Basic Mechanisms of Diabetic Heart Disease

Abstract

Diabetes mellitus predisposes affected individuals to a significant spectrum of cardiovascular complications, one of the most debilitating in terms of prognosis is heart failure. Indeed, the increasing global prevalence of diabetes mellitus and an aging population has given rise to an epidemic of diabetes mellitus-induced heart failure. Despite the significant research attention this phenomenon, termed diabetic cardiomyopathy, has received over several decades, understanding of the full spectrum of potential contributing mechanisms, and their relative contribution to this heart failure phenotype in the specific context of diabetes mellitus, has not yet been fully resolved. Key recent preclinical discoveries that comprise the current state-of-the-art understanding of the basic mechanisms of the complex phenotype, that is, the diabetic heart, form the basis of this review. Abnormalities in each of cardiac metabolism, physiological and pathophysiological signaling, and the mitochondrial compartment, in addition to oxidative stress, inflammation, myocardial cell death pathways, and neurohumoral mechanisms, are addressed. Further, the interactions between each of these contributing mechanisms and how they align to the functional, morphological, and structural impairments that characterize the diabetic heart are considered in light of the clinical context: from the disease burden, its current management in the clinic, and where the knowledge gaps remain. The need for continued interrogation of these mechanisms (both known and those yet to be identified) is essential to not only decipher the how and why of diabetes mellitus-induced heart failure but also to facilitate improved inroads into the clinical management of this pervasive clinical challenge.

Keywords: diabetes mellitus; diabetic cardiomyopathy; fibrosis; heart diseases; heart failure; oxidative stress; ventricular remodelling.

Figure 1.

Oxidative stress, inflammation, alterations in metabolic pathways (including abnormalities in substrate utilization, mitochondrial function, advanced glycation end-product [AGE] formation and O-GlcNAcylation), as well as changes at the level of insulin signaling, gene regulation, endoplasmic reticulum (ER) stress, neurohumoral activation and cardiac cell death, have all been widely accepted as mediators of diabetes-induced myocardial remodeling and dysfunction (see text for references).

Figure 2.

The contributing mechanisms to the cardiac phenotype of diabetes-induced cardiomyopathy are complex and multifactorial, as are their consequences. Indeed, there is significant intersection between many of these, driving the diabetic myocardium towards failure (see text for references). Illustration Credit: Ben Smith.

Figure 3.

A stylized overview of current understanding of the time-course of diabetes progression, from the initial onset of hyperglycemia, through the mid and late stages of the disease, and their consequences for the phenotype of the diabetic myocardium (see text for references).