischemic heart disease. This has been
stimulated by recent clinical successes with GIK treatment of
acute myocardial infarction,[2] as well as the
publication of a meta-analysis of previous trials showing a 28%
reduction in in-hospital mortality using GIK.[3] In
this issue of Heart and Metabolism, articles by Dr Rafael Díaz
and by Dr Carl Apstein review the clinical evidence supporting
the use of GIK therapy following an acute myocardial infarction.
The purpose of this ‘basic metabolism’ article is to describe
some of the possible mechanisms by which GIK may exert these
beneficial effects. In order to do this, it is important to first
provide an overview of the metabolic actions of insulin on the
heart. How GIK may modify metabolism in the heart, and how this
may account for its clinical benefits are then discussed.
Insulin control of glucose metabolism
in the heart
Cardiomyocytes oxidize fatty acids derived from both the plasma and the breakdown
of intracellular triacylglycerol stores, while pyruvate is derived from either
lactate dehydrogenase or glycolysis. The rates of these metabolic pathways
are tightly coupled to the rate of contractile work, and conversely, contractile
work is coupled to the supply of oxygen and the rate of oxidative phosphorylation.
Studies in animals and humans have shown that after an overnight fast the heart
extracts free fatty acids (FFA), lactate and glucose from the blood, and that
if one assumes complete oxidation of extracted substrates, fatty acids are
the major oxidative fuel for the heart (60–80% of the oxygen consumption),
with a lesser contribution from lactate and glucose (10–20% from each) (see
references [4] and [5] for reviews). The
regulation of myocardial metabolism is complex in that it is linked to plasma
substrate and hormone levels, coronary flow, inotropic state and the nutritional
status of the tissue. GIK infusion has profound effects on myocardial metabolism
that are mediated by the hyperglycemia, the direct effects of insulin on the
cardiomyocytes, and by the indirect action of insulin on circulating FFA levels.
Regulation of glucose uptake
The uptake of extracellular glucose is regulated by the transmembrane glucose
gradient and the concentration and activity of glucose transporters in the
plasma membrane. Two isoforms from the glucose transporter family have been
identified in the myocardium: GLUT-1 and GLUT-4, with GLUT-4 being predominant.
Both transporters are located in the sarcolemmal membrane and in intracellular
microsomal vesicles (Figure 1).
Figure 1. Insulin control of glucose uptake in the heart.
The capacity of the cell to take up glucose is
dependent upon the fraction of the glucose transporters that
reside in the plasma membrane. Insulin results in translocation
of GLUT-1 and GLUT-4 from the intracellular site into the sarcolemmal
membrane, which results in an increase in the membrane capacitance
for glucose transport.[6,7] With regard to GIK,
it is particularly relevant to note that the effects of insulin
and moderate severity ischemia on glucose transporter translocation
and glucose uptake are additive.[7] Thus, treatment
of ischemic patients with hyperinsulinemia will result in greater
glucose uptake in the ischemic myocardium.
The rate of glucose uptake by the heart is also very dependent upon the concentration
of glucose in the interstitial fluid outside the cardiomyocyte. The interstitial
glucose concentration is the major determinant of the transmembrane glucose
gradient and, thus, the driving force for glucose transport across the plasma
membrane. There is very little free glucose in the cell. The interstitial glucose
concentration is a function of the arterial glucose concentration and blood
flow. During myocardial ischemia there is a fall in interstitial glucose levels
in proportion to the decrease in the rate of glucose delivery to the tissue.[8] Thus
a reduction in coronary blood flow increases the cell membrane’s ability to
transport glucose, but at the same time less glucose outside the cell is available
to be transported into the cell. If the severity of myocardial ischemia is
extremely severe there will be almost no blood flow and, thus, no glucose uptake.
In human ischemia, even with acute myocardial infarction, there is residual
myocardial blood flow due to incomplete blockage of the artery, and/or blood
flow from collateral coronary arteries. Studies in swine show that acute hyperglycemia
during myocardial ischemia results in a profound increase in interstitial glucose
and greater glucose uptake by the heart, even in the absence of an increase
in plasma insulin.[9] Thus, the hyperglycemia that can occur
with GIK therapy results in greater glucose uptake by increasing interstitial
glucose in the myocardium. Upon entering the cell, free glucose is rapidly
phosphorylated by hexokinase to form glucose 6-phosphate, thus, rendering the
carbon skeleton of glucose impermeable to the cell membrane.
In addition to its effects on glucose transport, insulin also results in stimulation
of hexokinase and glycogen synthetase activities, resulting in increased glucose
phosphorylation and glycogen synthesis; the mechanism for this effect in heart
is unclear, but could be at least partially due to the increase in glucose
and glucose 6-phosphate that occurs secondary to insulin-stimulated glucose
transport.
Regulation of glucose oxidation
After glucose enters the cell and is phosphorylated to glucose 6-phosphate,
it proceeds down the glycolytic pathway to pyruvate. Under normal aerobic conditions,
pyruvate enters the mitochondria and is decarboxylated to acetyl coenzyme A
(CoA). Under ischemic conditions pyruvate is reduced in the cytosol to lactate.
Pyruvate decarboxylation is the key irreversible step in carbohydrate oxidation
and is catalyzed by pyruvate dehydrogenase (PDH). PDH is a multi-enzyme complex
located in the mitochondrial matrix. The activity of PDH is regulated by a
variety of mechanisms: in particular, it is inactivated by phosphorylation
by a specific PDH kinase (Figure 2).
Figure 2. Insulin control of glucose oxidation in the
heart. CoA-SH, Coenzyme A; NAD+, oxidized form of nicotinamide
dinucleotide; NADH, reduced form of nicotinamide adenine dinucleotide.
The rate of pyruvate oxidation is very dependent
on the degree of phosphorylation of PDH, and also on the concentrations
of its substrates and products in the mitochondria, as these
control flux through the active dephosphorylated form of the
enzyme.[10,11]
GIK therapy increases the oxidation of pyruvate by PDH. Pyruvate oxidation
and the activity of PDH in the heart are enhanced by suppression of FFA oxidation
induced by a decrease in plasma FFA levels. The high plasma insulin levels
that occur during GIK treatment will suppress the release of FFA from subcutaneous
fat stores, rapidly lower plasma FFA concentration, and decrease the rate of
fatty acid oxidation by the heart. This will relieve fatty acid-induced inhibition
of pyruvate oxidation. High rates of fatty acid oxidation elevate the concentrations
of nicotinamide adenine dinucleotide (NADH) and acetyl CoA in the mitochondrial
matrix, and result in activation of PDH kinase and inhibition of PDH and pyruvate
oxidation. Insulin lowers plasma FFA levels and the rate of fatty acid oxidation
and, thus, removes NADH and acetyl CoA activation of PDH kinase activity. This
results in activation of PDH and a greater rate of pyruvate oxidation. Thus,
GIK therapy activates PDH indirectly through suppression of fatty acid oxidation.
It has long been thought that insulin may act through a second messenger to
activate PDH by inhibiting PDH kinase, though a mechanism for this effect has
not yet been identified.
