title: Squamosamide Derivative FLZ Protects Pancreatic β-Cells from Glucotoxicity by Stimulating Akt-FOXO1 Pathway.
abstract: 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.
authors.affiliation: Diabetes Center, Shenzhen University, Shenzhen 518060, China.
authors.forename: Xiangchen
authors.initials: X
authors.lastname: Kong
authors.affiliation: Diabetes Center, Shenzhen University, Shenzhen 518060, China.
authors.forename: Longmei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Diabetes Center, Shenzhen University, Shenzhen 518060, China ; University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Xianxin
authors.initials: X
authors.lastname: Hua
authors.affiliation: Diabetes Center, Shenzhen University, Shenzhen 518060, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Ma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D044482:Benzeneacetamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D051381:Rats
chemical_list: D044482:Benzeneacetamides; D004365:Drugs, Chinese Herbal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D009419:Nerve Tissue Proteins; D010636:Phenols; C084439:squamosamide; C074639:Foxo1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose