| Chronic high level of free fatty acids and glucose in type 2 diabetes increases the oxidative stress, leading to detrimental effect onβcell function and eventually inducingβcell apoptosis. Therefore, it is an important therapeutic strategy for type 2 diabetes to improveβcell function and its survival. Endogenous incretin hormones glucagon-like peptide-1(GLP-1), through activation on its receptor, has various effects onβcell including enhancing glucose-stimulated insulin secretion, differentiation of ductular cell in pancreas to endocrine cells and anti-apoptosis. In our previous work, we reported that geniposide, a novel agonist for GLP-1 receptor, induced insulin secretion and enhanced glucose-stimulated insulin secretion in INS-1 cells. Furthermore, geniposide also decreased blood glucose in streptozotocin-induced diabetic rats, suggesting that geniposide might be a promising compound in the treatment of diabetes in future. The aim of this study is to explore whether geniposide prevents INS-1 cells from apoptosis induced by palimitate (Pal) and its signal pathway.MTT results show that geniposide increases cell viability induced by 0.4 mM Pal for 7 h in a dose-dependent manner in INS-1 cells. To explore the protective mechanisms of geniposide in INS-1 cells, western blot was taken to probe the phosphorylation of PKB, FoxO1 and JNK in Pal-treated cell in the presence or absence of geniposide, the results demonstrated that, compared to the group of Pal treatment alone, geniposide enhanced the phosphorylation of PKB and FoxO1, and decreased the phosphorylation of JNK in INS-1 cells. But, when the treated time of Pal increased to 7 h, the level of phosphorylation of JNK reduced dramatically (P<0.01), accompanied with this, phosphorylated Foxo1 and expression of PDX-1 (P<0.05) were upregulated by geniposide. These data suggested that geniposide could promote survival of INS-1 cells through regulating PKB and FoxO1 kinases and elevating expression of PDX-1.To further investigate the effect of geniposide on the viability and kinases of INS-1 cells treated with Pal for a long term, the time during which the INS-1 cell were treated with 0.4 mM was prolonged up to 18 hours. But under this condition, treatment with 0.4 mM PA caused most cells dead. Therefore, the final concentration of Pal had to be reduced to 0.2 mM. The cells were collected and cell apoptosis was analyzed by flow cytometry. The results showed that, though treatment with 0.2 mM Pal/0.5% BSA could induce a few cell apoptosis, geniposide significantly prevented cell apoptosis induced by PA in INS-1 cells. However, the Western blot analysis showed that, in the same treated cells, geniposide increased the phosphorylation of PKB, but had no significant effect on the phosphorylation of JNK, the expression of Bcl-2 and PDX-1.To explore the reasons for the decreasing of the protection of geniposide in long-term PA treated INS-1 cells, we determined the effect of Ex-3, an antagonist for GLP-1R and the expression of GLP-1R in long-term PA treated INS-1 cells, the results showed that pretreatment with Ex-3 inhibited the protection of geniposide in PA-induced INS-1 cells damage, and accompanied with this, the level of GLP-1R expression in long-term PA treated INS-1 cells decreased significantly, suggesting GLP-1R plays a critical role in geniposide protecting INS-1 cells from PA-induced damage.
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