New Molecular Insights of Insulin in Diabetic Cardiomyopathy

Abstract

Type 2 diabetes mellitus (T2DM) is a highly prevalent disease worldwide. Cardiovascular disorders generated as a consequence of T2DM are a major cause of death related to this disease. Diabetic cardiomyopathy (DCM) is characterized by the morphological, functional and metabolic changes in the heart produced as a complication of T2DM. This cardiac disorder is characterized by constant high blood glucose and lipids levels which eventually generate oxidative stress, defective calcium handling, altered mitochondrial function, inflammation and fibrosis. In this context, insulin is of paramount importance for cardiac contractility, growth and metabolism and therefore, an impaired insulin signaling plays a critical role in the DCM development. However, the exact pathophysiological mechanisms leading to DCM are still a matter of study. Despite the numerous questions raised in the study of DCM, there have also been important findings, such as the role of micro-RNAs (miRNAs), which can not only have the potential of being important biomarkers, but also therapeutic targets. Furthermore, exosomes also arise as an interesting variable to consider, since they represent an important inter-cellular communication mechanism and therefore, they may explain many aspects of the pathophysiology of DCM and their study may lead to the development of therapeutic agents capable of improving insulin signaling. In addition, adenosine and adenosine receptors (ARs) may also play an important role in DCM. Moreover, the possible cross-talk between insulin and ARs may provide new strategies to reverse its defective signaling in the diabetic heart. This review focuses on DCM, the role of insulin in this pathology and the discussion of new molecular insights which may help to understand its underlying mechanisms and generate possible new therapeutic strategies.

Keywords: adenosine; adenosine receptors; diabetic cardiomyopathy; exosomes; insulin; miRNAs.

Figure 1

Insulin signaling in the normal heart and diabetic cardiomyopathy. (A) Insulin binding to its receptor (insulin receptor, IR) promotes a biphasic [Ca²⁺]_i response in cardiomyocytes. The first phase of insulin-dependent [Ca²⁺]_i increase involves extracellular Ca²⁺ influx through L-type calcium channel (LTCC) and activation of ryanodine receptor (RyR) Ca²⁺ channel which in turn releases Ca²⁺ from the sarcoendoplasmic reticulum (SR). The second phase involves a non-inhibitory G protein coupled receptor (Gβγ subunits) that activates downstream effectors, including phosphatidylinositol 3-kinase (PI3K)γ and phospholipase C (PLC). PLC generates inositol-1,4,5-trisphosphate (IP₃) that opens the IP₃-ligated Ca²⁺channels in the SR. These mechanisms trigger the translocation of glucose transporter 4 (GLUT4) from an intracellular store to the plasma membrane (PM) and increase glucose uptake. Insulin also induces the translocation of the fatty acid (FA) transporter FAT/CD36 to the PM trough PI3K activation promoting the FA uptake. Increased lipid and glucose uptake increase mitochondrial oxidative metabolism generating adenosine triphosphate (ATP) that supports myocardial contractile function. Insulin activation of AKT, downstream of PI3K, inactivates the transcription factor FoxO1. In addition, miR-223 stimulates and miR-133 reduces GLUT4-dependent glucose uptake. (B) Insulin signaling is deficient in diabetic cardiomyopathy (DCM). FoxO1-dependent downregulation of insulin receptor substrate 1 (IRS1) and AKT are associated with reduced insulin-induced GLUT4 translocation to the PM and lower glucose uptake. At the same time, cardiomyocytes accumulate lipids, reducing mitochondrial oxidative metabolism and promoting mitochondrial uncoupling, which in turn, affects cardiomyocyte function. Also, miR-143 inhibits insulin signaling, whereas miR-141 may impact mitochondrial function and the production of ATP. On the other hand, miR-451 is associated with inhibition of AMPK, while miR-195 inhibits the expression of BCL-2 and SIRT-1. Both of these miRNAs are associated with hypertrophy, which will consequently generate contractile dysfunction. Adenosine may have a paracrine effect on cardiomyocytes, which could reduce hypertrophy and myocardial fibrosis through the activation of adenosine receptors (ARs). Exosomes can ferry miRNAs and proteins such as GLUT4 from one cell to another and therefore, they can be used as potential biomarkers or therapeutic agents/targets for DCM.