Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 286, Issue 29, Pages 25778-25789Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M111.246082
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Funding
- Wellcome Trust [081958/Z/07/Z]
- Servier IdS
- Royal Society
- MRC [G0401641] Funding Source: UKRI
- Wellcome Trust [081958/Z/07/Z] Funding Source: Wellcome Trust
- Medical Research Council [G0401641] Funding Source: researchfish
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Zn2+ is an important cofactor for insulin biosynthesis and storage in pancreatic beta-cells. Correspondingly, polymorphisms in the SLC30A8 gene, encoding the secretory granule Zn2+ transporter ZnT8, are associated with type 2 diabetes risk. Using a genetically engineered (FRET)-based sensor (eCALWY-4), we show here that elevated glucose time-dependently increases free cytosolic Zn2+ ([Zn2+](cyt)) in mouse pancreatic beta-cells. These changes become highly significant (853 +/- 96 pM versus 452 +/- 42 pM, p < 0.001) after 24 h and are associated with increased expression of the Zn2+ importer family members Slc39a6, Slc39a7, and Slc39a8, and decreased expression of metallothionein 1 and 2. Arguing that altered expression of the above genes is not due to altered [Zn2+] cyt, elevation of extracellular (and intracellular) [Zn2+] failed to mimic the effects of high glucose. By contrast, increases in intracellular cAMP prompted by 3-isobutyl-1-methylxanthine and forskolin partially mimicked the effects of glucose on metallothionein, although not ZiP, gene expression. Modulation of intracellular Ca2+ and insulin secretion with pharmacological agents (tolbutamide and diazoxide) suggested a possible role for changes in these parameters in the regulation of Slc39a6 and Slc39a7 but not Slc39a8, nor metallothionein expression. In summary, 1) glucose induces increases in [Zn2+] cyt, which are then likely to facilitate the processing and/or the storage of insulin and its cocrystallization with Zn2+, and 2) these increases are associated with elevated expression of zinc importers. Conversely, a chronic increase in [Zn2+] cyt following sustained hyperglycemia may contribute to beta-cell dysfunction and death in some forms of diabetes.
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