SREBP-1c, Pdx-1, and GLP-1R involved in palmitate-EPA regulated glucose-stimulated insulin secretion in INS-1 cells.

Impairment of glucose-stimulated insulin secretion (GSIS) caused by glucolipotoxicity is an essential feature in type 2 diabetes mellitus (T2DM). Palmitate and eicosapentaenoate (EPA), because of their lipotoxicity and protection effect, were found to impair or restore the GSIS in beta cells. Furthermore, palmitate was found to up-regulate the expression level of sterol regulatory element-binding protein (SREBP)-1c and down-regulate the levels of pancreatic and duodenal homeobox (Pdx)-1 and glucagon-like peptide (GLP)-1 receptor (GLP-1R) in INS-1 cells. To investigate the underlying mechanism, the lentiviral system was used to knock-down or over-express SREBP-1c and Pdx-1, respectively. It was found that palmitate failed to suppress the expression of Pdx-1 and GLP-1R in SREBP-1c-deficient INS-1 cells. Moreover, down-regulation of Pdx-1 could cause the low expression of GLP-1R with/without palmitate treatment. Additionally, either SREBP-1c down-regulation or Pdx-1 over-expression could partially alleviate palmitate-induced GSIS impairment. These results suggested that sequent SREBP-1c-Pdx-1-GLP-1R signal pathway was involved in the palmitate-caused GSIS impairment in beta cells.

Shao S ，Liu Z ，Yang Y ，Zhang M ，Yu X ... -  《-》

Activation of PPARβ/δ protects pancreatic β cells from palmitate-induced apoptosis by upregulating the expression of GLP-1 receptor.

We previously showed that activated peroxisome proliferator-activated receptor (PPAR)β/δ can protect pancreatic β cells against lipotoxic apoptosis. However, the molecular mechanism remained unclear. Glucagon-like peptide-1 receptor (GLP-1R) has been reported to exhibit a protective effect against lipotoxic apoptosis in pancreatic β cells. In the present study, we aimed to investigate the underlying molecular mechanisms that PPARβ/δ activation suppressed apoptosis and improved β cell function impaired by fatty acids, focusing on contribution of GLP-1R. Isolated rat islets and rat insulin-secreting INS-1 cells were treated with the PPARβ/δ agonist GW501516 (GW) in the presence or absence of palmitate (PA) and transfected with siRNA for PPARβ/δ or treated with the PPARβ/δ antagonist GSK0660. Apoptosis was assessed by DNA fragmentation, Hoechst 33342 staining and flow cytometry. GLP-1R expression in INS-1 cells and islets was assayed by immunoblotting, quantitative PCR (qPCR) and immunofluorescence staining. SREBP-1c, Caveolin-1, Akt, Bcl-2, Bcl-xl and caspase-3 expression was measured using immunoblotting and qPCR. Our results showed that PPARβ/δ activation decreased apoptosis in β cells and robustly stimulated GLP-1R expression under lipotoxic conditions. GW enhanced glucose-stimulated insulin secretion (GSIS) impaired by PA through stimulation of GLP-1R expression in β cells. Moreover, SREBP-1c/Caveolin-1 signaling was involved in PPARβ/δ-regulated GLP-1R expression. Finally, GW exerted anti-apoptotic effects via interfering with GLP-1R-dependent Akt/Bcl-2 and Bcl-xl/caspase-3 signaling pathways. Our study suggested that the anti-apoptotic action of GW may involve its transcriptional regulation of GLP-1R, and PPARβ/δ activation may represent a new therapeutic method for protecting pancreatic β cells from lipotoxicity.

Yang Y ，Tong Y ，Gong M ，Lu Y ，Wang C ，Zhou M ，Yang Q ，Mao T ，Tong N ... -  《-》

Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response.

Natalicchio A ，Biondi G ，Marrano N ，Labarbuta R ，Tortosa F ，Spagnuolo R ，D'Oria R ，Carchia E ，Leonardini A ，Cignarelli A ，Perrini S ，Laviola L ，Giorgino F ... -  《-》

Sterol regulatory element-binding protein-1c knockdown protected INS-1E cells from lipotoxicity.

Li J ，Liu X ，Ran X ，Chen J ，Li X ，Wu W ，Huang H ，Huang H ，Long Y ，Liang J ，Cheng J ，Tian H ... -  《-》

Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells.

Wang H ，Iezzi M ，Theander S ，Antinozzi PA ，Gauthier BR ，Halban PA ，Wollheim CB ... -  《-》