title: A live-cell, high-content imaging survey of 206 endogenous factors across five stress conditions reveals context-dependent survival effects in mouse primary beta cells.
abstract: OBJECTIVE
  Beta cell death is a hallmark of diabetes. It is not known whether specific cellular stresses associated with type 1 or type 2 diabetes require specific factors to protect pancreatic beta cells. No systematic comparison of endogenous soluble factors in the context of multiple pro-apoptotic conditions has been published.
  
  
  METHODS
  Primary mouse islet cells were cultured in conditions mimicking five type 1 or type 2 diabetes-related stresses: basal 5 mmol/l glucose, cytokine cocktail (25 ng/ml TNF-α, 10 ng/ml IL-1β, 10 ng/ml IFN-γ), 1 μmol/l thapsigargin, 1.5 mmol/l palmitate and 20 mmol/l glucose (all in the absence of serum). We surveyed the effects of a library of 206 endogenous factors (selected based on islet expression of their receptors) on islet cell survival through multi-parameter, live-cell imaging.
  
  
  RESULTS
  Our survey pointed to survival factors exhibiting generalised protective effects across conditions meant to model different types of diabetes and stages of the diseases. For example, our survey and follow-up experiments suggested that OLFM1 is a novel protective factor for mouse and human beta cells across multiple conditions. Most strikingly, we also found specific protective survival factors for each model stress condition. For example, semaphorin4A (SEMA4A) was toxic to islet cells in the serum-free baseline and serum-free 20 mmol/l glucose conditions, but protective in the context of lipotoxicity. Rank product testing supported the consistency of our observations.
  
  
  CONCLUSIONS
  Collectively, our survey reveals previously unidentified islet cell survival factors and suggest their potential utility in individualised medicine.
authors.affiliation: Department of Cellular and Physiological Sciences, Faculty of Medicine, Diabetes Research Group, Life Sciences Institute, University of British Columbia, 5358-2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3.
authors.forename: Yu Hsuan Carol
authors.initials: YH
authors.lastname: Yang
authors.forename: Quin F
authors.initials: QF
authors.lastname: Wills
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D019295:Computational Biology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology*; D007371:Interferon-gamma / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D010168:Palmitates / Q000378:metabolism; D015398:Signal Transduction; D019284:Thapsigargin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007328:Insulin; D053583:Interleukin-1beta; D010168:Palmitates; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; D019284:Thapsigargin; D007371:Interferon-gamma; D005947:Glucose