Mechanisms and therapeutics of insulin signaling transduction genes in diabetic cardiomyopathy: a comprehensive updated review

Abstract

Diabetic cardiomyopathy (DCM), a complication of type 2 diabetes mellitus (T2DM), is closely associated with key genes in the insulin signaling pathway. Insulin regulates cellular metabolism and growth under normal conditions by activating downstream signaling pathways through its receptors. Nonetheless, insulin resistance, which compromises the insulin signaling pathway and impairs cardiovascular system performance, is common in individuals with T2DM. The key insulin signaling genes include IRS1, IRS2, PIK3R1, and GLUT4 play important roles in insulin receptor signaling, PI3K complex assembly, and glucose transport, respectively. Mutations or abnormal expression of these genes may lead to disorders in the insulin signaling pathway, affecting the normal regulation of glucose metabolism and impairment of myocardial function, thereby promoting the development of DCM. This review delves into the specific roles of these genes in the pathogenic mechanisms and treatment of DCM, with the aim of providing scientific evidence and guidance for future research endeavors.

Keywords: diabetic cardiomyopathy; gene; heart failure; insulin signaling; treatment.

Figure 1

Metabolic alterations and pathophysiological processes of DCM.

Figure 2

Summary of the key elements of the insulin signaling pathway. First, upon binding to its ligand, insulin and the IGF-1 receptor are phosphorylated, thereby increasing their tyrosine kinase activity. Tyrosine phosphorylation and activation of the docking proteins insulin receptor substrates 1 and 2 (IRS1/2) bind to the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), which generates phosphatidylinositol 3,4,5-trisphosphate (PIP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). The serine-threonine kinases phosphatidylinositol-dependent protein kinase 1 (PDPK1) and Akt1 or Akt2 bind to PIP3 via their PH structural domains. PDPK1 in turn further phosphorylates Akt1/2, which in turn phosphorylates multiple targets. Phosphorylation of these targets induces a variety of cellular responses: phosphorylation of Bcl2 inhibits apoptosis, phosphorylation of FOXO proteins promotes nuclear export, which inhibits the expression of FOXO-regulated transcripts that mediate autophagy and apoptosis. Tsc1/2 phosphorylation promotes the activation of mTOR, which is activated by the binding of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) to eukaryotic translation initiation factor 4E (eIF4E), ribosomal protein S6 kinase (p70S6K), and Unc-51-like autophagy activating kinase 1 complex (ULK1) pathways, thereby increasing mRNA translation, promoting protein synthesis, cell growth, mitochondrial fusion, and inhibiting autophagy, among other physiological effects. Phosphorylation of glycogen synthase kinase (GSK) removes glycogen synthase inhibition and promotes glycogen synthesis. Phosphorylation of endothelial nitric oxide synthase (eNOS) by Akt increases nitric oxide (NO) production to promote vasorelaxation. Phosphorylation of Akt partially mediates the translocation of vesicles containing the glucose transport protein GLUT4 through phosphorylation, leading to increased glucose transport after insertion into the plasma membrane.

Figure 3

Genetic alterations in insulin signaling genes drive distinct pathophenotypes of DCM.