hZnT8 (Slc30a8) Transgenic Mice That Overexpress the R325W Polymorph Have Reduced Islet Zn2+ and Proinsulin Levels, Increased Glucose Tolerance After a High-Fat Diet, and Altered Levels of Pancreatic Zinc Binding Proteins.

Zinc (Zn) is involved in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The wild-type (WT) form of the β-cell-specific Zn transporter, ZNT8, is linked to T2DM susceptibility. ZnT8 null mice have a mild phenotype with a slight decrease in glucose tolerance, whereas patients with the ZnT8 R325W polymorphism (rs13266634) have decreased proinsulin staining and susceptibility to T2DM. We measured Zn, insulin, and proinsulin stainings and performed intraperitoneal glucose tolerance testing in transgenic mice overexpressing hZnT8 WT or hZnT8 R325W fed a normal or high-fat diet. The hZnT8 R325W transgenic line had lower pancreatic [Zn] and proinsulin and higher insulin and glucose tolerance compared with control littermates after 10 weeks of a high-fat diet in male mice. The converse was true for the hZnT8 WT transgenic line, and dietary Zn supplementation also induced glucose intolerance. Finally, pancreatic zinc binding proteins were identified by Zn-affinity chromatography and proteomics. Increasing pancreatic Zn (hZnT8WT) induced nucleoside diphosphate kinase B, and Zn reduction (hZnT8RW) induced carboxypeptidase A1. These data suggest that pancreatic Zn and proinsulin levels covary but are inversely variant with insulin or glucose tolerance in the HFD model of T2DM suggesting novel therapeutic targets.