UC Davis

Zinc transporter 8 (ZNT8) transports zinc from the cytoplasm into the secretory vesicle for insulin crystallization and storage in pancreatic beta-cells. Individuals with ZNT8 allelic insufficiency have reduced risk of type 2 diabetes. However, the underlying mechanism of this protective effect is not well understood. ZNT1-10 in pancreatic islets and in β-cell lines derived from human and mice were examined using immunohistochemistry and immunofluorescence microscopic analysis. The data suggests that there are functional conservations of the ZNT proteins between humans and mice and mouse models of zinc transporters can be used for studying mechanisms of zinc-associated risks of T2D in humans. When fed a high-fat diet (45% kcal fat) for 17 weeks, male Znt8+/- mice had an improved glucose tolerance compared to the wild type mice during glucose challenge. Importantly, the total glucagon secretion assessed by the area under the curve during glucose challenge was significantly lower (~40%) in male Znt8+/- mice than the control mice. Furthermore, quantitative RT-PCR results suggested that Znt8 mRNA expression was strongly and positively correlated with the expression of glucagon (R2=0.75, p=2.43*10-4) and Sst (R2=0.8788, p=6.78*10-6) in pancreatic islets. Most importantly, ZNT8 was found to colocalize with somatostatin in the mouse pylorus mucosa, but not with ghrelin, GIP, GLP1, and CCK. Znt8 heterozygotes may be protected from high-fat-induced glucose intolerance or type 2 diabetes due to enhanced suppression of glucagon levels leading to better glycemic control. Colocalized expression of ZNT8 and somatostatin suggest a role of ZNT8 in regulating SST production and secretion, which may have an indirect impact on the rate of digestion and absorption of foods in the gut as well as the secretions of pancreatic hormones after meals. These findings would provide new research targets to uncover the role of ZNT8 in T2D development.