Role of the type II diabetes-associated gene SLC30A8 in the pancreatic α-cell

• Main Author: Solomou, Antonia
• Other Authors: Rutter, Guy
• Published: Imperial College London 2015
• Subjects: 616.4
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.686313

The SLC30A8 locus encodes the Zn2+ transporter ZnT8, whose expression is largely restricted to α- and β-cells, endocrine cells of the pancreatic islet. Genome-wide association studies have revealed > 90 loci associated with Type 2 diabetes. The first such study identified a specific single nucleotide polymorphism that results in an amino acid substitution and a transporter with reduced activity. This risk variant is associated with increased Type 2 diabetes risk. More recently, rare loss-of-function variants were found to be protective. Here, we aimed to investigate the role of SLC30A8/ZnT8 in the regulation of glucagon secretion. ZnT8 was selectively deleted in the α-cell by crossing mice bearing floxed alleles at exon 1 with mice carrying a Cre recombinase transgene under the control of the preproglucagon promoter. Additionally, these mice were crossed to Rosa26 RFP mice for identification of α-cells. Fluorescence-activated sorting of RFP+ cells revealed that recombination at the RFP locus occurred in ~30% of α-cells. ZnT8 was deleted in ~50% of these labelled cells achieving a total of ~15% deletion in the whole α-cell population. Glucose tolerance and insulin sensitivity were normal, though during hypoglycaemic clamps female KO mice required lower glucose infusion rates and had enhanced glucagon secretion compared to control mice. Similarly, isolated islets from KO mice released significantly more glucagon at 1mM glucose. In addition, inducible overexpression of ZnT8 led to a reciprocal decrease of glucagon secretion from isolated islets at 1mM glucose. Hypoglycaemic clamps confirmed the finding of lowered glucagon release following ZnT8 overexpression. Cytosolic Ca2+ responses to low glucose were comparable in WT and KO cells. Both cytoplasmic and granular free Zn2+ levels were significantly reduced in the KO α-cells compared to control cells yet there were no changes in the gene expression levels of other ZnT famlily members. Thus it appears that ZnT8 is important in the α-cell for appropriate responses to hypoglycaemia and Zn2+ homeostasis.