Possible mechanisms that make the diabetic heart more or less susceptible to infarction following ischemia reperfusion. (A) Diabetes can render the heart more susceptible to infarction. (A1) A diabetes-associated increase in the activity of p53, leading to the initiation of cell death pathway [29]. (A2) High-glucose causes a decrease in the activity of transcription factor HIF-1α, a subsequent downregulation of VEGF and less revascularization following ischemia [66]. This results in cell death and larger infarct volume. (B) Diabetes can protect the heart against infarction. (B1) Hyperglycaemia is cardioprotective due to the increased availability of glucose which is the hearts preferred substrate in times of stress. (B2/3) The Na+/Ca2+ and Na+/H+ exchangers in the diabetic heart reportedly have decreased activity; therefore the diabetic heart accumulates less of these ions preventing overload and the associated detrimental effects [20]. (B4) Diabetes is associated with an increased release of reactive oxygen species (ROS); a possible subsequent release of free radical scavenging enzymes increase the level of antioxidants within the myocardium protecting the heart from the consequence of IRI [20]. (B5) An increased basal level of prosurvival kinases in diabetes [57]. (B6) PKC-ε increases in diabetes, activating the mitochondrial KATP channel causing subsequent reduction in calcium accumulation and increasing ATP synthesis. PKC-ε also persistently translocate during ischemia but only in diabetic hearts [52]. (B7) High glucose caused reduction in cell death proteins and increased anti apoptotic bcl-2 [49].
