Document Detail


Thioredoxin-interacting protein deficiency induces Akt/Bcl-xL signaling and pancreatic beta-cell mass and protects against diabetes.
MedLine Citation:
PMID:  18552236     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Pancreatic beta-cell loss through apoptosis represents a key factor in the pathogenesis of diabetes; however, no effective approaches to block this process and preserve endogenous beta-cell mass are currently available. To study the role of thioredoxin-interacting protein (TXNIP), a proapoptotic beta-cell factor we recently identified, we used HcB-19 (TXNIP nonsense mutation) and beta-cell-specific TXNIP knockout (bTKO) mice. Interestingly, HcB-19 mice demonstrate increased adiposity, but have lower blood glucose levels and increased pancreatic beta-cell mass (as assessed by morphometry). Moreover, HcB-19 mice are resistant to streptozotocin-induced diabetes. When intercrossed with obese, insulin-resistant, and diabetic mice, double-mutant BTBRlep(ob/ob)txnip(hcb/hcb) are even more obese, but are protected against diabetes and beta-cell apoptosis, resulting in a 3-fold increase in beta-cell mass. Beta-cell-specific TXNIP deletion also enhanced beta-cell mass (P<0.005) and protected against diabetes, and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) revealed a approximately 50-fold reduction in beta-cell apoptosis in streptozotocin-treated bTKO mice. We further discovered that TXNIP deficiency induces Akt/Bcl-xL signaling and inhibits mitochondrial beta-cell death, suggesting that these mechanisms may mediate the beta-cell protective effects of TXNIP deficiency. These results suggest that lowering beta-cell TXNIP expression could serve as a novel strategy for the treatment of type 1 and type 2 diabetes by promoting endogenous beta-cell survival.
Authors:
Junqin Chen; Simon T Hui; Francesca M Couto; Imran N Mungrue; Dawn B Davis; Alan D Attie; Aldons J Lusis; Roger A Davis; Anath Shalev
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-06-13
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  22     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-01     Completed Date:  2008-10-21     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3581-94     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / genetics
Carrier Proteins / genetics*
Cell Count
Diabetes Mellitus, Experimental / chemically induced,  genetics
Diabetes Mellitus, Type 1 / genetics*,  pathology
Diabetes Mellitus, Type 2 / genetics*,  pathology
Hypoglycemia
Insulin-Secreting Cells / metabolism,  pathology*
Mice
Mice, Knockout
Obesity / complications,  pathology
Proto-Oncogene Proteins c-akt / metabolism*
Signal Transduction
Thioredoxins / genetics*
bcl-X Protein / metabolism*
Grant Support
ID/Acronym/Agency:
R01 DK078752/DK/NIDDK NIH HHS; R01DK-078752/DK/NIDDK NIH HHS; R01HL-51648/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/Txnip protein, mouse; 0/bcl-X Protein; 52500-60-4/Thioredoxins; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

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


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