Valproate pretreatment protects pancreatic β-cells from palmitate-induced ER stress and apoptosis by inhibiting glycogen synthase kinase-3β

Background: reduction of pancreatic β-cells mass,major secondary to increased β-cells apoptosis,is increasingly recognized as one of the main contributing factors to the pathogenesis of type 2 diabetes (t2d),and saturated free fatty acid palmitate has been shown to induce endoplasmic reticulum (er) stress that may contribute to promoting β-cells apoptosis. recent literature suggests that valproate,a diffusely prescribed drug in the treatment of epilepsy and bipolar disorder,can inhibit glycogen synthase kinase-3β (gsk-3β) activity and has cytoprotective effects in neuronal cells and hepg2 cells. thus,we hypothesized that valproate may protect ins-1 β-cells from palmitate-induced apoptosis via inhibiting gsk-3β. results: valproate pretreatment remarkable prevented palmitate-mediated cytotoxicity and apoptosis (lipotoxicity) as well as er distension. furthermore,palmitate triggered er stress as evidenced by increased mrna levels of c/ebp homologous protein (chop) and activating transcription factor 4 (atf4) in a time-dependent fashion. however,valproate not only reduced the mrna and protein expression of chop but also inhibited gsk-3β and caspase-3 activity induced by palmitate,whereas,the mrna expression of atf4 was not affected. interestingly,tdzd-8,a specific gsk-3β inhibitor,also showed the similar effect on lipotoxicity and er stress as valproate in ins-1 cells. finally,compared with chop knockdown,valproate displayed better cytoprotection against palmitate. conclusions: valproate may protect β-cells from palmitate-induced apoptosis and er stress via gsk-3β inhibition,independent of atf4/chop pathway. besides,gsk-3β,rather than chop,may be a more promising therapeutic target for t2d. © 2014huang et al.; licensee biomed central ltd.