Zinc transporter 8 (ZnT8) and β cell function

Abstract

Human pancreatic β cells have exceptionally high zinc content. In β cells the highest zinc concentration is in insulin secretory granules, from which it is cosecreted with the hormone. Uptake of zinc into secretory granules is mainly mediated by zinc transporter 8 (ZnT8), the product of the SLC30A8 [solute carrier family 30 (zinc transporter), member 8] gene. The minor alleles of several single-nucleotide polymorphisms (SNPs) in SLC30A8 are associated with decreased risk of type 2 diabetes (T2D), but the precise mechanisms underlying the protective effects remain uncertain. In this article we review current knowledge of the role of ZnT8 in maintaining zinc homeostasis in β cells, its role in glucose metabolism based on knockout mouse studies, and current theories regarding the link between ZnT8 function and T2D.

Keywords: SLC30A8; Slc30a8; islet.

Figure I for BOX 1. Schematic representation of human ZnT8 transcripts and proteins

A. Exons comprising the 5′ UTR and initiator methionine of the 5 NCBI RefSeq transcripts are shown. Coding exons are shown in green and the 30bp exon 6 that contains 2 in-frame stop codons in red, or pink in the case of transcript 3 that lacks the start site in exon 5 and could give rise to a truncated product from a downstream in frame ATG in exon 7. Exons 2 and 5 contain multiple splice acceptor sites. All transcripts contain exons 8–13. The ZnT8 isoform potentially encoded by each transcript is shown. It should be noted that most studies of the expression of SLC30A8 mRNA in non-β cell tissues use primer pairs that will not distinguish the various transcripts. B. The domain structure of the two isoforms are shown. The light blue shapes indicate domains implicated in Zn2+ binding, and the bracket the approximate location of the polymorphic residue 325.

Figure 1. Hypothetical unified model to reconcile rare and common SLC30A8 genetic data

The best characterized pathway for GSIS is shown, though other pathways clearly contribute [100]. We speculate that the minor rs13266634 allele encoding the 325 Trp ZnT8 variant and rare mutations leading to haploinsufficiency are protective against T2D due by prolonging the transient increase in cytoplasmic zinc levels that occur during GSIS thereby reducing the deleterious effects of ROS. In Panel A we speculate that the minor rs13266634 allele encoding the 325 Trp ZnT8 variant enhances cytoplasmic zinc levels mainly through increased re-uptake of co-secreted Zn2+ at the plasma membrane. In Panel B we speculate that rare mutations leading to haploinsufficiency enhance cytoplasmic Zn2+ levels mainly through a reduced rate of uptake into ISGs and that SLC39 family members can compensate for the slight decrease in ZnT8 mediated uptake at the plasma membrane.