Insulin control of fatty
acid metabolism in the heart
Under most conditions, plasma FFA levels are the primary regulator of myocardial
glucose and lactate oxidation. High plasma FFA levels (>0.8 mM) inhibit both
the uptake and oxidation of glucose and lactate in human myocardium, while
pharmacologically lowering plasma FFA levels (<0.3 mM) results in an increase
in myocardial glucose and lactate uptake. This is primarily related to the
release of product inhibition on PDH and glycolysis as FFA concentration decreases
in the perfusate.
In addition to its effect on circulating FFA, insulin also has direct effects
on fatty acid oxidation in the heart. A key site at which myocardial fatty
acid oxidation is controlled is at the level of mitochondrial uptake of fatty
acids. A key enzyme in this process is carnitine palmitoyltransferase (CPT)-1
(Figure 3).
Figure 3. Insulin control of fatty acid oxidation in
the heart.
CPT-1 is the first committed step of fatty acid
oxidation, and transfers the fatty acid moiety from acyl CoA
to carnitine to form long chain acylcarnitine, which is then
transported into the mitochondria.[12] A potent inhibitor of
CPT-1 and, therefore, of fatty acid oxidation, is malonyl CoA,
which is produced by acetyl CoA carboxylase (ACC).[13] ACC
is in turn regulated by AMP-activated protein kinase (AMPK),
which can phosphorylate and inhibit cardiac ACC activity (Figure
3).[14,15] AMPK is very active in heart tissue[14]
and appears to act as a ‘fuel gauge’.[15] As
such, AMPK is activated by increased energy demand as occurs
during increased contractile activity or ischemia. By way of
effects on ACC and malonyl CoA levels, activation of AMPK upregulates
fatty acid oxidation, while a decrease in AMPK activity functions
to decrease fatty acid oxidation rates in times of low demand.
We recently demonstrated that insulin inhibits AMPK activity
in the heart.[16,17] Therefore, AMPK may function
to downregulate fatty acid oxidation in response to the increase
in glucose metabolism that occurs following insulin administration.
This provides an attractive mechanism by which fatty acid oxidation
and glucose metabolism in the heart can be coordinated. It is
therefore, possible that one of the additional beneficial effects
of GIK therapy is to inhibit AMPK activity (Figure 3), thereby
increasing malonyl CoA levels and inhibiting fatty acid uptake
into the mitochondria.
Potential mechanisms by which GIK
is beneficial during and following myocardial ischemia
The potential mechanisms responsible for the beneficial effects of GIK are
most clearly understood by considering those that occur during ischemia separately
from those that occur during reperfusion. During the development of an acute
myocardial infarction, coronary blood flow to the infarcting myocardium is
markedly reduced but still present.[18] This feature of acutely
infarcting myocardium is of critical importance in explaining the beneficial
effects of insulin during ischemia because it indicates that some degree of
substrate delivery and metabolite washout occurs at this time. During ischemia,
oxidative metabolism is reduced and anaerobic glycolysis becomes a major source
of myocardial ATP production.[4] Despite an increased reliance
on anaerobic glycolysis for ATP production, delivery of glucose to the myocardium
is significantly reduced during ischemia because of the reduction in coronary
flow.
Beneficial effects of GIK on glucose
uptake and glycolysis during ischemia
One mechanism to account for the beneficial effects of GIK is increased provision
of glucose, the substrate for glycolysis. Insulin and ischemia both increase
the capacity of the myocardium to take up glucose because both stimulate translocation
of GLUT-1 and GLUT-4 to the sarcolemma.[6,19] Importantly,
the effects of insulin and ischemia have been shown to be additive in terms
of glucose transporter translocation and glucose uptake.[7] By
way of effects on glucose uptake and enzymes of glycolysis, GIK therapy acts
to increase anaerobic glycolytic flux and, thereby, myocardial ATP production
during ischemia.[5] This increase in ATP production is beneficial
because it helps maintain critical membrane functions such as sodium and calcium
ion homeostasis.[20] Additionally, the enhanced production
of energy may delay and/or reduce the extent of ischemic myocardial necrosis,
a situation that accounts in part for the beneficial effects of GIK.[5,20] The
fact that residual coronary flow occurs in the region of the acute infarct
is important because it allows for removal of glycolytic products (lactate,
protons) that could be detrimental if they accumulated.
Beneficial effects of GIK on glucose
and fatty acid oxidation during reperfusion
During reperfusion, myocardial oxidative metabolism quickly recovers.[6] Fatty
acid oxidation, in particular, recovers and dominates as a source of myocardial
energy production during reperfusion.[5,21] Fatty
acid oxidation becomes dominant at this time for several reasons. First, circulating
fatty acid levels rise as a result of elevated endogenous catecholamines.[22,23] Heparin
administered therapeutically also likely contributes to the rise in fatty acid
levels seen with an acute myocardial infarction.[20] These
high levels of fatty acids lead to an increase in the rate of myocardial fatty
acid uptake and oxidation. Second, myocardial fatty acid oxidation is directly
stimulated during reperfusion. Myocardial malonyl CoA, a key regulatory intermediate,
decreases at this time, relieving inhibition of CPT-1-mediated mitochondrial
fatty acid uptake[21] (Figure 3). Malonyl CoA is reduced
because AMPK is stimulated in ischemic reperfused myocardium and phosphorylates
to inactivate ACC, the enzyme responsible for malonyl CoA synthesis.[21]
Even though a rapid return of oxidative metabolism is required for full recovery
of contractile function, the nature of the energy substrates used is a critical
determinant of the extent of functional recovery.[5] The dominance
of fatty acid oxidation during reperfusion leads to a reduction in glucose
utilization by the myocardium. Importantly, glucose oxidation is suppressed
to a greater extent than glycolysis.[5] As a result, there
is an uncoupling of glycolysis from glucose oxidation that is substantially
greater than normal. This increased uncoupling leads to accelerated proton
production. Accelerated proton production is considered to be an important
contributor to the myocardial dysfunction and decreased contractile efficiency
observed during reperfusion.[5] In support of this viewpoint,
stimulation of glucose oxidation, either directly or by inhibiting fatty acid
oxidation, has been shown to significantly improve myocardial function and
contractile efficiency.[5] Thus, high rates of fatty acid
oxidation contribute to myocardial dysfunction and contractile inefficiency
during reperfusion by decreasing glucose utilization, particularly by reducing
rates of glucose oxidation, and by increasing proton production from glucose
metabolism.
During reperfusion, a major beneficial effect of GIK therapy is a reduction
in circulating fatty acid levels[5,20] (Figure
4).
 Figure
4. Potential mechanisms by which GIK protects the heart
during ischemia.
As a result, myocardial fatty acid uptake and
oxidation are reduced. The importance of this effect is demonstrated
by observations that the greatest clinical benefit of GIK therapy
occurs with therapeutic regimens that maximally suppress circulating
fatty acid levels.[24] Insulin may also directly
decrease myocardial fatty acid oxidation during reperfusion by
inhibiting AMPK16 (Figure 3). A corollary of the GIK-induced
reduction in fatty acid oxidation is that myocardial glucose
use in general, and glucose oxidation in particular, are increased
during reperfusion, an effect that leads to improved coupling
of glycolysis to glucose oxidation, decreased proton production,
and, thereby, increased myocardial function and contractile efficiency.
