A
new look at insulin as a potential cardioprotective agent
Michael N. Sack1, Derek
M. Yellon2
1 The Hatter Institute for Cardiology Research,
MRC Inter-University Cape Heart Group, University of Cape Town
Medical School, South Africa;
2 The Hatter Institute for Cardiovascular
Studies, UCL Hospitals and Medical School, London, UK
Correspondence: Professor Derek M. Yellon, The Hatter Institute
and Centre for Cardiology, University College London Hospitals
and Medical School, Grafton Way, London WC1E 6DB, UK.
Tel: +44 20 7380 9888, fax: +44 20 7388 5095, e-mail:
hatter-institute@ucl.ac.uk
Introduction
The concept that the metabolic cocktail, glucose-insulin-potassium
(GIK), may protect ischemic cardiomyocytes was initially introduced
by Sodi-Pallares et al in 1962.[1] The rationale
for the use of this metabolic therapy was further delineated by
Opie, in 1970, when he described two chief mechanisms, ie, the
promotion of cardiac glycolysis and the inhibition of free fatty
acids (FFA) in the serum.[2] A number of early
clinical studies using this metabolic cocktail yielded promising
results and a subsequent metaanalysis suggested that GIK therapy
might have an important role in reducing inhospital mortality
after acute myocardial infarction.[3] Two subsequent
randomized, controlled clinical studies have been published. In
the first of these, the Estudios Cardiologicos Latinoamerica (ECLA)
study,[4] subjects who underwent reperfusion
strategies showed a reduction in inhospital mortality of 66% (2P
= 0.008) when GIK was coadministered with the reperfusion therapy.
In contrast, a Polish study by Ceremuzynski et al [5]
did not show any beneficial effect of low-dose GIK therapy. Apstein
and Opie reviewed the different GIK doses in these two studies
[6] and suggested that the ECLA study dose of
GIK was consistent with the previous studies that showed benefit
of high-dose GIK therapy (see reference [7]
for review).
Acceptance of the benefits and subsequent use of this metabolic
cocktail have not been forthcoming despite almost four decades
since the therapy was proposed. The reasons for the lack of enthusiasm
are probably multifactorial and include both the lack of large
clinical studies and a poor understanding of the basic mechanisms
of how this metabolic cocktail acts. Although the progress towards
a large clinical study using GIK is uncertain, recent research
in our laboratories has begun to delineate a possible novel hypothesis
whereby the insulin component of the GIK cocktail may promote
the cardioprotective effects of GIK. These studies are described
below in conjunction with the clinical data obtained from the
ECLA study.
GIK at reperfusion (more practical in
the clinical arena!)
As the majority of GIK trials were performed in the prethrombolytic
era, it was assumed that the benefit of this therapy may be less
applicable in the current aggressive thrombolytic era. However,
as was shown in the ECLA study, the only statistically significant
reduction in mortality was in acute myocardial infarction in patients
who received concomitant reperfusion treatment.4 Interestingly,
in the 1-year follow-up data, only the subjects who had received
the high-dose GIK therapy had a statistical survival advantage
over the control group.[4] The decision to use
a high-dose GIK regimen was based on the pioneering dose-response
studies of Rackley’s group,[8] who determined
the GIK infusion rates which would result in the maximal suppression
of FFA levels, as well as the maximal myocardial glucose uptake.
Concurrent to the ECLA clinical study, Jonassen and coworkers,[9]
in an experimental study using rats, compared the efficacy of
administering GIK prior to an ischemic insult or at the moment
of reperfusion following the ischemic insult. Interestingly, here
GIK was demonstrated to be equally effective in reducing the final
infarct size whether administered during the entire ischemia/reperfusion
period or solely during the reperfusion period alone. Moreover,
when GIK was administered at reperfusion, the early reperfusion
FFA and glucose levels were unchanged compared with vehicle-treated
controls. This was significantly different from the FFA and glucose
levels in the animals treated with GIK throughout the ischemia/reperfusion
period.[9] Taken together, the ECLA clinical
study and this experimental study suggest that GIK may mediate
a reperfusion cardioprotective effect. Moreover, the experimental
data questioned the exclusivity of the glucose/FFA hypothesis
concerning GIK’s cardioprotective effects!
