Types of cell death in diabetic cardiomyopathy: insights from animal models

Abstract

Approximately one-tenth of the global population is affected by diabetes mellitus, and its incidence continues to rise each year. In China, 1.4 million patients die of diabetes-related complications every year. Additionally, approximately 26% of patients with diabetes develop diabetic cardiomyopathy, with heart failure being one of the main causes of death in these patients. However, early detection of diabetic cardiomyopathy has proven to be difficult in a clinical setting; furthermore, there are limited guidelines and targeted means of prevention and treatment for this disease. In recent years, several studies have provided evidence for the occurrence of various forms of regulated cell death in diabetic myocardial cells, including apoptosis, necroptosis, ferroptosis, and cuproptosis, which are closely linked to the pathological progression of diabetic cardiomyopathy. Although most research on diabetic cardiomyopathy is currently in the animal trial phase, the inhibition of these regulatory cell death processes can limit or slow down the progression of diabetic cardiomyopathy. Therefore, this review discusses the appropriate animal experimental models currently available for diabetic cardiomyopathy and evaluates the roles of apoptosis, necroptosis, ferroptosis, and cuproptosis in diabetic cardiomyopathy. We hope to provide new methods and ideas for future research in diabetic cardiomyopathy.

1. Introduction

The prevalence of diabetes mellitus (DM) has rapidly increased worldwide, and DM has emerged as one of the most common chronic metabolic diseases of the century and poses an ongoing threat to human health. According to the Diabetes Atlas of the International Diabetes Federation [1], the global prevalence of DM among individuals aged 20–79 years in 2021 was estimated to be 10.5% (536.6 million people); additionally, this figure is projected to rise to 12.2% (783.2 million people) by 2045. China, in particular, has the highest number of DM patients in the world, with 140.9 million patients with DM in 2021 and an expected 174.4 million patients by 2045. In 2021, the global diabetes-related health expenditure (DRHE) was estimated to be USD 966 billion; this figure has increased 316% over the last 15 years and is predicted to increase to USD 1.054 trillion by 2045. In China, the DRHE was USD 165.3 billion in 2021, which was second only to that in the United States; furthermore, this figure is expected to rise to USD 193.1 billion by 2045.

The occurrence of associated complications is a major component that contributes to the overall disease burden of DM and should not be overlooked. Approximately one-third of patients with DM experience heart-related diseases; furthermore, 1.4 million patients die of diabetes-related complications every year in China [2]. Overall, patients with DM have a greater prevalence of chronic conditions than non-DM patients do; these conditions can include hypertension, chronic coronary syndrome, and congestive heart failure (CHF) [3]. In 1972, Rubler et al. [4] proposed the concept of diabetic cardiomyopathy (DCM), which refers to the occurrence of DM-related myocardial complications in the absence of coronary artery disease, valvular disease, or relevant cardiovascular risk factors and sequelae. Two years later, Kannel et al. [5] conducted a study that evaluated 5209 DM patients for up to 18 years. Consequently, they established that DM is a standalone risk factor for CHF; additionally, the incidence of CHF among DM patients was higher than that in non-DM patients (5-fold increase in women, 2.4-fold increase in men), even after being adjusted for other risk factors such as age, coronary heart disease, and hypertension. This hypothesis was then verified by several subsequent studies [6–8]. In 2020, Zghebi et al. [9] further demonstrated that DM was closely associated with CHF in a study involving more than 630,000 people (Odds Ratio 2.12 in women, 2.27 in men).