In addition to indirectly stimulating glucose use by way of effects
on fatty acid oxidation, GIK also directly stimulates glucose
uptake during reperfusion.[25]
Other potential beneficial effects of
GIK
Depletion of citric acid cycle intermediates has been proposed as a major cause
of impaired energy production by the heart during reperfusion.[26] Citric
acid cycle intermediates are replenished by a process termed anaplerosis.[20,26] Carboxylation
of pyruvate is a major mechanism of anaplerosis in the heart.[20] Importantly
in this regard, GIK therapy increases pyruvate production by increasing glucose
uptake and glycolytic flux. Therefore, an additional benefit of GIK therapy
may be rapid replenishment of the depleted citric acid cycle intermediate pool.
Recently, insulin-like growth factor-I and insulin have been shown to protect
against hypoxia- and ischemia-induced apoptosis.[27,28] The
high concentrations of insulin achieved with GIK therapy may activate these
receptors and reduce apoptotic myocardial cell loss associated with ischemia
and reperfusion. This may be another mechanism by which GIK therapy favorably
influences post-infarct remodeling.
Several other potentially important mechanisms may also contribute to the beneficial
effects of GIK therapy. By way of its effects on the vasculature,[19] insulin
may improve myocardial perfusion and decrease peripheral vascular resistance.
Additionally, insulin may have a direct inotropic effect on the myocardium.[29]
As originally proposed, GIK therapy may reduce ventricular ectopy by increasing
K+ reuptake through stimulation of the sarcolemmal Na+,K+-ATPase.[1]
Pharmacological agents with actions
similar to GIK
Numerous clinical and experimental studies have now convincingly demonstrated
that ischemic heart disease can be treated by optimizing energy metabolism
(see reference [30] for review). One approach used clinically
is to inhibit fatty acid oxidation in the heart, an action that may partly
explain the benefits of GIK. As discussed, during and following ischemia, high
levels of circulating fatty acids effectively compete with glucose as a source
of energy. This results in an accelerated acidosis in the muscle and an increase
in energy requirements for non-contractile purposes (i.e. a decrease in cardiac
efficiency). Inhibiting fatty acid oxidation and stimulating glucose oxidation
can significantly improve cardiac efficiency (cardiac work/oxygen consumed).
A number of pharmacological approaches can be used to achieve this, including
altering fatty acid and glucose uptake into the heart muscle, directly inhibiting
fatty acid oxidation, or directly stimulating the rate-limiting enzyme involved
in glucose oxidation, PDH.[30] Agents that have been shown
to produce these effects include dichloroacetate, trimetazidine, etomoxir,
ranolazine, L-carnitine, and propionyl L-carnitine.[30,31] Presently,
the only pharmacological agent clinically used on a widespread basis to treat
ischemic heart disease is trimetazidine, which acts by directly inhibiting
fatty acid oxidation.[32] This inhibition of fatty acid oxidation
is accompanied by a significant increase in PDH activity and an increase in
glucose oxidation.[32] This results in a decreased production
of acidosis in the myocardium, which appears to account for the cardioprotective
effects of trimetazidine observed in many experimental and clinical studies.
As a result, optimizing energy substrate preference is emerging as a novel
and effective approach to treating cardiovascular disease.
Conclusion
GIK has a number of actions on cardiac energy metabolism. These include increasing
glucose uptake and glucose oxidation, while directly and indirectly inhibiting
fatty acid oxidation. Additional actions on mitochondrial tricarboxylic acid
cycle activity, apoptosis and direct effects on vascular function may also
contribute to the beneficial effects of GIK. Combined with studies using
pharmacological agents that act by optimizing energy metabolism, GIK therapy
highlights the potential of metabolic modulation in the treatment of ischemic
heart disease.
REFERENCES
1. Sodi-Pallares D, Testelli MR, Fishleder BL Effects
of intravenous infusion of potassium-glucose-insulin solution on the electrocardiographic
signs of myocardial infarction. Am J Cardiol 1962; 9: 166–181.
-
Metabolic modulation of acute myocardial
infarction. The ECLA (Estudios Cardiologicos Latinoamerica)
Collaborative Group.
Diaz R, Paolasso EA, Piegas LS, Tajer CD, Moreno MG,
Corvalan R, Isea JE, Romero G.
Department of Cardiology, Instituto Cardiovascular de Rosario, Rosario, Argentina.
BACKGROUND: Several trials have been performed in the past using glucose,
insulin, and potassium infusion (GIK) for the treatment of acute myocardial
infarction (AMI). Because of continuing uncertainty about the potential role
of this therapeutic intervention, we conducted a randomized trial to evaluate
the impact of a GIK solution during the first hours of AMI. METHODS AND RESULTS:
Four hundred seven patients with suspected AMI admitted within 24 hours of
symptoms onset were enrolled. In a ratio of 2:1, 268 patients were allocated
to receive GIK (high- or low-dose) and 139 to receive control. Phlebitis
and serum changes in the plasma concentration of glucose or potassium were
observed more often with GIK. A trend toward a nonsignificant reduction in
major and minor in-hospital events was observed in patients allocated to
GIK. In 252 patients (61.9%) treated with reperfusion strategies, a statistically
significant reduction in mortality (relative risk [RR] 0.34; 95% CI: 0.15
to 0.78; 2P=0.008) and a consistent trend toward fewer in-hospital events
in the GIK group were observed. CONCLUSIONS: Our results confirm that a metabolic
modulation strategy in the first hours of an AMI is feasible, applicable
worldwide, and has mild side effects. The statistically significant mortality
reduction in patients who underwent a reperfusion strategy might have important
implications for the management of AMI patients. It is now essential to perform
a large-scale trial to reliably determine the magnitude of benefit.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 9867443 [PubMed - indexed for MEDLINE]
-
Comment in:
Glucose-insulin-potassium therapy for treatment of acute
myocardial infarction: an overview of randomized placebo-controlled trials.
Fath-Ordoubadi F, Beatt KJ.
Medical Research Council Clinical Sciences Centre, Postgraduate Medical School,
and Department of Cardiology, Hammersmith Hospital, London, UK. 100412.3302@compuserve.com
BACKGROUND: Glucose-insulin-potassium (GIK) therapy has been advocated for
the treatment of acute myocardial infarction. However, the results from the
clinical trials have been inconclusive, largely because of the small number
of patients recruited and discrepancies between protocols used in these studies.
METHOD AND RESULTS: A systematic MEDLINE search for all the randomized placebo-controlled
studies of GIK therapy in acute myocardial infarction was made, and a meta-analysis
of the mortality data was performed. Fifteen trials were identified, 5 were
excluded because of poor randomization, and 1 was excluded because recruitment
was limited to diabetic patients. The 9 remaining trials with a total of
1932 patients were included in the analysis. Hospital mortality was reduced
from 21% (205 of 972 patients) in the placebo group to 16.1% (154 of 956)
in the GIK group (P=.004; odds ratio, 0.72; 95% confidence interval [CI],
0.57 to 0.90). The proportional mortality reduction was 28% (CI, 10% to 43%).
