title: Overexpression of Insig-1 protects β cell against glucolipotoxicity via SREBP-1c.
abstract: BACKGROUND
  High glucose induced lipid synthesis leads to β cell glucolipotoxicity. Sterol regulatory element binding protein-1c (SREBP-1c) is reported to be partially involved in this process. Insulin induced gene-1 (Insig-1) is an important upstream regulator of Insig-1-SREBPs cleavage activating protein (SCAP)-SREBP-1c pathway. Insig-1 effectively blocks the transcription of SREBP-1c, preventing the activation of the genes for lipid biosynthesis. In this study, we aimed to investigate whether Insig-1 protects β cells against glucolipotoxicity.
  
  
  METHODS
  An Insig-1 stable cell line was generated by overexpression of Insig-1 in INS-1 cells. The expression of Insig-1 was evaluated by RT-PCR and Western blotting, then, cells were then treated with standard (11.2 mM) or high (25.0 mM) glucose for 0 h, 24 h and 72 h. Cell viability, apoptosis, glucose stimulated insulin secretion (GSIS), lipid metabolism and mRNA expression of insulin secretion relevant genes such as IRS-2, PDX-1, GLUT-2, Insulin and UCP-2 were evaluated.
  
  
  RESULTS
  We found that Insig-1 suppressed the high glucose induced SREBP-1c mRNA and protein expression. Our results also showed that Insig-1 overexpression protected β cells from ER stress-induced apoptosis by regulating the proteins expressed in the IRE1α pathway, such as p-IRE1α, p-JNK, CHOP and BCL-2. In addition, Insig-1 up-regulated the expression of IRS-2, PDX-1, GLUT-2 and Insulin, down-regulated the expression of UCP-2 and improved glucose stimulated insulin secretion (GSIS). Finally, we found that Insig-1 inhibited the lipid accumulation and free fatty acid (FFA) synthesis in a time-dependent manner.
  
  
  CONCLUSIONS
  There results suggest that Insig-1 may play a critical role in protecting β cells against glucolipotoxicity by regulating the expression of SREBP-1c.
authors.affiliation: Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.forename: Hong-hui
authors.initials: HH
authors.lastname: He
authors.forename: Yan-hong
authors.initials: YH
authors.lastname: Xie
authors.forename: Xiao-yun
authors.initials: XY
authors.lastname: Xie
authors.forename: Zhao-hui
authors.initials: ZH
authors.lastname: Mo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids / Q000096:biosynthesis / Q000633:toxicity*; D008565:Membrane Proteins / Q000378:metabolism*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
chemical_list: C491574:Insig1 protein, rat; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; D051780:Sterol Regulatory Element Binding Protein 1