title: 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.
abstract: Zinc (Zn2+) is involved in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The wild-type (WT) form of the β-cell-specific Zn2+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 Zn2+, 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 [Zn2+]iand 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 Zn2+supplementation also induced glucose intolerance. Finally, pancreatic zinc binding proteins were identified by Zn2+-affinity chromatography and proteomics. Increasing pancreatic Zn2+(hZnT8WT) induced nucleoside diphosphate kinase B, and Zn2+reduction (hZnT8RW) induced carboxypeptidase A1. These data suggest that pancreatic Zn2+and proinsulin levels covary but are inversely variant with insulin or glucose tolerance in the HFD model of T2DM suggesting novel therapeutic targets.
authors.affiliation: Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA.
authors.forename: Shi
authors.initials: S
authors.lastname: Bai
authors.affiliation: Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA christian.sheline@stonybrookmedicine.edu.|Department of Neurology, Stony Brook University Hospital, Stony Brook, NY.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Sheline
mesh_terms: D000818:Animals; D043422:Carboxypeptidases A / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics*; D059305:Diet, High-Fat; D019587:Dietary Supplements; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D054778:NM23 Nucleoside Diphosphate Kinases / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011384:Proinsulin / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology; D000075703:Zinc Transporter 8
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D054778:NM23 Nucleoside Diphosphate Kinases; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D011384:Proinsulin; C517941:Nme2 protein, mouse; D043422:Carboxypeptidases A; D015032:Zinc