title: P38 plays an important role in glucolipotoxicity-induced apoptosis in INS-1 cells.
abstract: OBJECTIVE
  The mechanism underlying the regulation of glucolipotoxicity-induced apoptosis by MAPKs was examined in INS-1 cells.
  
  
  METHODS
  The rat insulinoma cell line INS-1 was cotreated with glucose (30 mM) and palmitic acid (0.2 mM) (GLU+PA). Apoptosis was assessed by cell morphology and detection of PARP cleavage. The activation of MAPKs was examined by Western blotting using specific antibodies against the phosphorylated forms of JNK, ERK1/2, and P38.
  
  
  RESULTS
  (1) Live cell imaging studies showed that treatment with GLU+PA for 72 h induced significant cell death, concomitant with PARP-1 cleavage and caspase-3 activation, which peaked at 96 h of treatment. (2) Western blot analysis of the activation of MAPKs during GLU+PA-induced INS-1 cell apoptosis showed that phosphorylation of P38 increased gradually and reached a peak at 96 h, which coincided with PARP-1 cleavage. A transient increase of ERK activation was followed by a rapid decline at 96 h, whereas JNK phosphorylation status remained unchanged in response to GLU+PA. (3) Phosphorylation of insulin receptor substrate (IRS)-2 at 48 h of treatment triggered its degradation, which coincided with P38 activation. (4) Inhibition of P38, but not JNK or ERK, blocked GLU+PA-induced INS-1 cell apoptosis.
  
  
  CONCLUSIONS
  P38 may be involved in the regulation of glucolipotoxicity-induced apoptosis through the phosphorylation of IRS-2.
authors.affiliation: Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Lingli
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Xiaoling
authors.identifier: 0000-0002-7881-0543
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Xueyao
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing 100044, China.
authors.forename: Linong
authors.initials: L
authors.lastname: Ji
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism* / Q000473:pathology; D006949:Hyperlipidemias / Q000378:metabolism* / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007700:Kinetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019308:Palmitic Acid / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D005230:Fatty Acids, Nonesterified; D055504:Insulin Receptor Substrate Proteins; C526299:Irs2 protein, rat; D047428:Protein Kinase Inhibitors; D019308:Palmitic Acid; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3
references.citation: PLoS One. 2010 Dec 29;5(12):e15726
references.pmid: 21209957
references.citation: Endocr J. 2012;59(1):81-90
references.pmid: 22068113
references.citation: Diabetes. 1995 Apr;44(4):369-74
references.pmid: 7698502
references.citation: Science. 2002 Jun 28;296(5577):2345-7
references.pmid: 12089430
references.citation: Diabetes. 2005 Dec;54 Suppl 2:S108-13
references.pmid: 16306327
references.citation: J Nutr Metab. 2012;2012:542698
references.pmid: 23316349
references.citation: Diabetes Metab J. 2011 Oct;35(5):444-50
references.pmid: 22111034
references.citation: Exp Diabetes Res. 2012;2012:639762
references.pmid: 21977023
references.citation: Circulation. 2011 Feb 8;123(5):515-23
references.pmid: 21262998
references.citation: Curr Diabetes Rev. 2005 Feb;1(1):65-72
references.pmid: 18220583
references.citation: Obes Rev. 2000 Oct;1(2):57-9
references.pmid: 12119987
references.citation: Diabetes Care. 2010 Apr;33(4):804-10
references.pmid: 20097779
references.citation: Endocrinology. 2002 Feb;143(2):339-42
references.pmid: 11796484
references.citation: Diabetes. 2003 Jan;52(1):102-10
references.pmid: 12502499
references.citation: Exp Diabetes Res. 2012;2012:356487
references.pmid: 22550476
references.citation: Science. 2005 Jan 21;307(5708):380-4
references.pmid: 15662003