The diabetic heart: too sweet for its own good?

Abstract

Diabetes mellitus is a major risk factor for ischemic heart disease (IHD). Patients with diabetes and IHD experience worse clinical outcomes, suggesting that the diabetic heart may be more susceptible to ischemia-reperfusion injury (IRI). In contrast, the animal data suggests that the diabetic heart may be either more, equally, or even less susceptible to IRI. The conflicting animal data may be due to the choice of diabetic and/or IRI animal model. Ischemic conditioning, a phenomenon in which the heart is protected against IRI by one or more brief nonlethal periods of ischemia and reperfusion, may provide a novel cardioprotective strategy for the diabetic heart. Whether the diabetic heart is amenable to ischemic conditioning remains to be determined using relevant animal models of IRI and/or diabetes. In this paper, we review the limitations of the current experimental models used to investigate IRI and cardioprotection in the diabetic heart.

Figure 1

Endogenous factors contributing to ischemia-reperfusion injury. Following ischemia, blood flow is reestablished in the myocardium. The myocardium is subject to a number of abrupt changes during the transition from ischemia to reperfusion. Both biochemical and metabolic alterations occur including the generation of reactive oxygen species (ROS), decrease in ATP levels, an increase in inflammatory mediators, the rapid restoration of physiological pH, which in turn increases intracellular sodium and overload of intracellular calcium and mitochondrial calcium. These factors interact with each other to mediate reperfusion injury through the opening of the mitochondrial permeability transition pore (mPTP) and initiation of cell death pathways [13].

Figure 2

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 K_ATP 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].

Figure 3

The cellular mechanisms involved in Ischemic Preconditioning. IPC, IPost, or pharmacological agents initiates the release of G-protein-coupled receptor (GPCR) agonists which bind to the receptor and activate numerous signaling pathways. Phosphatidylinositol-3-kinase (PI3K) and Ras activation can lead to activation of a number of downstream molecules such as Akt, protein kinase C (PKC), extracellular regulated kinase (ERK), nitric oxide synthase (NOS), and inactivation of glycogen synthase kinase-3β (GSK-3β). These converge to activate the mitochondrial ATP-dependent potassium channel (K_ATP), closing the mitochondrial permeable transition pore (mPTP) resulting in protection from IRI [67].

Figure 4

Why is the diabetic heart harder to protect with conditioning strategies? The diabetic heart has been suggested to have a raised threshold for cardioprotection [55], this is caused by the downregulation of prosurvival kinase pathways [55, 88], resulting in dysregulation of mitochondrial permeability transition pore (mPTP), increased receptor activities for pharmacological agents [78], increased calcineurin activity [81] and evidence suggests a dysfunctional K_ATP channel in the mitochondria [76]. In diabetes, endoplasmic reticulum (ER) stress also causes alterations in kinase pathways leading to dysregulation of the mPTP [85]. Interestingly, some evidence suggests that the diabetic heart is in a paradoxical protective state therefore conditioning potential is lower [89].