Down-regulation of zinc transporter 8 in the pancreas of db/db mice is rescued by Exendin-4 administration.

Recent human genetic studies have revealed that common variants of the zinc transporter 8 (ZnT-8) gene are strongly associated with type 2 diabetes mellitus (T2DM). ZnT-8 has been suggested as a potential candidate in the regulation of insulin secretion in pancreatic β-cells. In this study, we aimed to explore the expression of ZnT-8 in the development of T2DM. The expression of ZnT-8 was investigated in the pancreas and adipose tissue of homozygous db/db mice compared to heterozygous sibling db/+ mice (n=6-8). Furthermore, the effect of Exendin-4 (an analogue of glucagon-like peptide-1) on ZnT-8 expression was examined in the db/db mice. Exendin-4 or vehicle (control) was administered (i.p., 1 nmol/kg) to diabetic 8-week-old db/db mice daily for 14 days (n=8). The results revealed that ZnT-8 protein levels in the pancreas of db/db mice were reduced, accompanied by a decrease in ZnT-8 mRNA. ZnT-8 mRNA and protein levels were also significantly reduced in the epididymal and visceral fat of the db/db mice. Treatment with Exendin-4 up-regulated ZnT-8 gene expression in the pancreas of the db/db mice, but did not affect its expression in adipose tissue. These findings suggest that ZnT-8 synthesis in the pancreas and adipose tissue is down-regulated in db/db mice. Reduced ZnT-8 production in the pancreas may advance defects in insulin secretion in diabetes. These may be reversed, at least partially, by the administration of Exendin-4.