Document Detail


Calcineurin signaling regulates human islet {beta}-cell survival.
MedLine Citation:
PMID:  20943662     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The calcium-regulated phosphatase calcineurin intersects with both calcium and cAMP-mediated signaling pathways in the pancreatic β-cell. Pharmacologic calcineurin inhibition, necessary to prevent rejection in the setting of organ transplantation, is associated with post-transplant β-cell failure. We sought to determine the effect of calcineurin inhibition on β-cell replication and survival in rodents and in isolated human islets. Further, we assessed whether the GLP-1 receptor agonist and cAMP stimulus, exendin-4 (Ex-4), could rescue β-cell replication and survival following calcineurin inhibition. Following treatment with the calcineurin inhibitor tacrolimus, human β-cell apoptosis was significantly increased. Although we detected no human β-cell replication, tacrolimus significantly decreased rodent β-cell replication. Ex-4 nearly normalized both human β-cell survival and rodent β-cell replication when co-administered with tacrolimus. We found that tacrolimus decreased Akt phosphorylation, suggesting that calcineurin could regulate replication and survival via the PI3K/Akt pathway. We identify insulin receptor substrate-2 (Irs2), a known cAMP-responsive element-binding protein target and upstream regulator of the PI3K/Akt pathway, as a novel calcineurin target in β-cells. Irs2 mRNA and protein are decreased by calcineurin inhibition in both rodent and human islets. The effect of calcineurin on Irs2 expression is mediated at least in part through the nuclear factor of activated T-cells (NFAT), as NFAT occupied the Irs2 promoter in a calcineurin-sensitive manner. Ex-4 restored Irs2 expression in tacrolimus-treated rodent and human islets nearly to baseline. These findings reveal calcineurin as a regulator of human β-cell survival in part through regulation of Irs2, with implications for the pathogenesis and treatment of diabetes following organ transplantation.
Authors:
Scott A Soleimanpour; Michael F Crutchlow; Alana M Ferrari; Jeffrey C Raum; David N Groff; Matthew M Rankin; Chengyang Liu; Diva D De León; Ali Naji; Jake A Kushner; Doris A Stoffers
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-10-13
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-12-14     Completed Date:  2011-01-11     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  40050-9     Citation Subset:  IM    
Affiliation:
Division of Endocrinology, Department of Medicine and the Institute for Diabetes, Obesity, and Metabolism, the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects
Calcineurin / metabolism,  pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects*
Cell Survival / drug effects
Cyclic AMP / metabolism
Diabetes Mellitus / etiology,  metabolism,  pathology
Gene Expression Regulation / drug effects
Humans
Hypoglycemic Agents / pharmacology
Immunosuppressive Agents / pharmacology
Insulin Receptor Substrate Proteins / metabolism
Insulin-Secreting Cells / metabolism*,  pathology
Mice
NFATC Transcription Factors / metabolism
Organ Transplantation / adverse effects
Peptides / pharmacology
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism
Rats
Rats, Sprague-Dawley
Receptors, Glucagon / agonists,  metabolism
Signal Transduction / drug effects*
Tacrolimus / pharmacology
Venoms / pharmacology
Grant Support
ID/Acronym/Agency:
DK062965/DK/NIDDK NIH HHS; DK49210/DK/NIDDK NIH HHS; K12RR017625/RR/NCRR NIH HHS; P30 DK50306/DK/NIDDK NIH HHS; T32 DK007314-27/DK/NIDDK NIH HHS; U42 RR016600/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Hypoglycemic Agents; 0/IRS2 protein, human; 0/Immunosuppressive Agents; 0/Insulin Receptor Substrate Proteins; 0/Irs2 protein, mouse; 0/Irs2 protein, rat; 0/NFATC Transcription Factors; 0/Peptides; 0/Receptors, Glucagon; 0/Venoms; 0/glucagon-like peptide-1 receptor; 109581-93-3/Tacrolimus; 141732-76-5/exenatide; 60-92-4/Cyclic AMP; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.1.3.16/Calcineurin
Comments/Corrections

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