Liraglutide Modulates Zinc Release and Improves Mitochondrial Function in Insulin-Resistant Senescent Cardiomyocytes

Aging and insulin resistance are intertwined factors in the development of metabolic diseases such as type 2 diabetes and cardiovascular disorders. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising cardioprotective effects in preclinical and clinical studies of metabolic diseases. Yet, its action on insulin-resistant aged subjects is not clearly defined. This study aimed to investigate the effects of liraglutide on intracellular zinc levels, including its modulation of oxidative stress, mitochondrial function, and Endoplasmic Reticulum (ER) stress in a novel insulin-resistant senescent model. Insulin resistance and senescence were confirmed by reduced glucose uptake and increased β-Galactosidase Staining and increased p-H2A.X (Ser139) levels after 24 h of co-incubation with bovine serum albumin (BSA) conjugated palmitic acid (PA; 50 µM) and 278 mM D-galactose (D-Gal) in human AC16 cells. Our findings showed upregulated expression of ER and mitochondrial proteostasis markers in the early minutes of liraglutide treatment. In addition, chronic but not acute liraglutide treatment significantly increased intracellular zinc levels, accompanied by improved mitochondrial membrane potential and reduced reactive oxygen species in the insulin-resistant senescent model. Casein kinase 2 inhibition completely abolished liraglutide-induced zinc elevation and mitochondrial improvements in the chronic context, highlighting the role of casein kinase 2 in the subcellular signaling of liraglutide. These findings indicate that liraglutide alters intracellular zinc and modulates endoplasmic reticulum-mitochondria communication, giving insight into its therapeutic potential in metabolic cardiomyopathies linked to insulin resistance and aging.