Reperfusion injury and the potential
effects of GIK
Although reperfusion is a prerequisite for tissue salvage following
a myocardial infarction, there is a price to pay in terms of distinct
reperfusion-associated pathologies (see reference
[10] for review). One postulated aspect of this pathology
is the development of reperfusion-induced myocyte loss beyond
that sustained as a consequence of ischemia alone. In this regard
it has recently been suggested that, in addition to necrosis,
a component of cell death not previously considered in reperfusion
injury, ie, programmed cell death or apoptosis, may play a biologically
significant role.[11] Under experimental conditions,
an increase in apoptosis has been observed in cardiac reperfusion
models, suggesting that the deleterious effects of reperfusion
are, at least in part, due to apoptosis.[12,13]
Taking these data into consideration, we have suggested that GIK,
or a component therein (insulin), may antagonize apoptosis during
reperfusion and hence result in cardioprotection.[11]
Recent experimental evidence has suggested that insulin can indeed
attenuate such apoptotic processes in the brain.[14]
Collectively, these data suggested to us that insulin may be the
appropriate candidate in the GIK cocktail which could promote
a cardioprotective effect at reperfusion, via an effect which
may be independent of the original ‘GIK hypothesis’.
Insulin, the chief mediator of reperfusion
protection in the GIK cocktail
To test initially the hypothesis that insulin is the major protagonist
of cardioprotection when administered at the time of reperfusion,
we studied insulin’s putative cardioprotective effects in ischemia
and reoxygenation experiments in rat neonatal cardiomyocyte experiments.
The administration of insulin (0.3 mU/mL) at the moment of reoxygenation
enhanced myocardial cell viability by 20% compared with vehicle-treated
control cardiomyocytes (P < 0.001).[15]
To evaluate the putative role of insulin in the attenuation of
reperfusion apoptosis, markers of apoptosis were ascertained in
these experiments. Consistent with the cell viability data, insulin
administration at reoxygenation reduced apoptosis by approximately
20–30% compared with vehicle-treated control cardiomyocytes.[15
]As insulin is thought to confer antiapoptotic effects via
the activation of tyrosine kinase and phosphatidyl 3-kinase (PI3-kinase)-mediated
cell signaling pathways, we used pharmacologic inhibitors of these
signaling transduction pathways. In these experiments we demonstrated
that the cardioprotective and antiapoptotic effects of insulin
were completely abolished by tyrosine kinase and PI3-kinase inhibitors.[15]
Furthermore, we have recently confirmed the cardioprotective effects
of insulin at reperfusion in the isolated rat heart using infarct
size as the endpoint.[16] In these studies
we showed that early administration of insulin during reoxygenation/reperfusion
appears to be an effective modality to reduce reoxygenation/reperfusion
injury in the myocardium, in part via the attenuation of ischemia/reoxygenation-induced
apoptosis. Moreover, the cardioprotective and antiapoptotic effects
of insulin appear to be mediated via tyrosine kinase and PI3-kinase
signaling pathways.
Conclusion
For a number of years clinical data have supported a role of GIK
in reducing morbidity and mortality following myocardial infarction.
The encouraging data from the ECLA study suggested that this cardioprotective
effect of GIK is achieved when reperfusion therapy is administered.
The recent experimental data from our and other laboratories suggest
that this reperfusion effect of GIK may be independent of the
glucose/FFA hypothesis of GIK’s cellular protective effects. Our
subsequent experimental data have further advanced the mechanisms
underlying this reperfusion cardiac cell protection, ie, the effect
seems to be mediated by insulin alone and this effect may be via
the attenuation of the known programmed cell death associated
with reperfusion injury.[10]
Finally, our data begin to delineate the signal transduction pathways
which may promote insulin-mediated cell survival effects. Thus
we are encouraged in that the laboratory-based understanding of
how GIK may promote cell survival is being actively pursued. However,
to paraphrase Apstein and Taegtmeyer,[17] the
need to reevaluate the clinical utilization of GIK is both timely
and could result in an effective and affordable addition to the
therapeutic armamentarium in the prevention of myocardial reperfusion
injury. We hope the call for a larger, randomized, controlled,
clinical study will be seriously considered in the very near future.
REFERENCES
1. Sodi-Pallares D, Testelli M, Fishelder F.
Effects of an intravenous infusion of a potassium-insulin-glucose
solution on the electrocardiographic signs of myocardial infarction.
Am J Cardiol. 1962;9:166–181.
