Document Detail

Identification of a pathway by which glucose regulates β-catenin signalling via the cAMP/protein kinase A pathway in β-cell models.
MedLine Citation:
PMID:  23198873     Owner:  NLM     Status:  Publisher    
Pancreatic β-cells are highly responsive to changes in glucose but the mechanisms involved are only partially understood. There is increasing evidence that the β-catenin signalling pathway plays an important role in regulating β-cell function but the mechanisms regulating β-catenin signalling in these cells is not well understood. Here we show that β-catenin levels and downstream signalling are regulated by changes in glucose levels in INS-1E and β-TC β-cell models. We found a glucose-dependent increase in levels of β-catenin in the cytoplasm and the nucleus of INS-1E cells. Expression of Cyclin D1 responded also increased with glucose and required the presence of β-catenin. This was associated with an increase in phosphorylation of β-catenin on Ser552, which is known to stabilise the molecule and increase its transcriptional activity. In a search for possible signalling intermediates we found forskolin and cell permeable cAMP analogues recapitulated the glucose effects suggesting a role for cAMP and PKA downstream of glucose. Further, glucose caused sustained increases in cAMP. Two different inhibitors of adenylate cyclase and PKA signalling blocked the effects of glucose while siRNA knockdown of PKA blocks the effects of glucose on β-catenin signaling. Finally, reducing β-catenin levels with either siRNA or pyrvinium impaired glucose and KCl stimulated insulin secretion. Together this defines a pathway by which changes in glucose levels can regulate β-catenin using a mechanism that involves cAMP production and the activation of PKA. This identifies a pathway that may be important in glucose-dependent regulation of gene expression and insulin secretion in β-cells.
Emmanuelle Cognard; Coralie G Dargaville; Deborah L Hay; Peter R Shepherd
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-3
Journal Detail:
Title:  The Biochemical journal     Volume:  -     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-3     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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