Abstract
ObjectiveMetabolic disturbances induce endoplasmic reticulum stress (ERS) in pancreatic beta cells. This study aims to investigate whether a common pathway exists in the ERS induced by various chemicals, including high levels of glucose and palmitate in INS-1-3 cells.MethodERS in INS-1-3 cells was induced by exposure cells to thapsigargin (TG), tunicamycin (TM) or palmitic acid (PA) +high glucose (HG). Digital gene expression (DGE) profiling technique was used to detect differentially expressed genes. The profile of gene expression was detected by gene oncology (GO) function and pathway enrichment analysis. Nkx6.1 over-expression was established in INS-1-3 cell lines by lentivirus infection to revert the inhibition of Nkx6.1 expression found in the situation of ERS. Real time reverse transcription polymerase chain reaction (RT-PCR) was used to verify the expression changes of key genes. Cell viability was measured by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. The apoptosis was determined by flow cytometry. INS-1-3 cell function was measured by glucose stimulated insulin secretion test(GSIS).ResultsAs compared to control, DGE demonstrated that there were 135, 57 and 74 differentially expressed genes in TM, TG and HG+PA groups, respectively. Those differentially expressed genes were enriched to ERS, antigen processing and presentation, protein export pathways, and interestingly, the maturity onset diabetes of the young (MODY) pathway. Nkx6.1 is one of common down-regulated gene in MODY signaling pathway among TM, TG and HG+PA groups. Over-expression of Nkx6.1 ameliorated glucolipotoxicity induced apoptosis rate by 45.4%, and increased proliferation by 40.9%. At the same time, GSIS increased by 1.82 folds.ConclusionsMODY pathway genes expression was changed in the state of ERS. Over-expression of Nkx6.1 protected the INS-1-3 cells from glucolipotoxicity.
Highlights
Ample evidences indicate that β-cell dysfunction determines the development and progression of type 2 diabetes (T2DM)
Digital gene expression (DGE) demonstrated that there were 135, 57 and 74 differentially expressed genes in TM, TG and HG+palmitic acid (PA) groups, respectively. Those differentially expressed genes were enriched to endoplasmic reticulum stress (ERS), antigen processing and presentation, protein export pathways, and interestingly, the maturity onset diabetes of the young (MODY) pathway
MODY pathway genes expression was changed in the state of ERS
Summary
Ample evidences indicate that β-cell dysfunction determines the development and progression of type 2 diabetes (T2DM). By using homeostasis model assessment (HOMA), UK Prospective Diabetes Study (UKPDS) finds that pancreatic β-cell function have already lost by 50% at the time of diagnosis and declined by 5% annually[1]. The function failure of β-cells is associated with worsening of metabolic control, which is the major underlying mechanism for the acute and chronic complications in type 2 diabetes[2,3]. The failure or dysfunction of pancreatic β-cell, at least partially, is caused by irreversible damage of ER stress, but the underlying molecular mechanism is to be clarified. Glucolipotoxicity induces ER stress both in vitro and in vivo and cause β cell dysfunction and plays an important role in development and progression of T2DM[4,5,6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
