Abstract
BackgroundThe human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is chiefly restricted to the endocrine pancreas. Single nucleotide polymorphisms (SNPs) in the human SLC30A8 gene have been associated, through genome-wide studies, with altered type 2 diabetes risk. In addition to a role in the control of insulin release, recent studies involving targeted gene ablation from the pancreatic α cell (Solomou et al., J Biol Chem 290(35):21432-42) have also implicated ZnT8 in the control of glucagon release. Up to now, however, the possibility that increased levels of the transporter in these cells may impact glucagon secretion has not been explored.MethodsHere, we use a recently-developed reverse tetracyline transactivator promoter-regulated ZnT8 transgene to drive the over-expression of human ZnT8 selectively in the α cell in adult mice. Glucose homeostasis and glucagon secretion were subsequently assessed both in vivo during hypoglycemic clamps and from isolated islets in vitro.ResultsDoxyclin-dependent human ZnT8 mRNA expression was apparent in both isolated islets and in fluorescence-activated cell sorting- (FACS) purified α cells. Examined at 12 weeks of age, intraperitoneal glucose (1 g/kg) tolerance was unchanged in transgenic mice versus wild-type littermates (n = 8-10 mice/genotype, p > 0.05) and sensitivity to intraperitoneal insulin (0.75U/kg) was similarly unaltered in transgenic animals. In contrast, under hyperinsulinemic-hypoglycemic clamp, a ~45 % (p < 0.001) reduction in glucose infusion rate was apparent, and glucagon release was significantly (~40 %, p < 0.01) impaired, in transgenic mice. Correspondingly, examined in vitro, glucagon secretion was significantly reduced (~30 %, p < 0.05) from transgenic versus control islets at low, stimulatory glucose concentrations (1 mM, p < 0.05) but not at high glucose (17 mM) glucose (p > 0.05). Over-expression of ZnT8 in glucagonoma-derived αTC1-9 cells increased granule free Zn2+ concentrations consistent with a role for Zn2+ in this compartment in the action of ZnT8 on glucagon secretion.ConclusionsIncreased ZnT8 expression, and a likely increase in intragranular free Zn2+ concentration, is deleterious in pancreatic α cells for stimulated glucagon release. These data provide further evidence that type 2 diabetes-associated polymorphisms in the SLC30A8/ZnT8 gene may act in part via alterations in glucagon release and suggest that ZnT8 activation may restrict glucagon release in some settings.
Highlights
The human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is restricted to the endocrine pancreas
In the case of the endocrine pancreas-restricted secretory granule zinc transporter SLC30A8/ZnT8, identified in genome-wide association (GWA) studies for Type 2 diabetes mellitus (T2D) [6], this approach has been pivotal in highlighting the role of the transporter in the control of secretory granule formation and Zn2+ storage [7, 8] insulin secretion [9] and hepatic clearance of the hormone [10]
In contrast to the recently described effect of α cell-selective deletion of ZnT8 to enhance glucagon secretion at low glucose [17], we demonstrate that ZnT8 over-expression results in the suppression of glucagon release during hypoglycaemia, enhancing glucose clearance
Summary
The human SLC30A8 gene encodes the secretory granule-localised zinc transporter ZnT8 whose expression is restricted to the endocrine pancreas. Genome-wide association (GWA) and other studies have in recent years identified multiple loci as affecting the risk T2D [2, 3], functional work in model systems remains important if we are fully to understand the physiological role(s), and potential as pharmacotherapeutic targets, of the implicated genes. Most such studies up to now have used gene deletion in mice, inactivating candidates either globally or in disease-relevant tissues [4, 5]. We have recently shown, by α cellselective deletion of ZnT8 in mice [17], an important role for this transporter in the control of glucagon secretion
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