title: Ceramide formation as a target in beta-cell survival and function.
abstract: BACKGROUND
  Ceramide may be synthesized de novo or generated by sphingomyelinase-dependent hydrolysis of sphingomyelin.
  
  
  METHODS
  The role of ceramide, ceramide-sensitive signaling and ion channels in β-cell apoptosis, lipotoxicity and amyloid-induced β-cell death.
  
  
  CONCLUSIONS
  Ceramide participates in β-cell dysfunction and apoptosis after exposure to TNFα, IL-1β and IFN-γ, excessive amyloid and islet amyloid polypeptide or non-esterified fatty acids (lipotoxicity). Knockout of sphingomyelin synthase 1, which converts ceramide to sphingomyelin, leads to impairment of insulin secretion. Increased ceramidase activity or pharmacological inhibition of ceramide synthetase, inhibits β-cell apoptosis. Ceramide contributes to endoplasmatic reticulum (ER) stress, decreased mitochondrial membrane potential in insulin-secreting cells and mitochondrial release of cytochrome c into the cytosol, which are all triggers of apoptotic cell death. Ceramide-dependent signaling involves activation of extracellularly regulated kinases 1 and 2 (ERK1/2), downregulation of Period (Per)-aryl hydrocarbon receptor nuclear translocator (Arnt)-single-minded (Sim) kinase (PASK), activation of okadaic-acid-sensitive protein phosphatase 2A (PP2A) and stimulation of NADPH-oxidase with generation of superoxides and lipid peroxides. Ceramide reduces the activity of voltage gated potassium (Kv)-channels in insulin-secreting cells. The role of ceramide in β-cell survival and function may be therapeutically relevant, because ceramide formation can be suppressed by pharmacological inhibition of ceramide synthetase and/or sphingomyelinase.
authors.affiliation: University of Tübingen, Institute of Physiology, Germany. florian.lang@uni-tuebingen.de
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Susanne
authors.initials: S
authors.lastname: Ullrich
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002518:Ceramides / Q000096:biosynthesis / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000503:physiopathology; D016503:Drug Delivery Systems; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007473:Ion Channels / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D051049:Sphingosine N-Acyltransferase / Q000378:metabolism
chemical_list: D000682:Amyloid; D002518:Ceramides; D007473:Ion Channels; D051049:Sphingosine N-Acyltransferase; D013108:Sphingomyelin Phosphodiesterase