University of Hertfordshire

From the same journal

By the same authors

  • Tamara J Nicolson
  • Elisa A Bellomo
  • Nadeeja Wijesekara
  • Merewyn K Loder
  • Jocelyn M Baldwin
  • Armen V Gyulkhandanyan
  • Vasilij Koshkin
  • Raffaella Carzaniga
  • Katrin Kronenberger
  • Tarvinder K Taneja
  • Gabriela da Silva Xavier
  • Sarah Libert
  • Philippe Froguel
  • Raphael Scharfmann
  • Volodymir Stetsyuk
  • Philippe Ravassard
  • Helen Parker
  • Fiona M Gribble
  • Frank Reimann
  • Robert Sladek
  • Stephen J Hughes
  • Paul R V Johnson
  • Myriam Masseboeuf
  • Remy Burcelin
  • Stephen A Baldwin
  • Ming Liu
  • Roberto Lara-Lemus
  • Peter Arvan
  • Frans C Schuit
  • Michael B Wheeler
  • Fabrice Chimienti
  • Guy A Rutter
View graph of relations
Original languageEnglish
Pages (from-to)2070-83
Number of pages14
JournalDiabetes
Volume58
Issue9
DOIs
Publication statusPublished - Sep 2009

Abstract

OBJECTIVE: Zinc ions are essential for the formation of hexameric insulin and hormone crystallization. A nonsynonymous single nucleotide polymorphism rs13266634 in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8, is associated with type 2 diabetes. We describe the effects of deleting the ZnT8 gene in mice and explore the action of the at-risk allele.

RESEARCH DESIGN AND METHODS: Slc30a8 null mice were generated and backcrossed at least twice onto a C57BL/6J background. Glucose and insulin tolerance were measured by intraperitoneal injection or euglycemic clamp, respectively. Insulin secretion, electrophysiology, imaging, and the generation of adenoviruses encoding the low- (W325) or elevated- (R325) risk ZnT8 alleles were undertaken using standard protocols.

RESULTS: ZnT8(-/-) mice displayed age-, sex-, and diet-dependent abnormalities in glucose tolerance, insulin secretion, and body weight. Islets isolated from null mice had reduced granule zinc content and showed age-dependent changes in granule morphology, with markedly fewer dense cores but more rod-like crystals. Glucose-stimulated insulin secretion, granule fusion, and insulin crystal dissolution, assessed by total internal reflection fluorescence microscopy, were unchanged or enhanced in ZnT8(-/-) islets. Insulin processing was normal. Molecular modeling revealed that residue-325 was located at the interface between ZnT8 monomers. Correspondingly, the R325 variant displayed lower apparent Zn(2+) transport activity than W325 ZnT8 by fluorescence-based assay.

CONCLUSIONS: ZnT8 is required for normal insulin crystallization and insulin release in vivo but not, remarkably, in vitro. Defects in the former processes in carriers of the R allele may increase type 2 diabetes risks.

ID: 15267600