Primordial Drivers of Diabetes Heart Disease: Comprehensive Insights into Insulin Resistance

Abstract

Insulin resistance has been regarded as a hallmark of diabetes heart disease (DHD). Numerous studies have shown that insulin resistance can affect blood circulation and myocardium, which indirectly cause cardiac hypertrophy and ventricular remodeling, participating in the pathogenesis of DHD. Meanwhile, hyperinsulinemia, hyperglycemia, and hyperlipidemia associated with insulin resistance can directly impair the metabolism and function of the heart. Targeting insulin resistance is a potential therapeutic strategy for the prevention of DHD. Currently, the role of insulin resistance in the pathogenic development of DHD is still under active research, as the pathological roles involved are complex and not yet fully understood, and the related therapeutic approaches are not well developed. In this review, we describe insulin resistance and add recent advances in the major pathological and physiological changes and underlying mechanisms by which insulin resistance leads to myocardial remodeling and dysfunction in the diabetic heart, including exosomal dysfunction, ferroptosis, and epigenetic factors. In addition, we discuss potential therapeutic approaches to improve insulin resistance and accelerate the development of cardiovascular protection drugs.

Keywords: Autonomic nervous system diseases; Cell cycle checkpoints; Diabetes mellitus; Diabetic cardiomyopathies; Energy metabolism; Exosomes; Heart failure.

Fig. 1.

The signaling pathway of insulin action and the selective impairment of insulin receptor substrate (IRS)-protein kinase B (Akt) signaling pathway in insulin resistance. (A) It shows that insulin binding to the insulin receptor α subunit on the target cell surface activates the receptor subunit tyrosine kinase, leading to the autophosphorylation and phosphorylation of the IRS1/2, which activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the RAS/mitogen-activated protein kinase (MAPK) pathway. (B) It shows that in insulin-resistant state, PI3K/Akt signaling is impaired, but the MAPK pathway is preserved, which may lead to a mitogenic-promoting effect of insulin in endothelial cells involved in vascular injury. GDP, guanosine 5´-diphosphate; GTP, guanosine 5´-triphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; GLUT-4, glucose transporter-4; RaF, rapidly accelerated fibrosarcoma; MEK, mitogen-activated protein kinase; PDPK1, phosphoinositide dependent protein kinase 1; ASC16, 6-O-ascorbyl palmitate ester; ERK, extracellular regulated kinase; eNOS, endothelial nitric oxide synthase; NF-κB, nuclear factor-κB; FoxO1, forkhead transcription factor O1; mTOR, mammalian target of rapamycin; GSK-3β, glycogen synthase kinase-3β; FFA, free fatty acid; CD36, cluster differentiation protein 36; PPAR, peroxisome proliferator-activated receptor.

Fig. 2.

Mechanisms of insulin resistance-induced diabetes heart disease (DHD). Insulin resistance affects the progression of DHD by altering cardiovascular risk factors and reducing the insulin signaling pathway, causing a number of cardiovascular diseases such as myocardial fibrosis, ventricular hypertrophy, atherosclerosis, impaired myocardial systolic and diastolic function, and hypertension. INS, insulinase-like proteases; NF-κB, nuclear factor-κB; NET, neutrophil extracellular trap; VSMC, vascular smooth muscle cells; GLUT-4, glucose transporter-4; CD36, cluster differentiation protein 36; FFA, free fatty acid; ROS, reactive oxygen species; ATP, adenosine triphosphate.