The number of lives saved per 1000 patients treated was 49 (95% CI, 14 to
83). CONCLUSIONS: The findings indicate that GIK therapy may have an important
role in reducing the in-hospital mortality after acute myocardial infarction.
The value of this therapy in the era of thrombolysis and acute revascularization
by primary angioplasty can be fully resolved only by conducting a large randomized
mortality study.
Publication Types:
PMID: 9286943 [PubMed - indexed for MEDLINE]
4. Neely JR, Morgan HE. Relationship
between carbohydrate and lipid metabolism and the energy balance
of heart muscle. Annu Rev Physiol 1974; 36: 413–459.
-
Regulation of myocardial carbohydrate
metabolism under normal and ischaemic conditions. Potential
for pharmacological interventions.
Stanley WC, Lopaschuk GD, Hall JL, McCormack JG.
CV Therapeutics, Palo Alto, CA 94304, USA. wcs4@po.cwru.edu
It is now clear that the availability of different metabolic substrates can
have a profound influence on the extent of damage incurred during episodes
of cardiac ischaemia, and on cardiac functional recovery on reperfusion following
ischaemia. In particular, increases in fatty acid availability and oxidation,
compared to glucose oxidation, under such conditions leads to a worsening
of outcome. Therefore metabolic interventions aimed at enhancing glucose
utilisation and pyruvate oxidation at the expense of fatty acid oxidation
is a valid therapeutic approach to the treatment of myocardial ischaemia.
In particular, the development of agents which will promote full glucose
oxidation as opposed to glycolysis alone, offer clear advantages. This can
be accomplished by different means, including direct or indirect inhibition
of CPT-I or inhibition of fatty acid beta-oxidation, or by direct or indirect
activation of PDH. It is not yet clear which of these approaches offers the
best treatment of cardiac ischaemia. To date, trimetazidine and carnitine
have received limited approval in Europe for the treatment of angina; large
scale clinical trials with the other agents mentioned above have not been
completed. The increasing availability of agents affecting these specific
sites, and the increasingly sophisticated techniques for assessing myocardial
metabolism, should allow elucidation of the optimum metabolic targets and
development of novel pharmacological agents for the treatment of ischaemic
heart disease.
Publication Types:
PMID: 9074687 [PubMed - indexed for MEDLINE]
-
Comment in:
Low-flow ischemia leads to translocation of canine heart
GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo.
Young LH, Renfu Y, Russell R, Hu X, Caplan M, Ren J,
Shulman GI, Sinusas AJ.
Department of Internal Medicine, Yale University School of Medicine, New
Haven, CT 06520-8017, USA. lawrence.young@quickmail.yale.edu
BACKGROUND: Myocardial ischemia increases heart glucose utilization in vivo.
However, whether low-flow ischemia leads to the translocation of glucose
transporter (GLUT)-4 and/or GLUT-1 to the sarcolemma in vivo is unknown.
METHODS AND RESULTS: In a canine model, we evaluated myocardial glucose metabolism
in vivo and the distribution of GLUT-4 and GLUT-1 by use of immunoblotting
of sarcolemma and intracellular membranes and immunofluorescence localization
with confocal microscopy. In vivo glucose extraction increased fivefold (P < .001)
and was associated with net lactate release in the ischemic region. Ischemia
led to an increase in the sarcolemma content of both GLUT-4 (15 +/- 2% to
30 +/- 3%, P < .02) and GLUT-1 (41 +/- 4% to 58 +/- 3%, P < .03) compared
with the nonischemic region and to a parallel decrease in their intracellular
contents. Immunofluorescence demonstrated the presence of both GLUT-4 and
GLUT-1 on cardiac myocytes. GLUT-1 had a more prominent cell surface pattern
than GLUT-4, which was primarily intracellular in the nonischemic region.
However, significant GLUT-4 surface labeling was found in the ischemic region.
CONCLUSIONS: Translocation of the insulin-responsive GLUT-4 transporter from
an intracellular storage pool to the sarcolemma occurs in vivo during acute
low-flow ischemia. GLUT-1 is also present in an intracellular storage pool
from which it undergoes translocation to the sarcolemma in response to ischemia.
These results indicate that both GLUT-1 and GLUT-4 are important in ischemia-mediated
myocardial glucose uptake in vivo.
PMID: 9008459 [PubMed - indexed for MEDLINE]
-
-
Additive effects of hyperinsulinemia and
ischemia on myocardial GLUT1 and GLUT4 translocation in vivo.
Russell RR 3rd, Yin R, Caplan MJ, Hu X, Ren J, Shulman
GI, Sinusas AJ, Young LH.
Section of Cardiovascular Medicine, Department of Cellular and Molecular
Physiology, Howard Hughes Medical Institute, Yale University School of Medicine,
New Haven, CT, USA.
BACKGROUND: Myocardial ischemia increases glucose uptake through the translocation
of GLUT1 and GLUT4 from an intracellular compartment to the sarcolemma. The
present study was performed to determine whether hyperinsulinemia causes
translocation of myocardial GLUT1 as well as GLUT4 in vivo and whether there
are additive effects of insulin and ischemia on GLUT1 and GLUT4 translocation.
METHODS ADN RESULTS: Myocardial glucose uptake and transporter distribution
were assessed by arteriovenous measurements, cell fractionation, and immunofluorescence.
In fasted anesthetized dogs, hyperinsulinemia increased myocardial glucose
extraction 3-fold (P<0.01) and the sarcolemmal content of GLUT4 by 90%
and GLUT1 by 50% (P<0.05 for both) compared with saline infusion. In subsequent
experiments, glucose uptake and transporter distribution were determined
in ischemic and nonischemic regions of hearts from hyperinsulinemic animals
during regional myocardial ischemia. Glucose uptake was 50% greater in the
ischemic region (P<0.05). This was associated with a 20% increase in sarcolemmal
GLUT1 and a 60% increase in sarcolemmal GLUT4 contents in the ischemic region
(P<0.05 for both). CONCLUSIONS: Insulin stimulates myocardial glucose
utilization through translocation of GLUT1 as well as GLUT4. Insulin and
ischemia have additive effects to increase in vivo glucose utilization and
augment glucose transporter translocation. We conclude that recruitment of
both GLUT1 and GLUT4 contributes to increased myocardial glucose uptake during
moderate reductions in coronary blood flow under insulin-stimulated conditions.
PMID: 9815873 [PubMed - indexed for MEDLINE]
-
Decreased interstitial glucose and transmural
gradient in lactate during ischemia.
Hall JL, Hernandez LA, Henderson J, Kellerman LA, Stanley
WC.
Institute of Pharmacology, Syntex Discovery Research, Palo Alto, CA.
