High-dose insulin in experimental myocardial infarction in rabbits: protection against effects of hyperglycaemia
Introduction
“Stress-induced hyperglycaemia” refers to elevated blood glucose levels in the absence of pre-existing diabetes which is caused by various stressful events including trauma, surgery and acute myocardial infarction (AMI). Hyperglycaemia has been consistently shown to be an independent predictor of survival and in-hospital complications following acute coronary occlusion syndromes in patients with and without diabetes (Aronson et al., 2007, Bellodi et al., 1989, Capes et al., 2000, Hadjadj et al., 2004, Rytter et al., 1985, Tansey and Opie, 1985, Wong et al., 2004). A recent study of 17,000 patients with AMI showed that 41% of patients have persistent hyperglycaemia (Kosiborod, Inzucchi, & Krumholz, 2008). It remains unclear whether acute elevation in the level of glucose is a marker for disease severity, or if it is directly hazardous to the ischemic myocardium (Zeller, Verges, L'Huillier, Brun, & Cottin, 2006). In recent years, there has been intense interest in the role of insulin as adjunct therapy for AMI. Apart from its obvious glucose lowering effect, insulin may confer a metabolic advantage to the ischaemic myocardium. This may be achieved through reduction of free fatty acids and inflammatory cytokines (Dandona et al., 2007, Oliver, 2001). Several clinical trials in the 1990s have shown benefits of insulin at the time of AMI, and perhaps insulin may play a complementary role to reperfusion therapy in the management of AMI (Diaz et al., 1998, Malmberg et al., 1995, van der Horst et al., 2003).
During myocardial ischaemia, coronary perfusion is interrupted, which may cause death of cardiomyocytes resulting in myocardial infarction. “Apoptotic cell death” of rabbit cardiomyocytes was first demonstrated following myocardial ischaemia/reperfusion (Gottlieb, Burleson, Kloner, Babior, & Engler, 1994). Subsequently, apoptosis has been reported in the border zone of human hearts with increased infarct size, and this may contribute to the development of congestive cardiac failure post-infarct (Olivetti et al., 1996). The interactive effect of insulin and acute elevations in glucose on heart cell death prior to the onset of ischaemia and reperfusion has not been examined. In the present study, we used an experimental model of myocardial infarction to determine the direct effect of acutely elevated levels of glucose prior to reperfusion and whether administration of insulin prior to initiating reperfusion would provide cardioprotection.
Section snippets
Methods
The study was conducted in accordance to the National Health & Medical Research Council Australian Code of Practice for the care and use of animals for scientific research, and was approved by the Joint Royal North Shore Hospital/University of Technology of Sydney Animal Care and Ethics committee. A total of 60 male New Zealand White rabbits (12–14 weeks, 2.5–3 kg) were used for this study and were all fed standard pellets and tap water ad lib. They were kept in controlled conditions (room
Results
At a glucose concentration of 5.5 mmol/L, insulin administered 5 min before reperfusion reduced infarct size in a dose dependent fashion (Fig. 1). At the lowest concentration of 75 μU/ml, insulin significantly reduced infarct size compared with I/R alone (0.280±0.03 versus 46.1%±2%, P<.001). At the higher concentrations of insulin (150 and 300 μU/ml), the infarct size was further decreased. The infarct size with the highest insulin dose (300 μU/ml) (10.9%±3%) was significantly smaller than
Discussion
In this study, the main finding is that insulin started 5 min before reperfusion significantly reduced infarct size following regional ischaemia and reperfusion in a dose-dependent manner. Exposure of rabbit hearts to acute elevation in glucose levels prior to inducing experimental infarction aggravates infarct size, which was accompanied by a higher degree of apoptosis in hearts exposed to acute hyperglycemia. This adverse effect of acute hyperglycemia was independent of the hyperosmolar
Acknowledgments
This study was supported by a grant from Northern Sydney Area Health as well as Novo Nordisk Regional Diabetes Support Scheme grant. We would like to thank Ms Belinda Ferrone for her technical assistance during the experiments.
References (45)
- et al.
Hyperglycemia and prognosis of acute myocardial infarction in patients without diabetes mellitus
American Journal of Cardiology
(1989) - et al.
The relationships of left ventricular ejection fraction, end-systolic volume index and infarct size to six-month mortality after hospital discharge following myocardial infarction treated by thrombolysis
Journal of the American College of Cardiology
(2002) - et al.
Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: A systematic overview
Lancet
(2000) - et al.
Programmed myocyte cell death affects the viable myocardium after infarction in rats
Experimental Cell Research
(1996) - et al.
Insulin administered at reoxygenation exerts a cardioprotective effect in myocytes by a possible anti-apoptotic mechanism
Journal of Molecular and Cellular Cardiology
(2000) - et al.
Reduction of myocardial infarct size by poloxamer 188 and mannitol in a canine model
American Heart Journal
(1991) - et al.
Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): Effects on mortality at 1 year
Journal of the American College of Cardiology
(1995) - et al.
Usefulness of technetium-99m sestamibi infarct size in predicting posthospital mortality following acute myocardial infarction
Journal of the American College of Cardiology
(1998) - et al.
Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart
Journal of Molecular and Cellular Cardiology
(1996) - et al.
One year outcomes after glucose-insulin-potassium in ST elevation myocardial infarction. The Glucose-insulin-potassium study II
International Journal of Cardiology
(2007)