More importantly, this change preceded the induction of cleaved caspase 3, which was apparent after treatment of thapsigargin or high glucose and palmitic acid. Overall, these data suggest that CHOP plays a detrimental role in ER stress induction and that CHOP silencing may be a therapeutic approach to modulating beta-cell function and survival in T2D. In our studies, activation of ER stress markers was reversed after treatment with chaperones. In thapsigargin or high glucose and palmitic acid treatment, the addition of chemical chaperones TUDCA and PBA was able to prevent activation of ER-stress protein markers. Similar effects were observed after transduction with adenovirus encoding for endogenous chaperones BiP and PDI after high glucose and palmitic acid treatment. In accordance with our results, BiP overexpression has been shown to diminish apoptosis by attenuating the induction of CHOP in ER stress. In line with other BKM120 PI3K inhibitor reports, we noted that beta-cell overexpression of hIAPP shows a failure in insulin secretion in response to glucose stimulation. The results obtained in hIAPP-INS1E cells demonstrate that treatment with chaperones BiP, TUDCA and PBA ameliorate insulin secretory response under basal conditions. In contrast, PDI showed a marked increase in insulin secretion, accompanied with a significant decrease in insulin content. Although PDI is present in human islets and has been shown to play an important role in sulphide bond formation and isomeration or protein degradation, its overexpression has been associated with induced ER stress resulting from accumulation of proinsulin in the ER, suggesting that PDI overexpression may have a detrimental effect that disrupts normal insulin processing. Treatment with high glucose and palmitic acid diminished insulin secretion in hIAPP-INS1E cells, confirming a glucolipotoxic effect. Interestingly, chaperone treatment was able to recover glucose-stimulated insulin secretion. Therapeutic interventions that reduce ER stress have been studied in order to provide strategies for treating ER stress-related human diseases such as T2D. BiP has been shown to be elevated in beta-cells of hIAPP-transgenic mouse models. This increase of BiP can be related to the UPR in response to an increased overload of hIAPP. In addition, BiP has direct interaction with amyloidogenic peptides and has been shown to attenuate the formation of amyloidlike aggregates, suppressing the misfolding of hIAPP. Furthermore, transgenic mice overexpressing BiP specifically in beta-cells were protected against the injury of obesity-induced T2D, maintaining beta-cell function and improving glucose homeostasis. In a similar way, BiP overexpression has been shown to improve insulin sensitivity in ob/ob mice. A promising approach is the use of pharmacological agents, such as orally active chemical chaperones, which can stabilize protein conformation, improve ER folding capacity and facilitate the trafficking of mutant proteins. Ozcan et al. have shown that chemical chaperones, such as PBA and TUDCA, reduce ER stress and restore glucose homeostasis in a mouse model of T2D.