The purpose of this investigation was to assess the effects of ischemia and
reperfusion on the transmural levels of glucose and lactate in the interstitium
in 11 open-chest swine. Microdialysis probes were used to estimate changes
in interstitial metabolities across the ventricular wall. Probes were placed
in the subepicardium and the subendocardium of the left anterior descending
(LAD) coronary artery perfusion bed and in the midmyocardium of the circumflex
(CFX) perfusion bed. The LAD coronary artery was cannulated and perfused
with blood from the femoral artery through an extracorporal perfusion circuit.
Ischemia was induced in the LAD perfusion bed by reducing the flow of the
LAD perfusion pump by 60% for 50 min, and was followed by 30 min of reperfusion.
Regional myocardial blood flow was assessed with fluorescent microspheres.
Ischemia resulted in a transmural gradient in blood flow, with the most severe
reduction in flow occurring in the subendocardium (p < 0.05). We found
a significant reduction in interstitial glucose in both the LAD subepicardium
(1.26 +/- 0.24 mM) (p = 0.0009) and subendocardium (0.89 +/- 0.21 mM) (p
= 0.0001) during ischemia compared to the aerobic (non-ischemic) period (1.97
+/- 0.25 mM, 2.03 +/- 0.29 mM for the subepicardium and subendocardium, respectively).
This coincided with a significant reduction in glucose delivery (LAD pump
flow * arterial glucose) to the LAD perfusion bed during ischemia (54.5 +/-
8.5 mumol/min) compared to aerobic values (182.1 +/- 25.3 mumol/min) (p < 0.05).
Interstitial lactate levels were significantly increased during ischemia
in the LAD subendocardium (3.39 +/- 0.46 mM) compared to the aerobic values
(1.73 +/- 0.46 mM) (p < 0.0029). A transmural gradient in interstitial
lactate levels was observed during ischemia: this gradient was not seen during
the aerobic period and was negated upon reperfusion. In conclusion, ischemia
resulted in a decrease in interstitial glucose in both the LAD subepicardium
and subendocardium, and an increase in interstitial lactate in the LAD subendocardium.
Further, a transmural gradient in interstitial lactate levels was observed
during ischemia, with the highest lactate values appearing in the subendocardium.
PMID: 7702538 [PubMed - indexed for MEDLINE]
9. Hall JL, Henderson J, Hernandez LA, Stanley WC. Hyperglycemia
causes an increase in myocardial interstitial glucose and glucose uptake during
ischemia in swine. Metabolism 1996; 45: 542–549.
10. Randle PJ, Hales CN, Garland PB, Newsholme EA. The glucose
fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances
of diabetic mellitus. Lancet 1963; i: 785–789.
-
Regulation of glucose uptake by muscle.
8. Effects of fatty acids, ketone bodies and pyruvate, and
of alloxan-diabetes and starvation, on the uptake and metabolic
fate of glucose in rat heart and diaphragm muscles.
Randle PJ, Newsholme EA, Garland PB.
PMID: 4220952 [PubMed - indexed for MEDLINE]
-
Regulation of ketogenesis and the renaissance
of carnitine palmitoyltransferase.
McGarry JD, Woeltje KF, Kuwajima M, Foster DW.
Department of Internal Medicine, University of Texas Southwestern Medical
Center, Dallas.
Publication Types:
PMID: 2656156 [PubMed - indexed for MEDLINE]
-
Myocardial triglyceride turnover and contribution
to energy substrate utilization in isolated working rat hearts.
Saddik M, Lopaschuk GD.
Department of Pediatrics, University of Alberta, Edmonton, Canada.
The objective of this study was to determine the contribution of myocardial
triglycerides to overall ATP production in isolated working rat hearts. Endogenous
lipid pools were initially prelabeled (pulsed) by perfusing hearts for 60
min with Krebs-Henseleit buffer containing 1.2 mM [1-14C]palmitate. During
a subsequent 60-min period (chase), hearts were perfused with either no fat,
low fat (0.4 mM [9,10-3H] palmitate), or high fat (1.2 mM [9,10-3H]palmitate).
All buffers contained 11 mM glucose. During the "chase," 14CO2
production (a measure of endogenous fatty acid oxidation) and 3H2O production
(a measure of exogenous fatty acid oxidation) were determined. Oxidative
rates of endogenous fatty acids during the chase were 279 +/- 50, 88 +/-
14, and 88 +/- 8 nmol of [14C]palmitate oxidized per g dry weight.min in
the no fat, low fat, and high fat groups, respectively, compared to exogenous
palmitate oxidation rates of 0, 361 +/- 68, and 633 +/- 60 nmol of [3H]palmitate/g
dry weight.min, in the no fat, low fat, and high fat groups, respectively.
Endogenous [14C]palmitate oxidation rates were matched by loss of [14C]palmitate
from endogenous myocardial triglycerides. Overall triglyceride content decreased
during the no fat and low fat chase perfusion but did not change during the
high fat chase. Loss of triglyceride [14C]palmitate during the high fat chase
was matched by incorporation of exogenous [3H]palmitate in triglycerides.
In a second series of perfusions, three groups of hearts were perfused under
similar conditions, except that unlabeled palmitate was used during the "pulse" and
that 11 mM [2-3H/U-14C]glucose and unlabeled palmitate was present during
the chase. During the chase, both glycolysis (3H2O production) and glucose
oxidation (14CO2 production) rates were measured. Rates of glucose oxidation
were inversely related to the fatty acid concentration in the perfusate (1257
+/- 158, 366 +/- 40, and 124 +/- 26 nmol of glucose oxidized per min.g dry
weight in the no fat, low fat, and high fat groups, respectively), while
rates of glycolysis were not significantly different between these groups.
Calculation of overall ATP production from both oxidative and glycolytic
sources determined that even in the presence of high concentrations of fatty
acids, myocardial triglyceride turnover can provide over 11% of steady state
ATP production in the aerobically perfused heart. In the absence of fatty
acids, myocardial triglyceride fatty acids can become the major energy substrate
of the heart.(ABSTRACT TRUNCATED AT 400 WORDS)
PMID: 1902472 [PubMed - indexed for MEDLINE]
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High rates of fatty acid oxidation during
reperfusion of ischemic hearts are associated with a decrease
in malonyl-CoA levels due to an increase in 5'-AMP-activated
protein kinase inhibition of acetyl-CoA carboxylase.
Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD.
Department of Pediatrics and Pharmacology, Faculty of Medicine, University
of Alberta, Edmonton, Canada.
We determined whether high fatty acid oxidation rates during aerobic reperfusion
of ischemic hearts could be explained by a decrease in malonyl-CoA levels,
which would relieve inhibition of carnitine palmitoyl-transferase 1, the
rate-limiting enzyme involved in mitochondrial uptake of fatty acids. Isolated
working rat hearts perfused with 1.2 mM palmitate were subjected to 30 min
of global ischemia, followed by 60 min of aerobic reperfusion. Fatty acid
oxidation rates during reperfusion were 136% higher than rates seen in aerobically
perfused control hearts, despite the fact that cardiac work recovered to
only 16% of pre-ischemic values. Neither the activity of carnitine palmitoyltransferase
1, or the IC50 value of malonyl-CoA for carnitine palmitoyl-transferase 1
were altered in mitochondria isolated from aerobic, ischemic, or reperfused
ischemic hearts. Levels of malonyl-CoA were extremely low at the end of reperfusion
compared to levels seen in aerobic controls, as was the activity of acetyl-CoA
carboxylase, the enzyme which produces malonyl-CoA. The activity of 5'-AMP-activated
protein kinase, which has been shown to phosphorylate and inactivate acetyl-CoA
carboxylase in other tissues, was significantly increased at the end of ischemia,
and remained elevated throughout reperfusion. These results suggest that
accumulation of 5'-AMP during ischemia results in an activation of AMP-activated
protein kinase, which phosphorylates and inactivates ACC during reperfusion.
