title: Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic ß cell exhaustion.
abstract: BACKGROUND
  Diabetes mellitus is characterized by high blood glucose levels. Pancreatic ß cell death contributes to type 1 and type 2 diabetes. Akita mice, which harbor a human permanent neonatal diabetes-linked mutation (Cys96Tyr) in the insulin gene, are well established as an animal model of diabetes caused by pancreatic ß cell exhaustion. Mutant Insulin 2 protein (Ins2(C96Y)) induces endoplasmic reticulum (ER) stress and pancreatic ß cell death in Akita mice, although the molecular mechanism of Ins(C96Y)-induced cell death remains unclear.
  
  
  METHODS
  We investigate the mechanisms of Ins2(C96Y)-induced pancreatic ß cell death in vitro and in vivo, using p38 inhibitor (SB203580), MIN6 cell (pancreatic ß cell line), Akita mice and apoptosis signal-regulating kinase 1 (ASK1) knockout mice.
  
  
  RESULTS
  The expression of Ins(C96Y) activated the ASK1-p38 pathway. Deletion of ASK1 mitigated Ins(C96Y)-induced pancreatic ß cell death and delayed the onset of diabetes in Akita mice. Moreover, p38 inhibitor suppressed Ins(C96Y)-induced MIN6 cell death.
  
  
  CONCLUSIONS
  These findings suggest that ER stress-induced ASK1-p38 activation, which is triggered by the accumulation of Ins(C96Y), plays an important role in the pathogenesis of diabetes.
  
  
  CONCLUSIONS
  Pancreatic ß cell death caused by insulin overload appears to be involved in the pathogenesis of type 1 and type 2 diabetes. Inhibition of the ASK1-p38 pathway may be an effective therapy for various types of diabetes.
authors: The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
authors: Kiyoshi
authors: K
authors: Yamaguchi
authors: Kohsuke
authors: K
authors: Takeda
authors: Hisae
authors: H
authors: Kadowaki
authors: Ikumi
authors: I
authors: Ueda
authors: Yoshio
authors: Y
authors: Namba
authors: Yasuyoshi
authors: Y
authors: Ouchi
authors: Hideki
authors: H
authors: Nishitoh
authors: Hidenori
authors: H
authors: Ichijo
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000201:enzymology* / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; C561967:Ins2 protein, mouse; D007328:Insulin; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse; C093642:SB 203580