title: Molecular Genetic Regulation of Slc30a8/ZnT8 Reveals a Positive Association With Glucose Tolerance.
abstract: Zinc transporter 8 (ZnT8), encoded by SLC30A8, is chiefly expressed within pancreatic islet cells, where it mediates zinc (Zn(2+)) 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 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, Zn(2+) 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 Zn(2+) 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 Zn(2+) rather than insulin release in vitro. Activation of ZnT8 in β-cells might therefore provide the basis of a novel approach to treating T2D.
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Mitchell
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Ming
authors.initials: M
authors.lastname: Hu
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Pauline L
authors.initials: PL
authors.lastname: Chabosseau
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cane
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Gargi
authors.initials: G
authors.lastname: Meur
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Bellomo
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Carzaniga
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Collinson
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Wen-Hong
authors.initials: WH
authors.lastname: Li
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: Section of Cell Biology and Functional Genomics (R.K.M., M.H., P.L.C., M.C.C., G.M., E.A.B., D.J.H., G.A.R.), Division of Diabetes, Endocrinology and Metabolism, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0NN, United Kingdom; Electron Microscopy Unit (R.C., L.M.C.), Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, United Kingdom; and Department of Cell Biology and Biochemistry (W.-H.L.), The University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D022142:Secretory Vesicles / Q000378:metabolism; D000075703:Zinc Transporter 8
chemical_list: D027682:Cation Transport Proteins; D007328:Insulin; C516348:Slc30a8 protein, mouse; D000075703:Zinc Transporter 8