2. Opie LH. The glucose hypothesis: relation
to acute myocardial ischemia. J Mol Cell Cardiol. 1970;1:107–114.
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Comment in:
 |
Circulation. 1997 Aug 19;96(4):1074-7 |
|
Circulation. 1998 Jun 9;97(22):2278-9 |
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:
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Meta-analysis |
PMID: 9286943 [PubMed - indexed for MEDLINE]
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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:
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Clinical trial |
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Multicenter study |
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Randomized controlled trial |
PMID: 9867443 [PubMed - indexed for MEDLINE]
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-
Comment in:
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Cardiovasc Drugs Ther. 1999
May;13(3):185-9 |
Low-dose glucose-insulin-potassium is ineffective in acute
myocardial infarction: results of a randomized multicenter Pol-GIK
trial.
Ceremuzynski L, Budaj A, Czepiel A, Burzykowski T, Achremczyk
P, Smielak-Korombel W, Maciejewicz J, Dziubinska J, Nartowicz
E, Kawka-Urbanek T, Piotrowski W, Hanzlik J, Cieslinski A, Kawecka-Jaszcz
K, Gessek J, Wrabec K.
Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland.
proclin@warman.com.pl
We aimed to assess the clinical efficacy of glucose-insulin-potassium
(GIK) in acute myocardial infarction. Experimental data provided
evidence of the beneficial effects of GIK on ischemic myocardium.
The clinical trials, mostly uncontrolled and conducted mainly
before the thrombolytic era, were inconclusive due to the small
number of patients and discrepancies in protocols. In order
to evaluate the efficacy of this intervention, we have performed
a prospective multicenter randomized study. The study consisted
of 954 patients with acute myocardial infarction (MI) randomized
within 24 hours from the onset of symptoms to low-dose GIK (n
= 494), which consisted of 1000 mL 10% dextrose, 32-20 U insulin,
and 80 mEq K-, or to the control group (n = 460), which was
given 1000 mL 0.89% sodium chloride, by intravenous 24-hour
infusion at a rate of 42 mL/h. Cardiac mortality and the occurrence
of cardiac events at 35 days did not differ between GIK and
control-allocated patients (32 (6.5%) vs. 21 (4.6%), respectively;
OR 1.45, 95% CI 0.79-2.68, P = 0.20; and 214 (43.3%) vs. 192
(41.7%), OR 1.07, 95% CI 0.82-1.38, P = 0.62). Total mortality
at 35 days was significantly higher in the GIK than in the control
group (44 (8.9%) vs. 22 (4.8%), respectively, OR 1.95, 95% CI
1.12-3.47, P = 0.01). The excess of non-cardiac deaths in the
GIK group may have occurred by chance. Low-dose GIK treatment
does not improve the survival and clinical course in acute MI.
Publication Types:
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Clinical trial |
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Multicenter study |
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Randomized controlled trial |
PMID: 10439881 [PubMed - indexed for MEDLINE]
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Comment in:
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Cardiovasc Drugs Ther. 2000
Feb;14(1):93-4 |
Comment on:
|
Cardiovasc Drugs Ther. 1999
May;13(3):191-200 |
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:
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Comment |
|
Editorial |
|
Review |
|
Review, tutorial |
PMID: 10439880 [PubMed - indexed for MEDLINE]
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Glucose-insulin-potassium for acute myocardial infarction:
remarkable results from a new prospective, randomized trial.
Apstein CS.
Publication Types:
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Editorial |
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Review |
|
Review, tutorial |
PMID: 9826307 [PubMed - indexed for MEDLINE]
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Effects of glucose-insulin-potassium on myocardial substrate
availability and utilization in stable coronary artery disease.
Studies on myocardial carbohydrate, lipid and oxygen arterial-coronary
sinus differences in patients with coronary artery disease.
Stanley AW Jr, Moraski RE, Russell RO, Rogers WJ, Mantle
JA, Kreisberg RA, McDaniel HG, Rackley CE.
To assess the metabolic effects of myocardial substrate alteration
in patients with coronary artery disease, glucose-insulin-potassium
solution was administered intravenously for 30 minutes to 14
men with stable angiographically documented coronary artery
disease. The glucose-insulin-potassium solution (300 g of glucose,
50 units of regular insulin and 80 mEq of potassium chloride
per liter of water) was infused at a constant rate in each patient,
but individual infusion rates ranged from 0.013 to 0.032 ml/kg
per min (4 to 10 mg glucose/kg per min) in the 14 patients.
