High-dose insulin in experimental myocardial infarction in rabbits: protection against effects of hyperglycaemia

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Abstract

Introduction

Hyperglycaemia at the time of acute myocardial infarction (AMI) is a predictor of survival and is associated with increased mortality and morbidity in patients with or without diabetes mellitus. On the other hand, insulin has been shown to reduce myocardial injury in experimental studies but its benefits have not been confirmed in clinical studies.

Methods

The isolated perfused heart model was used to examine the direct effect of incremental doses of insulin and varying degrees of hyperglycaemia on infarct size and cardiomyocyte apoptosis in rabbit hearts. The rabbit hearts were subjected to 30-min ischaemia and 2.5-h reperfusion.

Results

Insulin, given alone just before reperfusion, dramatically reduced infarct size in a dose-dependent manner (75–300 μU/ml) during experimental myocardial infarction (46%±2% to 10.9%±3%, P<.001). Acutely elevated glucose levels (33 mmol/L) induced a significantly greater infarct size and cardiomyocyte apoptosis compared to hearts subjected to normal glucose levels. On the other hand, high-dose insulin (300 μU/ml) given 5 min before reperfusion attenuated the extent of infarction and reduced apoptosis in hearts that were exposed to high glucose levels.

Conclusion

Acutely elevated levels of glucose induced larger infarct area during ischaemia-reperfusion, and this is mediated through proapoptotic pathways. Insulin, when given just before reperfusion, confers cardioprotection in a dose-dependent manner and reverses the detrimental effect of acute hyperglycaemia. High-dose insulin as well as maintaining normoglycaemia remain important factors that improve outcomes following myocardial infarction.

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.

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