Molecular genetic regulation of Slc30a8/ZnT8 reveals a positive association with glucose tolerance

Ryan K. Mitchell, Ming Hu, Pauline L. Chabosseau, Matthew C. Cane, Gargi Meur, Elisa A. Bellomo, Raffaella Carzaniga, Lucy M. Collinson, Wen Hong Li, David J. Hodson, Guy A. Rutter

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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 nonsynony-mous 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 β-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 β-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 β-cell ZnT8 activity increases, and remarkably, these changes track Zn2+ rather than insulin release in vitro. Activation of ZnT8 in β-cells might therefore provide the basis of a novel approach to treating T2D.

Original languageEnglish (US)
Pages (from-to)77-91
Number of pages15
JournalMolecular Endocrinology
Volume30
Issue number1
DOIs
StatePublished - Jan 1 2016

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Molecular Biology
Glucose
Insulin
Type 2 Diabetes Mellitus
Islets of Langerhans
Homeostasis
Secretory Vesicles
Transgenic Mice
zinc-binding protein
Zinc
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

Mitchell, R. K., Hu, M., Chabosseau, P. L., Cane, M. C., Meur, G., Bellomo, E. A., ... Rutter, G. A. (2016). Molecular genetic regulation of Slc30a8/ZnT8 reveals a positive association with glucose tolerance. Molecular Endocrinology, 30(1), 77-91. https://doi.org/10.1210/me.2015-1227

Molecular genetic regulation of Slc30a8/ZnT8 reveals a positive association with glucose tolerance. / Mitchell, Ryan K.; Hu, Ming; Chabosseau, Pauline L.; Cane, Matthew C.; Meur, Gargi; Bellomo, Elisa A.; Carzaniga, Raffaella; Collinson, Lucy M.; Li, Wen Hong; Hodson, David J.; Rutter, Guy A.

In: Molecular Endocrinology, Vol. 30, No. 1, 01.01.2016, p. 77-91.

Research output: Contribution to journalArticle

Mitchell, RK, Hu, M, Chabosseau, PL, Cane, MC, Meur, G, Bellomo, EA, Carzaniga, R, Collinson, LM, Li, WH, Hodson, DJ & Rutter, GA 2016, 'Molecular genetic regulation of Slc30a8/ZnT8 reveals a positive association with glucose tolerance', Molecular Endocrinology, vol. 30, no. 1, pp. 77-91. https://doi.org/10.1210/me.2015-1227
Mitchell, Ryan K. ; Hu, Ming ; Chabosseau, Pauline L. ; Cane, Matthew C. ; Meur, Gargi ; Bellomo, Elisa A. ; Carzaniga, Raffaella ; Collinson, Lucy M. ; Li, Wen Hong ; Hodson, David J. ; Rutter, Guy A. / Molecular genetic regulation of Slc30a8/ZnT8 reveals a positive association with glucose tolerance. In: Molecular Endocrinology. 2016 ; Vol. 30, No. 1. pp. 77-91.
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