Simultaneous arterial and coronary sinus samples were obtained
at 15 minute intervals during a stable 30 minute control period
and again at 15 minute intervals during the infusion; samples
were assayed for glucose, lactate, free fatty acid and oxygen
content. In all 14 patients, during the glucose-insulin-potassium
infusion, arterial glucose and lactate increased and arterial
free fatty acid levels fell; the magnitude of the changes in
arterial lactate and free fatty acids was related to the rate
of infusion. Arterial-coronary sinus differences (A-Cs) for
glucose, lactate and free fatty acid levels correlated with
the arterial concentrations of these substrates (r = 0.66, 0.87
and 0.79, respectively). Regression analyses demonstrated myocardial
thresholds for the uptake of these substrates as follows: glucose
79 mg/100 ml; lactate 300 mu mole/liter; and free fatty acids
100 to 200 mu Eq/liter. Finally and most importantly, the reduction
in A-Cs oxygen values after glucose-insulin-potassium infusion
correlated with the reduction in A-Cs free fatty acid levels
(r = 0.64, P less than 0.0001). This observation suggests that,
in patients with coronary artery disease, glucose-insulin-potassium
infusion may significantly diminish myocardial oxygen requirements
by reduction of myocardial free fatty acid utilization and simultaneous
enhancement of myocardial carbohydrate utilization. Myocardial
substrate availability may be an important determinant of myocardial
oxygen demand in patients with coronary artery disease. Infusion
of glucose-insulin-potassium solution has the potential to alter
myocardial substrate availability, thus improving the balance
between myocardial oxygen demand and supply.
PMID: 1199950 [PubMed - indexed for MEDLINE]-
Glucose-insulin-potassium reduces infarct size when administered
during reperfusion.
Jonassen AK, Aasum E, Riemersma RA, Mjos OD, Larsen TS.
Department of Medical Physiology, Institute of Medical Biology,
University of Tromso, Norway. annek@fagmed.uit.no
Coronary reperfusion improves ventricular function and survival
after infarction, but the metabolic conditions at this time
may not be optimal to protect the heart. The objective of this
study was to evaluate if metabolic support with glucose-insulin-potassium
(GIK) administered at the time of coronary reperfusion could
elicit the same cardioprotection as GIK infusion during the
entire ischemia/reperfusion period. Three groups of anesthetized,
open-chest rats were subjected to 30 minutes of regional ischemia
and 180 minutes of reperfusion. Groups 1 (controls) and 2 (GIK(IR))
received saline or GIK, respectively, throughout the whole experimental
period, whereas a third group (GIK(R)) received GIK from the
onset of reperfusion only. Infarct size was significantly reduced
in the GIK-treated groups, compared with controls (GIK(IR) 44
+/- 5% and GIK(R) 45 +/- 5% vs. control 66 +/- 4%; P < 0.05).
Postischemic recovery of cardiac function improved when GIK
was only administered during the reperfusion phase. Furthermore,
infusion of GIK resulted in reduced plasma concentrations of
free fatty acids and increased plasma glucose (both P < 0.05)
compared with controls. This study demonstrates that glucose-insulin-potassium
administration at the onset of the postischemic reperfusion
period is as cardioprotective as administration of GIK during
the entire ischemia/reperfusion period.
PMID: 11300362 [PubMed - indexed for MEDLINE]-
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Reperfusion injury revisited: is there a role for growth
factor signaling in limiting lethal reperfusion injury?
Yellon DM, Baxter GF.
The Hatter Institute & Centre for Cardiology, University
College London Hospitals and Medical School, London, UK.
Myocardial reperfusion injury represents an important therapeutic
target. The ability of several peptide growth factors, including
transforming growth factor-beta1, insulin, insulin-like growth
factor-1, cardiotrophin-1 and fibroblast growth factors, to
modify reperfusion injury has been examined in recent studies.
The protective effects of these agents may be related to the
inhibition of apoptosis, especially during reperfusion, probably
through p42/p44 MAP kinase and PI3-kinase/Akt signaling. Growth
factor signaling may therefore represent a novel approach for
the development of pharmacological strategies that attenuate
reperfusion injury in the heart.