The subsequent decrease in malonyl-CoA levels wil result in accelerated fatty
acid oxidation rates during reperfusion of ischemic hearts.
PMID: 7615556 [PubMed - indexed for MEDLINE]
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An emerging role for protein kinases:
the response to nutritional and environmental stress.
Hardie DG.
Biochemistry Department, The University, Dundee, U.K.
Publication Types:
PMID: 7718402 [PubMed - indexed for MEDLINE]
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Insulin inhibition of 5' adenosine monophosphate-activated
protein kinase in the heart results in activation of acetyl
coenzyme A carboxylase and inhibition of fatty acid oxidation.
Gamble J, Lopaschuk GD.
Department of Pediatrics, University of Alberta, Edmonton, Canada.
Acetyl coenzyme A (CoA) carboxylase (ACC) is an important regulator of fatty
acid oxidation in the heart, since it produces malonyl CoA, a potent inhibitor
of mitochondrial fatty acid uptake. Under conditions of metabolic stress,
5'adenosine monophosphate-activated protein kinase (AMPK), which is highly
expressed in cardiac muscle, can phosphorylate and decrease ACC activity.
In this study, we determined if fatty acid oxidation in the heart could be
regulated by insulin, due to alterations in AMPK regulation of ACC activity.
Isolated working rat hearts were perfused with Krebs-Henseleit solution containing
11 mmol/L glucose, 0.4 mmol/L [9,10(-3)H]palmitate, and either 100 microU/mL
insulin or 1,000 microU/mL insulin. Increasing insulin concentration resulted
in a decrease in fatty acid oxidation rates (P < .05), a decrease in AMPK
activity (P < .05), and an increase in ACC activity (P < .05) compared
with the low-insulin group. A negative correlation was observed between AMPK
and ACC activity (r = -.76). We conclude that insulin, acting through inhibition
of AMPK and stimulation of ACC, is capable of inhibiting myocardial fatty
acid oxidation.
PMID: 9361684 [PubMed - indexed for MEDLINE]
-
Upregulation of 5'-AMP-activated protein
kinase is responsible for the increase in myocardial fatty
acid oxidation rates following birth in the newborn rabbit.
Makinde AO, Gamble J, Lopaschuk GD.
Cardiovascular Disease Research Group, Faculty of Medicine, University of
Alberta, Edmonton, Canada.
In newborn rabbits, fatty acid oxidation rates in the heart significantly
increase between 1 and 7 days after birth. This is due in part to a decrease
in malonyl coenzyme A (CoA) production by acetyl CoA carboxylase (ACC). In
other tissues, 5'-AMP-activated protein kinase (AMPK) can phosphorylate and
inhibit ACC activity. In this study, we show that 1- and 7-day-old rabbit
hearts have a high AMPK activity, with AMPK expression and activity being
greatest in 7-day-old hearts. Hearts were also perfused in the Langendorff
mode with Krebs-Henseleit buffer containing 0.4 mmol/L [14C]palmitate and
11 mmol/L glucose +/- 100 microU/mL insulin. In the absence of insulin, fatty
acid oxidation rates were significantly higher in 7-day-old hearts compared
with 1-day-old hearts. AMPK activity was also greater in 7-day-old hearts
compared with 1-day-old hearts (909 +/- 60 and 585 +/- 75 pmol.min-1.mg protein-1,
respectively; P < .05). In 1-day-old hearts, the presence of insulin resulted
in a significant decrease in AMPK activity, an increase in ACC activity,
and a decrease in fatty acid oxidation rates. In 7-day-old hearts, AMPK activity
was also decreased by insulin, although ACC activity remained low and fatty
acid oxidation rates remained high. Stimulation of AMPK in 7-day-old hearts
with 200 mumol/L 5-amino 4-imidazolecarboxamide ribotide resulted in a further
decrease in ACC activity and an increase in fatty acid oxidation rates. These
data suggest that AMPK, ACC, and fatty acid oxidation are sensitive to insulin
in 1-day-old rabbit hearts and that the decrease in circulating insulin levels
seen after birth leads to an increased activity of AMPK. This can then lead
to a phosphorylation and inhibition of ACC activity, with a resultant increase
in fatty acid oxidation rates.
PMID: 9118478 [PubMed - indexed for MEDLINE]
-
-
Time to therapy and salvage in myocardial
infarction.
Milavetz JJ, Giebel DW, Christian TF, Schwartz RS, Holmes
DR Jr, Gibbons RJ.
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinical
and Mayo Foundation, Rochester, Minnesota 55905, USA.
OBJECTIVES: This study sought to examine the influence of time to reperfusion
on myocardial salvage. BACKGROUND: Major trials of reperfusion therapy for
myocardial infarction (MI) have demonstrated improved outcome for patients
achieving earlier reperfusion. However, some patients experience significant
benefit despite delayed reperfusion. METHODS: Fifty-five patients with a
first anterior MI underwent successful reperfusion therapy (angioplasty or
thrombolysis). Technetium-99m (Tc-99m) sestamibi was injected before reperfusion
therapy and again at hospital discharge to determine the myocardial salvage
index for each patient. Residual flow to the infarct territory was assessed
by the nadir of the Tc-99m sestamibi count-profile curve. RESULTS: The salvage
index showed wide variability (range -0.04 to 1.0), and extreme values were
seen in 34.5% of the group (<0.10 in 9%, >0.90 in 25%). A high salvage
index was associated with reperfusion therapy before 2 h (p=0.02) or good
residual blood flow (p < 0.01). For the 10 patients who received reperfusion
therapy within 2 h, residual blood flow was not correlated with salvage (p=0.12).
For the 45 patients treated after 2 h, residual blood flow correlated significantly
with salvage (r=0.57, p < 0.0001). There was a significant interaction
(p < 0.05) between residual blood flow and time to therapy, indicating
that the effect of each variable on salvage depended on the value of the
other. Multiple historic and hemodynamic variables were examined, but none
demonstrated any association with residual flow or myocardial salvage. CONCLUSIONS:
In patients with acute MI, successful reperfusion therapy within 2 h is associated
with the greatest degree of myocardial salvage. For patients treated after
2 h, residual blood flow to the infarct-related territory appears to be the
most important determinant of myocardial salvage.
PMID: 9581715 [PubMed - indexed for MEDLINE]
-
-
Actions of insulin on the mammalian heart:
metabolism, pathology and biochemical mechanisms.
Brownsey RW, Boone AN, Allard MF.
