Squamosamide Derivative FLZ Protects Pancreatic β -Cells from Glucotoxicity by Stimulating Akt-FOXO1 Pathway

Chronic hyperglycemia increases apoptosis and reduces glucose-stimulated insulin secretion. although protective agents have been searched extensively,none has been found so far. here we tested flz,a synthetic derivative of squamosamide from a chinese herb,as a potential candidate for antiglucotoxicity in ins-1e cells and mouse islets. chronic culture of β-cells in 30 mm glucose caused progressive reduction of cell viability,accompanied with increased apoptosis and reduced insulin secretion. these effects on apoptosis and insulin were reversed by flz in a dose-dependent manner. flz treatment also increased forkhead box o1 protein phosphorylation and reduced its nuclear location. on the contrary,flz increased pancreatic and duodenal homeobox-1 expression and its nuclear localization,an effect mediated by increased p-akt. consistently,akt selective inhibitor mk-2206 completely abolished antiglucotoxicity effect of flz. furthermore,flz treatment increased cytosolic atp/adp ratio. taken together,our results suggest that flz could be a potential therapeutic agent to treat the hyperglycemia-induced β-cell failure. © 2015 xiangchen kong et al.