Publication Types:
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Review |
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Review, tutorial |
PMID: 11094333 [PubMed - indexed for MEDLINE]
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Protecting the ischaemic and reperfused myocardium in acute
myocardial infarction: distant dream or near reality?
Yellon DM, Baxter GF.
The Hatter Institute, Department of Academic & Clinical
Cardiology, University College London Hospitals & Medical
School, Grafton Way, London WC1E 6DB, UK. hatter-institute@ucl.ac.uk
Publication Types:
|
Review |
|
Review, tutorial |
PMID: 10722532 [PubMed - indexed for MEDLINE]
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Reperfusion injury induces apoptosis in rabbit cardiomyocytes.
Gottlieb RA, Burleson KO, Kloner RA, Babior BM, Engler RL.
Department of Molecular and Experimental Medicine, Research
Institute of Scripps Clinic, La Jolla, California 92038.
The most effective way to limit myocardial ischemic necrosis
is reperfusion, but reperfusion itself may result in tissue
injury, which has been difficult to separate from ischemic injury.
This report identifies elements of apoptosis (programmed cell
death) in myocytes as a response to reperfusion but not ischemia.
The hallmark of apoptosis, nucleosomal ladders of DNA fragments
(approximately 200 base pairs), was detected in ischemic/reperfused
rabbit myocardial tissue but not in normal or ischemic-only
rabbit hearts. Granulocytopenia did not prevent nucleosomal
DNA cleavage. In situ nick end labeling demonstrated DNA fragmentation
predominantly in myocytes. The pattern of nuclear chromatin
condensation was distinctly different in reperfused than in
persistently ischemic tissue by transmission electron microscopy.
Apoptosis may be a specific feature of reperfusion injury in
cardiac myocytes, leading to late cell death.
PMID: 7929838 [PubMed - indexed for MEDLINE]-
Apoptosis in ischemic and reperfused rat myocardium.
Fliss H, Gattinger D.
Department of Physiology, Faculty of Medicine, University of
Ottawa (Canada). hfliss@labsun1.med.uottawa.ca
Apoptosis has been observed previously in hearts subjected to
either continuous ischemia or ischemia followed by reperfusion.
The purpose of this study was to compare the timing and extent
of apoptosis in both continuously ischemic and reperfused myocardium.
We show that rats subjected to continuous coronary artery occlusion
display characteristic signs of apoptosis solely in the ischemic
myocardium after only 2.25 hours of ischemia, as illustrated
by positive in situ end labeling (ISEL) of apoptotic cardiomyocyte
nuclei in tissue sections and/or the presence of DNA "ladders"
in agarose gels. In contrast, reperfusion after a 45-minute
occlusion accelerated the process, with apoptosis becoming evident
solely in the reperfused myocardium after only 1 hour of reperfusion.
ISEL and DNA ladder intensity increased with duration of ischemia
or reperfusion. The volume of myocardium in which ISEL was observed
was smaller in the reperfused hearts, and the ISEL-stained nuclei
represented 23% and 33% of the total nuclei in the reperfused
and permanently occluded myocardium, respectively. Therefore,
the data suggest that reperfusion lowers the extent of apoptosis
in ischemic myocardium but, paradoxically, accelerates the residual
apoptosis, possibly because of reperfusion injury. A large accumulation
of neutrophils was observed in both the permanently occluded
and reperfused myocardium, suggesting that the inflammatory
response may have contributed to apoptosis in both settings.
This study therefore confirms that both ischemic and reperfused
rat myocardium can undergo apoptotic cell death. However, the
data suggest that although reperfusion lowers the number of
myocytes undergoing apoptosis, it accelerates apoptosis in the
nonsalvageable cells.
PMID: 8888687 [PubMed - indexed for MEDLINE]-
Phosphatidylinositol 3-kinase-mediated regulation of neuronal
apoptosis and necrosis by insulin and IGF-I.
Ryu BR, Ko HW, Jou I, Noh JS, Gwag BJ.
Department of Pharmacology, Ajou University School of Medicine,
Suwon, Kyungkido, Korea.
We examined effects of two insulin-like growth factors, insulin
and insulin-like growth factor-I (IGF-I), against apoptosis,
excitotoxicity, and free radical neurotoxicity in cortical cell
cultures. Like IGF-I, insulin attenuated serum deprivation-induced
neuronal apoptosis in a dose-dependent manner at 10-100 ng/mL.