Department of Biochemistry and Molecular Biology, University of British Columbia,
Vancouver, Canada. rogerb@unixg.ubc.ca
Publication Types:
PMID: 9217868 [PubMed - indexed for MEDLINE]
-
Comment on:
Glucose-insulin-potassium in acute myocardial infarction:
the time has come for a large, prospective trial.
Apstein CS, Taegtmeyer H.
Publication Types:
PMID: 9286931 [PubMed - indexed for MEDLINE]
-
Fatty acid oxidation in the reperfused
ischemic heart.
Kantor PF, Dyck JR, Lopaschuk GD.
Cardiovascular Research Group, University of Alberta, Edmonton, Canada.
Myocardial ATP production is dependent chiefly on the oxidative decarboxylation
of glucose and fatty acids. The co-utilization of these and other substrates
is determined by both the amount of any given substrate supplied to the heart
as well as by complex intracellular regulatory mechanisms. This regulated
balance is altered during and after ischemia. During aerobic reperfusion
of ischemic myocardium, a rapid recovery of energy production is desirable
for the complete recovery of muscle contractile function. It is now clear
that the type of energy substrate used by the heart during reperfusion will
directly influence this contractile recovery. By increasing the relative
proportion of glucose oxidized to that of fatty acids, the mechanical function
of the reperfused heart can be improved. However, fatty acid oxidation recovers
quickly during reperfusion and dominates as a source of oxygen consumption.
These high rates of fatty acid oxidation occur at the expense of glucose
oxidation, resulting in a decreased recovery of both cardiac function and
efficiency during reperfusion. One contributory factor to these high rates
of fatty acid oxidation is a decrease in myocardial malonyl-coenzyme A (CoA)
levels. Malonyl-CoA, which is synthesized by acetyl-CoA carboxylase, is an
essential metabolic intermediary in the regulation of fatty acid oxidation.
A decrease in malonyl-CoA level results in an increase of carnitine palmitoyl
transferase-1 mediated fatty acid uptake into the mitochondria. This mechanism
seems important in the regulation of fatty acid oxidation in the postischemic
heart and is discussed in detail in this review, with reference to specific
clinical scenarios of ischemia and reperfusion and options for modulating
cardiac energy metabolism.
Publication Types:
PMID: 10408755 [PubMed - indexed for MEDLINE]
-
Plasma fatty acid levels in infants and
adults after myocardial ischemia.
Lopaschuk GD, Collins-Nakai R, Olley PM, Montague TJ,
McNeil G, Gayle M, Penkoske P, Finegan BA.
Department of Pediatrics, University of Alberta, Edmonton, Canada.
High levels of fatty acids are detrimental during reperfusion of ischemic
hearts in part because of an inhibition of myocardial glucose use. We therefore
measured plasma fatty acids during and after myocardial ischemia in both
adult and pediatric patients. In adult patients undergoing thrombolytic therapy
after an acute myocardial infarction, plasma fatty acids levels were elevated
on admission to hospital (0.96 +/- 0.06 vs 0.40 +/- 0.01 mmol/L in healthy
control subjects) and remained elevated throughout the initial 48 hours of
hospitalization. In adult patients undergoing cardiac surgery, plasma fatty
acids were markedly increased during surgery and at the time of the release
of the aortic cross clamp (2.21 +/- 0.54 and 1.61 +/- 0.32 mmol/L, respectively).
In children and infants (mean age 4.33 +/- 0.44 years) who had surgery to
correct congenital heart defects, fatty acid levels during surgery increased
to 3.27 +/- 0.26 mmol/L and remained elevated during immediate reperfusion
(1.91 +/- 0.15 mmol/L) and for 24 hours after surgery (1.67 +/- 0.22 mmol/L).
Because experimental studies have shown that high levels of fatty acids are
detrimental to recovery of adult animal hearts, we determined the effect
of high fatty acid levels on reperfusion recovery of isolated working hearts
from 1-day-old rabbits perfused with 0.4 mmol/L palmitate (normal fat) or
1.2 mmol/L palmitate (high fat) and subjected to 50 minutes of global ischemia
followed by aerobic reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
PMID: 8017285 [PubMed - indexed for MEDLINE]
-
Regulation of fatty acid oxidation in
the mammalian heart in health and disease.
Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schonekess
BO.
Department of Pediatrics, Faculty of Medicine, University of Alberta, Edmonton,
Canada.
Publication Types:
PMID: 8049240 [PubMed - indexed for MEDLINE]
-
Comment in:
Comment on:
Glucose-insulin-potassium (GIK) for acute myocardial infarction:
a negative study with a positive value.
Apstein CS, Opie LH.
Glucose-insulin-therapy for acute myocardial infarction (AMI) has had a long
history, going back 37 years to the pioneering concepts of Sodi-Pallares.
Although a recent meta-analysis of a number of smaller trials has suggested
mortality benefit, it is only the South American trial, published in Circulation
in 1998, that has been large enough to show a mortality benefit of GIK infusions
when compared with controls in the same trial. In contrast, the Polish study
published in this issue of this journal produced a negative result. The two
chief differences between the studies are the much higher risk of mortality
of the patients chosen for the positive trial, and the much higher dose of
GIK that was used. Despite this positive trial information, and the very
extensive experimental background (which is here reviewed), the present data
are not firm nor extensive enough to support the routine use of GIK in patients
with AMI. Thus more trials based on the concepts of metabolic therapy are
required and are being organized. At present, a careful strategy of patient
selection is advocated. In the case of diabetics with AMI, current evidence
is already strong enough to recommend routine use of modified GIK for all
such patients.
Publication Types:
- Comment
- Editorial
- Review
- Review, Tutorial
PMID: 10439880 [PubMed - indexed for MEDLINE]
-
Effects of insulin on glucose uptake by
rat hearts during and after coronary flow reduction.
Chen TM, Goodwin GW, Guthrie PH, Taegtmeyer H.
Department of Internal Medicine, University of Texas-Houston Medical School
77030, USA.
We tested the hypothesis that low-flow ischemia increases glucose uptake
and reduces insulin responsiveness. Working hearts from fasted rats were
perfused with buffer containing glucose alone or glucose plus a second substrate
(lactate, octanoate, or beta-hydroxybutyrate). Rates of glucose uptake were
measured by 3H2O production from [2-3H]glucose. After 15 min of perfusion
at a physiological workload, hearts were subjected to low-flow ischemia for
45 min, after which they were returned to control conditions for another
30 min. Insulin (1 mU/ml) was added before, during, or after the ischemic
period. Cardiac power decreased by 70% with ischemia and returned to preischemic
values on reperfusion in all groups. Low-flow ischemia increased lactate
production, but the rate of glucose uptake during ischemia increased only
when a second substrate was present. Hearts remained insulin responsive under
all conditions. Insulin doubled glucose uptake when added under control conditions,
during low-flow ischemia, and at the onset of the postischemic period. Insulin
also increased net glycogen synthesis in postischemic hearts perfused with
glucose and a second substrate. Thus insulin stimulates glucose uptake in
normal and ischemic hearts of fasted rats, whereas ischemia stimulates glucose
uptake only in the presence of a cosubstrate. The results are consistent
with two separate intracellular signaling pathways for hexose transport,
one that is sensitive to the metabolic requirements of the heart and another
that is sensitive to insulin.
