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

Abstract EN

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.