The anti-apoptosis effect of insulin against serum deprivation
disappeared by addition of a broad protein kinase inhibitor,
staurosporine, but not by calphostin C, a selective protein
kinase C inhibitor. Addition of PD98059, a mitogen-activated
protein kinase kinase (MAPKK) inhibitor, blocked insulin-induced
activation of extracellular signal-regulated protein kinases
(ERK1/2) without altering the neuroprotective effect of insulin.
Cortical neurons underwent activation of phosphatidylinositol
(PI) 3-kinase as early as 1 min after exposure to insulin. Inclusion
of wortmannin or LY294002, selective inhibitors of PI 3-K, reversed
the insulin effect against apoptosis. In contrast to the anti-apoptosis
effect, neither insulin nor IGF-I protected excitotoxic neuronal
necrosis following continuous exposure to 15 microM N-methyl-D-aspartate
or 40 microM kainate for 24 h. Surprisingly, concurrent inclusion
of 50 ng/mL insulin or IGF-I aggravated free radical-induced
neuronal necrosis over 24 h following continuous exposure to
10 microM Fe2+ or 100 microM buthionine sulfoximine. Wortmannin
or LY294002 also reversed this potentiation effect of insulin.
These results suggest that insulin-like growth factors act as
anti-apoptosis factor and pro-oxidant depending upon the activation
of PI 3-kinase.
PMID: 10380075 [PubMed - indexed for MEDLINE]-
Insulin administered at reoxygenation exerts a cardioprotective
effect in myocytes by a possible anti-apoptotic mechanism.
Jonassen AK, Brar BK, Mjos OD, Sack MN, Latchman DS, Yellon
DM.
Department of Medical Physiology, University of Tromso, Tromso,
Norway.
The metabolic cocktail of glucose-insulin-potassium (GIK) has
been shown to reduce mortality in humans and reduce infarct
size in the rat when administered from the onset of reperfusion
following an ischemic insult. The mechanisms underlying GIK
mediated cardioprotection are, however, still unclear. Recent
data implicates insulin "alone" as the major protagonist
of cardioprotection when administered at the time of reperfusion.
We have therefore begun to investigate an insulin activated
signalling pathway and the putative role of apoptosis in this
insulin-induced cardioprotection. Simulated ischemia and reoxygenation
were induced in rat neonatal cardiocyte experiments. The administration
of insulin [0.3 mU/ml] at the moment of reoxygenation (Ins(R))
enhanced myocardial cell viablility as assessed by trypan blue
exclusion compared to vehicle alone treated control myocytes
(Ins(R)50+/-2%v controls 70+/-1%, P<0.001). This insulin-mediated
cardioprotection was due, in part to a reduction in myocyte
apoptosis as measured by TUNEL (Ins(R)29+/-2%v controls 49+/-3%,
P<0.001) and Annexin V staining (Ins(R)34+/-2%v controls
65+/-3%, P<0.001). These cardioprotective and anti-apoptotic
effects of insulin were completely abolished by the tyrosine
kinase inhibitor lavendustin A and by the phosphatidylinositol
3-kinase (PI3-kinase) inhibitor wortmannin. Thus, we conclude
that the early administration of insulin appears to be an effective
modality to reduce reoxgygenation injury in cardiocytes, in
part, via the attenuation of ischemia/reoxygenation-induced
apoptosis. Moreover, the cardioprotective and anti-apoptotic
effects of insulin are mediated via tyrosine kinase and PI3-kinase
signalling pathways. Copyright 2000 Academic Press.
PMID: 10775481 [PubMed - indexed for MEDLINE]
16. Jonassen AK, Brar BK, Mjos
OD, Sack MN, Latchman DA, Yellon DM. Insulin modifies myocyte
apoptosis and reduces myocardial infarct size when administered
at reperfusion: a novel mechanism of protection. Br J Pharmacol.
1999;126(suppl):201P.
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-
Comment on:
|
Circulation. 1997 Aug 19;96(4):1152-6 |
Glucose-insulin-potassium in acute myocardial infarction:
the time has come for a large, prospective trial.
Apstein CS, Taegtmeyer H.
Publication Types:
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Comment |
|
Editorial |
PMID: 9286931 [PubMed - indexed for MEDLINE]
|
