Abstract
Zinc (Zn(2+)) is involved in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The wild-type (WT) form of the β-cell-specific Zn(2+) 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(2+), 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(2+)](i) 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(2+) supplementation also induced glucose intolerance. Finally, pancreatic zinc binding proteins were identified by Zn(2+)-affinity chromatography and proteomics. Increasing pancreatic Zn(2+) (hZnT8WT) induced nucleoside diphosphate kinase B, and Zn(2+) reduction (hZnT8RW) induced carboxypeptidase A1. These data suggest that pancreatic Zn(2+) and proinsulin levels covary but are inversely variant with insulin or glucose tolerance in the HFD model of T2DM suggesting novel therapeutic targets.