title: Lactogens protect rodent and human beta cells against glucolipotoxicity-induced cell death through Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling.
abstract: OBJECTIVE
  A leading cause of type 2 diabetes is a reduction in functional beta cell mass partly due to increased beta cell death, triggered by stressors such as glucolipotoxicity (GLT). This study evaluates the hypothesis that lactogens can protect beta cells against GLT and examines the mechanism behind the pro-survival effect.
  
  
  METHODS
  The effect of exogenous treatment or endogenous expression of lactogens on GLT-induced beta cell death was examined in INS-1 cells, and in rodent and human islets. The mechanism behind the pro-survival effect of lactogens was determined using an inhibitor, siRNAs, a dominant negative (DN) mutant, and Cre-lox-mediated gene deletion analysis.
  
  
  RESULTS
  Lactogens significantly protect INS-1 and primary rodent beta cells against GLT-induced cell death. The pro-survival effect of lactogens in rodent beta cells is mediated through activation of the Janus kinase-2 (JAK2)/signal transducer and activator of transcription-5 (STAT5) signalling pathway. Lactogen-induced increase in the anti-apoptotic B cell lymphoma-extra large (BCLXL) protein is required to mediate its pro-survival effects in both INS-1 cells and primary rodent beta cells. Most importantly, lactogens significantly protect human beta cells against GLT-induced cell death, and their pro-survival effect is also mediated through the JAK2/STAT5 pathway.
  
  
  CONCLUSIONS
  These studies, together with previous work, clearly demonstrate the pro-survival nature of lactogens and identify the JAK2/STAT5 pathway as an important mediator of this effect in both rodent and human beta cells. Future studies will determine the effectiveness of this peptide in vivo in the pathophysiology of type 2 diabetes.
authors.affiliation: Division of Endocrinology, University of Pittsburgh, 200 Lothrop St, BST-E1157, Pittsburgh, PA 15261, USA.
authors.forename: N Guthalu
authors.initials: NG
authors.lastname: Kondegowda
authors.forename: A
authors.initials: A
authors.lastname: Mozar
authors.forename: C
authors.initials: C
authors.lastname: Chin
authors.forename: A
authors.initials: A
authors.lastname: Otero
authors.forename: A
authors.initials: A
authors.lastname: Garcia-Ocaña
authors.forename: R C
authors.initials: RC
authors.lastname: Vasavada
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010928:Placental Lactogen / Q000494:pharmacology*; D034741:RNA, Small Interfering; D051381:Rats; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D010928:Placental Lactogen; D053614:Janus Kinase 2