PMID: 9374750 [PubMed - indexed for MEDLINE]
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Energy metabolism of the heart: from basic
concepts to clinical applications.
Taegtmeyer H.
Division of Cardiology, University of Texas-Houston Medical School.
Publication Types:
PMID: 8174388 [PubMed - indexed for MEDLINE]
27. Matsui T, Li L, del Monte
F Adenoviral gene transfer of activated phosphatidylinositol
3.-kinase and Akt inhibits apoptosis of hypoxia cardiomyocytes
in vivo. Circulation 1999; 100: 2373–2379.
28. Jonassen AK, Bhawnajit KB, Mjos OD Cardioprotective
role of insulin at reperfusion may in part be due to an anti-apoptotic mechanism.
Circulation 1999; 100: I–10.
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Influence of adenosine on the stimulatory
effect of isoprenaline and insulin on myocardial contractility
in vivo.
Law WR, Carney PJ, McLane MP.
Department of Surgery, Loyola University, Stritch School of Medicine, Maywood,
IL.
STUDY OBJECTIVE--In vitro investigations have indicated that adenosine can
inhibit beta adrenergic stimulated increases in cardiac contractility. The
present study was designed to determine the ability of adenosine to inhibit
isoprenaline induced increases in contractility in vivo. Adenosine has been
reported to exert its inhibitory effects on contractility by inhibiting adenylate
cyclase. Thus, adenosine should have no effect on positive inotropic agents
that act independently of adenylate cyclase. We therefore assessed the ability
of this nucleoside to inhibit the positive inotropic effect of insulin, a
hormone that exerts a positive inotropic effect independently of alterations
in cyclic AMP. DESIGN--Saline or adenosine (10 mumol.ml-1) was infused into
the circumflex artery at 1 ml.min-1 as a background. Isoprenaline (20 or
200 pmol.min-1) was infused into the artery during saline or adenosine infusion.
The response to insulin was determined during hyperinsulinaemic euglycaemic
clamp. SUBJECTS--16 adult mongrel dogs were anaesthetised with pentobarbitone.
Five dogs were used in isoprenaline studies, and 11 dogs in insulin studies.
MEASUREMENTS AND MAIN RESULTS--Dogs were instrumented to obtain measurements
of mean arterial blood pressure, heart rate, circumflex artery blood flow
(Q), instantaneous left ventricular pressure, and posterior left ventricular
wall thickness. We used the slope of the end systolic pressure-dimension
relationship (Ees) as an index of myocardial contractility, previously shown
to reflect changes in myocardial inotropic state independent of influence
from afterload and preload. Left ventricular dP/dtmax was derived from left
ventricular pressure with respect to time, and Ees was determined from left
ventricular pressure and wall thickness. Neither adenosine, isoprenaline,
nor insulin alone caused any significant changes in mean arterial pressure
or heart rate. Adenosine caused a significant increase in Q. Both left ventricular
dP/dtmax and Ees were significantly increased by either insulin or both doses
of isoprenaline. Adenosine inhibited the increases in these indices caused
by isoprenaline, but not those caused by insulin. CONCLUSIONS--Adenosine
is capable of inhibiting the positive inotropic effect of isoprenaline in
vivo. The results suggest that adenosine does not inhibit positive inotropic
responses that act independently of the stimulation of adenylate cyclase.
PMID: 1742765 [PubMed - indexed for MEDLINE]
30. Lopaschuk GD. Optimizing cardiac energy metabolism a new
approach to treating ischaemic heart disease. Eur Heart J 1999; 1 (suppl O):
O32–O39
-
Comment on:
Glucose metabolism in the ischemic heart.
Lopaschuk GD, Stanley WC.
Publication Types:
- Comment
- Editorial
- Review
- Review, Tutorial
PMID: 9008441 [PubMed - indexed for MEDLINE]
-
Comment in:
The antianginal drug trimetazidine shifts cardiac energy
metabolism from fatty acid oxidation to glucose oxidation by inhibiting
mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
Kantor PF, Lucien A, Kozak R, Lopaschuk GD.
Cardiovascular Research Group and the Division of Pediatric Cardiology, University
of Alberta, Edmonton, Canada.
Trimetazidine is a clinically effective antianginal agent that has no negative
inotropic or vasodilator properties. Although it is thought to have direct
cytoprotective actions on the myocardium, the mechanism(s) by which this
occurs is as yet undefined. In this study, we determined what effects trimetazidine
has on both fatty acid and glucose metabolism in isolated working rat hearts
and on the activities of various enzymes involved in fatty acid oxidation.
Hearts were perfused with Krebs-Henseleit solution containing 100 microU/mL
insulin, 3% albumin, 5 mmol/L glucose, and fatty acids of different chain
lengths. Both glucose and fatty acids were appropriately radiolabeled with
either (3)H or (14)C for measurement of glycolysis, glucose oxidation, and
fatty acid oxidation. Trimetazidine had no effect on myocardial oxygen consumption
or cardiac work under any aerobic perfusion condition used. In hearts perfused
with 5 mmol/L glucose and 0.4 mmol/L palmitate, trimetazidine decreased the
rate of palmitate oxidation from 488+/-24 to 408+/-15 nmol x g dry weight(-1)
x minute(-1) (P<0.05), whereas it increased rates of glucose oxidation
from 1889+/-119 to 2378+/-166 nmol x g dry weight(-1) x minute(-1) (P<0.05).
In hearts subjected to low-flow ischemia, trimetazidine resulted in a 210%
increase in glucose oxidation rates. In both aerobic and ischemic hearts,
glycolytic rates were unaltered by trimetazidine. The effects of trimetazidine
on glucose oxidation were accompanied by a 37% increase in the active form
of pyruvate dehydrogenase, the rate-limiting enzyme for glucose oxidation.
No effect of trimetazidine was observed on glycolysis, glucose oxidation,
fatty acid oxidation, or active pyruvate dehydrogenase when palmitate was
substituted with 0.8 mmol/L octanoate or 1.6 mmol/L butyrate, suggesting
that trimetazidine directly inhibits long-chain fatty acid oxidation. This
reduction in fatty acid oxidation was accompanied by a significant decrease
in the activity of the long-chain isoform of the last enzyme involved in
fatty acid beta-oxidation, 3-ketoacyl coenzyme A (CoA) thiolase activity
(IC(50) of 75 nmol/L). In contrast, concentrations of trimetazidine in excess
of 10 and 100 micromol/L were needed to inhibit the medium- and short-chain
forms of 3-ketoacyl CoA thiolase, respectively. Previous studies have shown
that inhibition of fatty acid oxidation and stimulation of glucose oxidation
can protect the ischemic heart. Therefore, our data suggest that the antianginal
effects of trimetazidine may occur because of an inhibition of long-chain
3-ketoacyl CoA thiolase activity, which results in a reduction in fatty acid
oxidation and a stimulation of glucose oxidation.
PMID: 10720420 [PubMed - indexed for MEDLINE]
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