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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. [ABSTRACT FROM AUTHOR]

Angiogenesis, the formation of new blood vessels from pre-existing ones, is vital for vertebrate development and adult homeostasis. Acid α-glucosidase (GAA) is a glycoside hydrolase involved in the lysosomal breakdown of glycogen. Our previous study showed that GAA was highly expressed in mouse pulmonary veins. While whether GAA was involved in angiogenesis remained largely unknown, thus, we performed knockdown experiments both in vivo and in vitro and endothelial cell function experiments to clarify this concern point. We identified that GAA expressed widely at different levels during zebrafish embryonic development and GAA morphants showed excessive angiogenesis of ISV at later stage. In GAA knockdown HUVECs, the migration and tube formation capacity were increased, resulted from the formation of large lamellipodia-like protrusions at the edge of cells. By analyzing autophagic flux, we found that autophagy disorder was the mechanism of GAA knockdown-induced excessive angiogenesis. The block of autophagic flux caused upregulation of Rac1, a small GTPase, and the latter promoted excessive sprouts in zebrafish and enhanced angiogenic behavior in HUVECs. In addition, overexpression of transcription factor E3, a master regulator of autophagy, rescued upregulation of RAC1 and enhanced angiogenic function in GAA-knockdown HUVECs. Also, inhibition of Rac1 partly restored enhanced angiogenic function in GAA-knockdown HUVECs. Taken together, our study firstly reported a novel function of GAA in angiogenesis which is mediated by upregulation of Rac1 induced by autophagy disorder. • GAA deficiency promotes excessive angiogenesis in zebrafish intersegmental vessels. • GAA deficiency enhances migration and tube formation of human umbilical vein endothelial cells. • GAA deficiency mediated the excessive angiogenesis through autophagy buildup and subsequent upregulation of RAC1. • Regulation of autophagy and inhibition of RAC1 restored the GAA deficiency-mediated excessive angiogenesis. [ABSTRACT FROM AUTHOR]