Phosphoinositide 3-kinases and Diabetic Cardiomyopathy

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Cardiovascular mortality is the major lethal complication of diabetes mellitus. Despite many studies describing altered metabolism, contractility, and other functions in the diabetic heart, it remains controversial as to whether diabetes mellitus has a direct negative effect on the myocardium that is independent of other risk factors such as hypertension and coronary artery disease that are highly prevalent in this patient population. Furthermore, it has been a common belief that hyperglycemia itself is the primary cause of increased cardiovascular risk in diabetes mellitus, even in patients with type 2 diabetes. However, a number of clinical trials aiming to maintain tight control of blood glucose levels in type 2 diabetes failed to show a reduction in cardiovascular complications.1–3 In this issue, Li et al (PI3Ks in Diabetic Cardiomyopathy. J Cardiovasc Pharmacol 2017;70:XX–XX) summarize how altered signaling by different phosphoinositide 3-kinase (PI3K) isoforms and their downstream signaling molecules contributes to the development of diabetic cardiomyopathy. This review highlights a potential explanation for why interventions to control glucose levels were not more successful at reducing cardiac complications in patients with diabetes.
Hyperglycemia is a consequence of insulin resistance in multiple tissues of patients with diabetes. Drugs that lower the blood glucose level without increasing insulin sensitivity in a particular tissue will not ameliorate an insulin signaling deficit that could have pathological consequences independently of hyperglycemia. It is now well accepted that insulin activation of PI3K signaling is a critical event in tissues responsive to the hormone, including skeletal muscle, liver, and adipose tissue. The myocardium is also an insulin-responsive organ, and attenuated activation of PI3K signaling has been demonstrated in animal models of type 2 diabetes. As discussed by Li et al, decreased PI3Kα signaling can lead to contractile dysfunction and abnormal glucose/lipid utilization, perhaps contributing to pathological hypertrophy. By contrast, PI3Kγ signaling is upregulated in the diabetic myocardium, leading to increased inflammation and cardiac fibrosis. This effect, however, is due to increased PI3Kγ signaling in leukocytes and not to activation of this signaling pathway in cardiac myocytes. Although not discussed in this review, PI3Kα signaling also regulates a number of cardiac ion channels.4 Diabetes-induced changes in these ion channels, especially an increase in the persistent sodium current, can lead to QT interval prolongation on the electrocardiogram, which is associated with an increased risk of ventricular arrhythmias.5 This mechanism might contribute to the increased risk of sudden cardiac death in the diabetic patient population.
Unlike skeletal muscle and adipose tissue, where decreased PI3K/Akt signaling is well documented in humans with diabetes, well-controlled studies comparing cardiac insulin/PI3K/Akt signaling in the nondiabetic and diabetic myocardium are rare due to the obvious difficulties in obtaining cardiac tissue. An intensified effort to perform this type of clinical study may increase our awareness that diabetic cardiomyopathy is at least partly due to intrinsic PI3K/Akt signaling changes in the myocardium and hopefully will lead to better treatments for patients with diabetes. However, systemic pharmacological treatments to increase cardiac PI3Kα/Akt signaling would be problematic because increased PI3Kα signaling in some other tissue types is a major contributor to carcinogenesis. Future studies that discover effectors downstream of PI3Kα/Akt that control cardiac contractility and energy utilization but that are independent of cell growth/death regulation may lead to better treatments for this difficult and deadly diabetic complication.
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