Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion

Lynley D. Pound, Suparna A. Sarkar, Richard K.P. Benninger, Yingda Wang, Adisak Suwanichkul, Melanie K. Shadoan, Richard L. Printz, James K. Oeser, Catherine E. Lee, David W. Piston, Owen P. McGuinness, John C. Hutton, David R. Powell, Richard M. O'Brien

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128 Scopus citations

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 contentwas 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 (∼31%) and male (∼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 ∼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.

Original languageEnglish
Pages (from-to)371-376
Number of pages6
JournalBiochemical Journal
Volume421
Issue number3
DOIs
StatePublished - Aug 1 2009
Externally publishedYes

Keywords

  • Autoantigen
  • Glucose
  • Insulin
  • Islet
  • Mouse
  • Zinc transporter

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    Pound, L. D., Sarkar, S. A., Benninger, R. K. P., Wang, Y., Suwanichkul, A., Shadoan, M. K., Printz, R. L., Oeser, J. K., Lee, C. E., Piston, D. W., McGuinness, O. P., Hutton, J. C., Powell, D. R., & O'Brien, R. M. (2009). Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochemical Journal, 421(3), 371-376. https://doi.org/10.1042/BJ20090530