期刊
MOLECULAR ENDOCRINOLOGY
卷 30, 期 1, 页码 77-91出版社
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2015-1227
关键词
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资金
- Wellcome Trust [081958/Z/07/Z, WT098424AIA]
- Medical Research Council Programme [MR/J0003042/1]
- European Foundation for the Study of Diabetes
- Diabetes UK [BDA 11/0004210]
- Royal Society Wolfson Research Merit Award
- Diabetes UK R.D. Lawrence Grant [12/0004431]
- European Foundation for the Study of Diabetes/Novo Nordisk Rising Star Fellowships
- Medical Research Council Project Grant [MR/N00275X/1]
- NIH [R01 GM077593]
- Cancer Research UK
- MRC
- Biotechnology and Biological Sciences Research Council
- Engineering and Physical Sciences Research Council [MR/K01580X/1]
- Innovative Medicines Initiative Joint Undertaking Grant [155005]
- European Union
- European Federation of Pharmaceutical Industries and Associations companies'
- MRC [MR/K001981/1, MR/N00275X/1] Funding Source: UKRI
- Diabetes UK [12/0004431] Funding Source: researchfish
- Medical Research Council [MR/K001981/1, MR/N00275X/1] Funding Source: researchfish
- The Francis Crick Institute [10004] Funding Source: researchfish
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM077593] Funding Source: NIH RePORTER
Zinc transporter 8 (ZnT8), encoded by SLC30A8, is chiefly expressed within pancreatic islet cells, where it mediates zinc (Zn2+) uptake into secretory granules. Although a common nonsynonymous polymorphism (R325W), which lowers activity, is associated with increased type 2 diabetes (T2D) risk, rare inactivating mutations in SLC30A8 have been reported to protect against T2D. Here, we generate and characterize new mouse models to explore the impact on glucose homeostasis of graded changes in ZnT8 activity in the beta-cell. Firstly, Slc30a8 was deleted highly selectively in these cells using the novel deleter strain, Ins1Cre. The resultant Ins1CreZnT8KO mice displayed significant (P < .05) impairments in glucose tolerance at 10 weeks of age vs littermate controls, and glucose-induced increases in circulating insulin were inhibited in vivo. Although insulin release from Ins1CreZnT8KO islets was normal, Zn2+ release was severely impaired. Conversely, transgenic ZnT8Tg mice, overexpressing the transporter inducibly in the adult beta-cell using an insulin promoter-dependent Tet-On system, showed significant (P < .01) improvements in glucose tolerance compared with control animals. Glucose-induced insulin secretion from ZnT8Tg islets was severely impaired, whereas Zn2+ release was significantly enhanced. Our findings demonstrate that glucose homeostasis in the mouse improves as beta-cell ZnT8 activity increases, and remarkably, these changes track Zn2+ rather than insulin release in vitro. Activation of ZnT8 in beta-cells might therefore provide the basis of a novel approach to treating T2D.
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