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- Title
Insulin Storage and Glucose Homeostasis in Mice Null for the Granule Zinc Transporter ZnT8 and Studies of the Type 2 Diabetes-Associated Variants.
- Authors
Nicolson, Tamara J.; Bellomo, Elisa A.; Wijesekara, Nadeeja; Loder, Merewyn K.; Baldwin, Jocelyn M.; Gyulkhandanyan, Armen V.; Koshkin, Vasilij; Tarasov, Andrei I.; Carzaniga, Raffaella; Kronenberger, Katrin; Taneja, Tarvinder K.; da Silva Xavier, Gabriela; Libert, Sarah; Froguel, Philippe; Scharfmann, Raphael; Stetsyuk, Volodymir; Ravassard, Philippe; Parker, Helen; Gribble, Fiona M.; Reimann, Frank
- 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[sup 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. Diabetes 58:2070-2083, 2009
- Subjects
ZINC in the body; INSULIN; GLUCOSE; CARBOHYDRATE metabolism; BIOLOGICAL transport; INSULIN resistance; TYPE 2 diabetes; LABORATORY mice
- Publication
Diabetes, 2009, Vol 58, Issue 9, p2070
- ISSN
0012-1797
- Publication type
Article
- DOI
10.2337/db09-0551