title: Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion.
abstract: The Slc30a8 gene encodes the islet-specific zinc transporter ZnT-8, which provides zinc for insulin-hexamer formation. Polymorphic variants in amino acid residue 325 of human ZnT-8 are associated with altered susceptibility to Type 2 diabetes and ZnT-8 autoantibody epitope specificity changes in Type 1 diabetes. To assess the physiological importance of ZnT-8, mice carrying a Slc30a8 exon 3 deletion were analysed histologically and phenotyped for energy metabolism and pancreatic hormone secretion. No gross anatomical or behavioural changes or differences in body weight were observed between wild-type and ZnT-8-/- mice, and ZnT-8-/- mouse islets were indistinguishable from wild-type in terms of their numbers, size and cellular composition. However, total zinc content was markedly reduced in ZnT-8-/- mouse islets, as evaluated both by Timm's histochemical staining of pancreatic sections and direct measurements in isolated islets. Blood glucose levels were unchanged in 16-week-old, 6 h fasted animals of either gender; however, plasma insulin concentrations were reduced in both female (approximately 31%) and male (approximately 47%) ZnT-8-/- mice. Intraperitoneal glucose tolerance tests demonstrated no impairment in glucose clearance in male ZnT-8-/- mice, but glucose-stimulated insulin secretion from isolated islets was reduced approximately 33% relative to wild-type littermates. In summary, Slc30a8 gene deletion is accompanied by a modest impairment in insulin secretion without major alterations in glucose metabolism.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, TN 37232, USA.
authors.forename: Lynley D
authors.initials: LD
authors.lastname: Pound
authors.forename: Suparna A
authors.initials: SA
authors.lastname: Sarkar
authors.forename: Richard K P
authors.initials: RK
authors.lastname: Benninger
authors.forename: Yingda
authors.initials: Y
authors.lastname: Wang
authors.forename: Adisak
authors.initials: A
authors.lastname: Suwanichkul
authors.forename: Melanie K
authors.initials: MK
authors.lastname: Shadoan
authors.forename: Richard L
authors.initials: RL
authors.lastname: Printz
authors.forename: James K
authors.initials: JK
authors.lastname: Oeser
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Lee
authors.forename: David W
authors.initials: DW
authors.lastname: Piston
authors.forename: Owen P
authors.initials: OP
authors.lastname: McGuinness
authors.forename: John C
authors.initials: JC
authors.lastname: Hutton
authors.forename: David R
authors.initials: DR
authors.lastname: Powell
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D001786:Blood Glucose; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017384:Sequence Deletion; D015032:Zinc / Q000378:metabolism; D000075703:Zinc Transporter 8
chemical_list: D001786:Blood Glucose; D027682:Cation Transport Proteins; D007328:Insulin; C516348:Slc30a8 protein, mouse; D000075703:Zinc Transporter 8; D015032:Zinc