title: Tissue inhibitor of metalloproteinase-1 counteracts glucolipotoxicity in the pancreatic β-cell line INS-1.
abstract: BACKGROUND
  Glucolipotoxicity might play an important role in the β cell decompensation stage during the development of obesity-associated type 2 diabetes. Tissue inhibitor of metalloproteinase-1 (TIMP-1) inhibits matrix metalloproteinase (MMP) activity and regulates proliferation and apoptosis of a variety of cell types, including pancreatic β-cells. In the present study, we investigated whether TIMP-1 counteracts glucolipotoxicity in the pancreatic β-cell line INS-1.
  
  
  METHODS
  INS-1 cells were incubated in normal or high glucose, with or without palmitate (0.4 mmol/L), in the presence of TIMP-1 or MMP inhibitor GM60001. In some experiments, cells were pretreated with phosphatidylinositol-3 (PI-3) kinase inhibitor, LY294002 or wortmannin. The amount of dead INS-1 cells was determined by HO342 and propidium iodide staining. Akt phosphorylation was evaluated by Western blotting analysis to investigate a possible mechanism of TIMP-1's action.
  
  
  RESULTS
  TIMP-1 protected INS-1 cells from glucolipotoxicity independent of MMP inhibition. TIMP-1 stimulated Akt phosphorylation. Inhibition of the PI-3 kinase pathway abolished the survival effect of TIMP-1.
  
  
  CONCLUSIONS
  TIMP-1 may counteract glucolipotoxicity induced β-cell death via a PI-3 kinase pathway.
authors.affiliation: Institute of Nephrology, General Hospital of Chinese People's Liberation Army, Beijing 100853, China.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Jiang
authors.forename: Han-Yu
authors.initials: HY
authors.lastname: Zhu
authors.forename: Jian-Zhong
authors.initials: JZ
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Yang
authors.initials: Y
authors.lastname: Lü
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.forename: Yuan-Sheng
authors.initials: YS
authors.lastname: Xie
authors.forename: Xiang-Mei
authors.initials: XM
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D005947:Glucose / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000494:pharmacology*
chemical_list: D010168:Palmitates; D019715:Tissue Inhibitor of Metalloproteinase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose