Journal
DIABETES
Volume 58, Issue 9, Pages 2070-2083Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db09-0551
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Funding
- Wellcome Trust [081958/Z/07/Z]
- Medical Research Council [G0401641]
- National Institutes of Health [ROI DK-071962-01]
- European Union FP6
- Imperial College
- Biotechnology and Biological Sciences Research Council [BBS/B/14418]
- University of Leeds
- Gene Ontology Annotation [2004/11]
- European Community [LSHM-CT-2006-518153]
- Juvenile Diabetes Research Fund [1-2006-182]
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- Association Fran se des Diabetiques (AFD)
- Canadian Institutes of Health Research (CIHR) [MOP-49521]
- Biotechnology and Biological Sciences Research Council [BBS/B/14418] Funding Source: researchfish
- Medical Research Council [G0401641, G0700342, G0600717B, G0600331] Funding Source: researchfish
- MRC [G0401641, G0700342, G0600331] Funding Source: UKRI
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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 Zn2+ 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
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