GLP‑1 receptor agonist protects palmitate-induced insulin resistance in skeletal muscle cells by up-regulating sestrin2 to promote autophagy

Abstract

In this study, we aimed to determine whether liraglutide could effectively reduce insulin resistance (IR) by regulating Sestrin2 (SESN2) expression in L6 rat skeletal muscle cells by examining its interactions with SESN2, autophagy, and IR. L6 cells were incubated with liraglutide (10–1000 nM) in the presence of palmitate (PA; 0.6 mM), and cell viability was detected using the cell counting kit-8 (CCK-8) assay. IR-related and autophagy-related proteins were detected using western blotting, and IR and autophagy-related genes were analyzed using quantitative real-time polymerase chain reaction. Silencing SESN2 was used to inhibit the activities of SESN2. A reduction in insulin-stimulated glucose uptake was observed in PA-treated L6 cells, confirming IR. Meanwhile, PA decreased the levels of GLUT4 and phosphorylation of Akt and affected SESN2 expression. Further investigation revealed that autophagic activity decreased following PA treatment, but that liraglutide reversed this PA-induced reduction in autophagic activity. Additionally, silencing SESN2 inhibited the ability of liraglutide to up-regulate the expression of IR-related proteins and activate autophagy signals. In summary, the data showed that liraglutide improved PA-induced IR in L6 myotubes by increasing autophagy mediated by SESN2.

Effects of GLP-1 receptor agonists on mitochondrial function, inflammatory markers and leukocyte-endothelium interactions in type 2 diabetes

“…Indeed, the expression levels of genes related to the pathogenesis of atherosclerosis, such as those involved in leukocyte recruitment, leukocyte rolling and adhesion/extravasation, showed altered expression in mouse models of atherosclerosis that were reversed when mice were treated with GLP-1 RA [ 45 ]. Interestingly, evidence supports that GLP-1 RA may act through inducing autophagy [ 46 , 47 ], a key energy homeostasis response associated to therapeutic effects of weight loss in obese patients [ 18 ]. Our findings suggest that, in addition to these mechanisms, GLP-1 RA ameliorate leukocyte’s redox state, mitochondrial function and reduce their interaction with the endothelium, ultimately contributing to a lower cardiovascular risk.…”

Mechanism of action of the bile acid receptor TGR5 in obesity

“…Furthermore, GLP-1 can promote the expression of the glycogen synthesis gene glycogen synthase 1/2 (GYS1/2) by promoting AMPK phosphorylation, and may also affect the translocation of GLUT4 to the cell membrane 170 , 171 . Furthermore, GLP-1 analogues can promote autophagy by regulating Sestrin2 (SESN2) in skeletal muscle cells, promote the expression of GLUT4 and effectively increase glucose uptake 172 ( Fig. 7 ).…”

Recent advances in understanding the mechanisms in skeletal muscle of interaction between exercise and frontline antihyperglycemic drugs

“…In addition to blood flow, GLP1 receptor agonists have direct actions on pathways regulating muscle viability and function, such as autophagy which is needed to be activated to promote muscle mass (Masiero et al, 2009) and glucose adaptations during exercise training (He et al, 2012). Liraglutide prevented the loss of cell viability and increased autophagy markers during palmitate treatment in L6 cells (Tian et al, 2023). The direct actions of GLP1 on muscle combined with cardiovascular control provide several potential mechanisms by which GLP1 receptor agonists may interact with exercise training.…”