Mechanistic exploration of hexokinase 2 and metabolism in diabetic cardiomyopathy

Metabolic disorders induced by high glucose (HG) and insulin resistance are closely linked to the development of DCM. Protein glycosylation resulting from HG leads to an increase in advanced glycation end products (AGEs), which further promotes collagen cross-linking, myocardial fibrosis and impaired diastolic function, ultimately triggering the onset of DCM. Previous research has demonstrated that HG, insulin resistance, AGEs, collagen cross-linking, myocardial fibrosis and impaired diastolic function play crucial roles in the progression of DCM (9). Emerging evidence highlights the potential of bariatric surgery, particularly Roux-en-Y gastric bypass and sleeve gastrectomy, in ameliorating DCM. Insulin resistance is a central pathogenic driver of DCM, leading to impaired myocardial insulin signaling, mitochondrial dysfunction and endoplasmic reticulum (ER) stress. In the setting of insulin resistance or hyperinsulinemia, the heart experiences profound metabolic dysregulation, characterized by diminished glucose uptake and utilization alongside heightened dependence on fatty acid oxidation. These metabolic shifts exacerbate cardiac dysfunction by fostering oxidative stress, chronic inflammation and cellular injury, collectively contributing to the progression of DCM. The energy and lipid metabolism associated with DCM, along with its regulatory mechanisms, are complex and not yet fully understood. Therefore, it is crucial to investigate the pathogenesis of DCM through a combined analysis of genomics and metabolomics, as well as to explore the underlying mechanisms of DCM at the metabolic level in greater depth.