Diabetic Cardiomyopathy: Mechanisms and Therapeutic Targets

Abstract

The incidence and prevalence of diabetes mellitus are each increasing rapidly in our society. The majority of patients with diabetes succumb ultimately to heart disease, much of which stems from atherosclerotic disease and hypertension. However, cardiomyopathy can develop independent of elevated blood pressure or coronary artery disease, a process termed diabetic cardiomyopathy. This disorder is a complex diabetes-associated process characterized by significant changes in the physiology, structure, and mechanical function of the heart. Here, we review recently derived insights into mechanisms and molecular events involved in the pathogenesis of diabetic cardiomyopathy.

Figure 1. Triggers, mediators, and consequences involved in the pathogenesis of diabetic cardiomyopathy

RAAS, Renin-Angiotensin-Aldosterone System; PKC, Protein Kinase C; ROS, Reactive Oxygen Species; AGE, Advanced Glycation End products; PPARα, Peroxisome Proliferator Activated Receptor-α; FoxO, Forkhead box O group transcription factors; NO, Nitric Oxide.

Figure 2. FoxO transcription factors in cardiac insulin signaling

In normal cardio-myocytes, insulin triggers the PI3K-Akt signaling pathway, resulting in increased Akt phosphorylation. Phosphorylated Akt moves into the nucleus, phosphorylates and inactivates FoxO by promoting nuclear exclusion. At the same time, FoxO activation triggers production of atrogin-1, which degrades calcineurin, releasing Akt from calcineurin-dependent dephosphory-lation. This calcineurin/PP2A-dependent mechanism promotes hyperphosphorylation of endogenous Akt and consequent diminished insulin sensitivity and impaired glucose metabolism. Activation of FoxO factors also up-regulates various target genes involved in myocyte remodeling, autophagy, apoptosis, ROS detoxification, cell cycle/differentiation, and metabolic control.