Document Detail

Overexpression of ZAC impairs glucose-stimulated insulin translation and secretion in clonal pancreatic beta-cells.
MedLine Citation:
PMID:  22865650     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: ZAC (Zinc finger protein that regulates apoptosis and cell-cycle arrest) is a candidate gene for transient neonatal diabetes mellitus (TNDM). This condition involves severe insulin deficiency at birth that reverses over weeks or months but may relapse with diabetes recurring in later life. ZAC overexpression in transgenic mice has previously been shown to result in complex changes in both beta-cell mass and possibly function. The present study therefore aimed to examine the role of ZAC in beta-cell function in vitro, independent of the confounder of a reduced beta-cell mass at birth.
METHODS: Overexpression of ZAC was achieved through the tetracycline-regulatable system in the beta-cell line, INS-1.
RESULTS: We found that ZAC overexpression exerted no significant effect on proliferation in this transformed cell line at any of the glucose concentrations examined. By contrast, glucose-stimulated insulin secretion was impaired through a mechanism downstream of cytosolic Ca(2+) increases. Furthermore, glucose-stimulated proinsulin biosynthesis was inhibited despite an increase in insulin transcript level. Finally, we found that glucose downregulated ZAC expression in both INS-1 cells and primary mouse islets.
CONCLUSIONS: These results indicate that ZAC is a negative regulator of the acute stimulatory effects of glucose on beta-cells, and provide a possible explanation for both insulin deficiency in the neonate and the later relapse of diabetes in patients with transient neonatal diabetes mellitus cases.
Xiaoyu Du; Houria Ounissi-Benkalha; Merewyn K Loder; Guy A Rutter; Constantin Polychronakos
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Diabetes/metabolism research and reviews     Volume:  28     ISSN:  1520-7560     ISO Abbreviation:  Diabetes Metab. Res. Rev.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-06     Completed Date:  2013-04-30     Revised Date:  2014-02-24    
Medline Journal Info:
Nlm Unique ID:  100883450     Medline TA:  Diabetes Metab Res Rev     Country:  England    
Other Details:
Languages:  eng     Pagination:  645-53     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 John Wiley & Sons, Ltd.
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MeSH Terms
Calcium / metabolism
Cell Cycle Proteins / biosynthesis*
Cell Line
Cell Proliferation / drug effects
Genes, Tumor Suppressor
Glucose / pharmacology
Insulin / biosynthesis,  metabolism,  secretion*
Insulin-Secreting Cells / drug effects,  metabolism*
Mice, Transgenic
Proinsulin / biosynthesis
Transcription Factors / biosynthesis*
Grant Support
081958/2/07/Z//Wellcome Trust; 098424//Wellcome Trust; G0401641//Medical Research Council
Reg. No./Substance:
0/Cell Cycle Proteins; 0/Insulin; 0/Plagl1 protein, mouse; 0/Transcription Factors; 9035-68-1/Proinsulin; IY9XDZ35W2/Glucose; SY7Q814VUP/Calcium

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

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