Document Detail


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.
MedLine Citation:
PMID:  22382519     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS/HYPOTHESIS: 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/INTERPRETATION: 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:
N Guthalu Kondegowda; A Mozar; C Chin; A Otero; A Garcia-Ocaña; R C Vasavada
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-03-03
Journal Detail:
Title:  Diabetologia     Volume:  55     ISSN:  1432-0428     ISO Abbreviation:  Diabetologia     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-07     Completed Date:  2012-08-29     Revised Date:  2012-10-09    
Medline Journal Info:
Nlm Unique ID:  0006777     Medline TA:  Diabetologia     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1721-32     Citation Subset:  IM    
Affiliation:
Division of Endocrinology, University of Pittsburgh, 200 Lothrop St, BST-E1157, Pittsburgh, PA 15261, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line, Tumor
Cells, Cultured
Female
Humans
Insulin-Secreting Cells / cytology,  drug effects
Islets of Langerhans / cytology*,  drug effects*,  metabolism
Janus Kinase 2 / genetics,  metabolism*
Male
Mice
Mice, Transgenic
Placental Lactogen / pharmacology*
RNA, Small Interfering
Rats
STAT5 Transcription Factor / genetics,  metabolism*
Signal Transduction / drug effects*,  genetics
Grant Support
ID/Acronym/Agency:
DK072264/DK/NIDDK NIH HHS; DK078060/DK/NIDDK NIH HHS; R01 DK067351-08/DK/NIDDK NIH HHS; R01 DK072264-01/DK/NIDDK NIH HHS; R01 DK078060-05/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/RNA, Small Interfering; 0/STAT5 Transcription Factor; 9035-54-5/Placental Lactogen; EC 2.7.10.1/Janus Kinase 2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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