title: Overexpression of ZAC impairs glucose-stimulated insulin translation and secretion in clonal pancreatic beta-cells.
abstract: 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.
authors.affiliation: Division of Pediatric Endocrinology, McGill University Health Center Research Institute (Children's Hospital), Montreal, QC, Canada.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Du
authors.forename: Houria
authors.initials: H
authors.lastname: Ounissi-Benkalha
authors.forename: Merewyn K
authors.initials: MK
authors.lastname: Loder
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
authors.forename: Constantin
authors.initials: C
authors.lastname: Polychronakos
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011384:Proinsulin / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis*
chemical_list: D018797:Cell Cycle Proteins; D007328:Insulin; C498423:Plagl1 protein, mouse; D014157:Transcription Factors; D011384:Proinsulin; D005947:Glucose; D002118:Calcium