Potential positive and negative consequences of ZnT8 inhibition

in Journal of Endocrinology
Authors:
Kristen E Syring Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine

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Karin J Bosma Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine

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Slavina B Goleva Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

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Kritika Singh Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

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James K Oeser Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine

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Christopher A Lopez Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

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Eric P Skaar Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

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Owen P McGuinness Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine

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Lea K Davis Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine
Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee

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David R Powell Lexicon Pharmaceuticals Incorporated, 8800 Technology Forest Place, The Woodlands, Texas

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Richard M O’Brien Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine

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https://orcid.org/0000-0003-2153-9761

Correspondence should be addressed to R M O’Brien; richard.obrien@vanderbilt.edu

*(K E Syring and K J Bosma contributed equally)

DOI:
https://doi.org/10.1530/JOE-20-0138
Volume/Issue:
Volume 246: Issue 2
Article Type:
Research Article
Page Range:
189–205
Online Publication Date:
Aug 2020
Copyright:
© 2020 Society for Endocrinology 2020
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SLC30A8 encodes the zinc transporter ZnT8. SLC30A8 haploinsufficiency protects against type 2 diabetes (T2D), suggesting that ZnT8 inhibitors may prevent T2D. We show here that, while adult chow fed Slc30a8 haploinsufficient and knockout (KO) mice have normal glucose tolerance, they are protected against diet-induced obesity (DIO), resulting in improved glucose tolerance. We hypothesize that this protection against DIO may represent one mechanism whereby SLC30A8 haploinsufficiency protects against T2D in humans and that, while SLC30A8 is predominantly expressed in pancreatic islet beta cells, this may involve a role for ZnT8 in extra-pancreatic tissues. Consistent with this latter concept we show in humans, using electronic health record-derived phenotype analyses, that the ‘C’ allele of the non-synonymous rs13266634 SNP, which confers a gain of ZnT8 function, is associated not only with increased T2D risk and blood glucose, but also with increased risk for hemolytic anemia and decreased mean corpuscular hemoglobin (MCH). In Slc30a8 KO mice, MCH was unchanged but reticulocytes, platelets and lymphocytes were elevated. Both young and adult Slc30a8 KO mice exhibit a delayed rise in insulin after glucose injection, but only the former exhibit increased basal insulin clearance and impaired glucose tolerance. Young Slc30a8 KO mice also exhibit elevated pancreatic G6pc2 gene expression, potentially mediated by decreased islet zinc levels. These data indicate that the absence of ZnT8 results in a transient impairment in some aspects of metabolism during development. These observations in humans and mice suggest the potential for negative effects associated with T2D prevention using ZnT8 inhibitors.

Supplementary Materials

    • Supplemental Material
    • Supplemental Figure 1. Analysis of Slc30a8 Expression, Fasting Blood Glucose plus Plasma Insulin and Glucose Tolerance in Adult Male Beta Cell-Specific Slc30a8 Heterozygous and KO Mice in vivo.
    • Supplemental Figure 2. Comparison of Individual Diabetes Disease Phenotype Assignments within BioVU Electronic Health Records (EHRs).
    • Supplemental Figure 3. Comparison of the Effects of ZnT8 Overexpression on Zinc- and Calcium-Regulated Fusion Gene Expression in the TC-3 Cell Line.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
17
Article Type:
Research Article
Received Date:
04 May 2020
Accepted Date:
02 Jun 2020
Print Publication Date:
01 Aug 2020
Online Publication Date:
Aug 2020

  • Andrews GK, Kage K, Palmiter-Thomas P & Sarras MP, Jr. 1990 Metal ions induce expression of metallothionein in pancreatic exocrine and endocrine cells. Pancreas 5 548–554. (https://doi.org/10.1097/00006676-199009000-00009)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Boesgaard TW, Zilinskaite J, Vanttinen M, Laakso M, Jansson PA, Hammarstedt A, Smith U, Stefan N, Fritsche A, Haring H, et al. 2008 The common SLC30A8 Arg325Trp variant is associated with reduced first-phase insulin release in 846 non-diabetic offspring of type 2 diabetes patients – the EUGENE2 study. Diabetologia 51 816–820. (https://doi.org/10.1007/s00125-008-0955-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bosma KJ, Syring KE, Oeser JK, Lee JD, Benninger RKP, Pamenter ME & O’Brien RM 2019 Evidence that evolution of the diabetes susceptibility gene SLC30A8 that encodes the zinc transporter ZnT8 drives variations in pancreatic islet zinc content in multiple species. Journal of Molecular Evolution 87 147–151. (https://doi.org/10.1007/s00239-019-09898-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Boustead JN, Martin CC, Oeser JK, Svitek CA, Hunter SI, Hutton JC & O’Brien RM 2004 Identification and characterization of a cDNA and the gene encoding the mouse ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein. Journal of Molecular Endocrinology 32 33–53. (https://doi.org/10.1677/jme.0.0320033)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chausmer AB 1998 Zinc, insulin and diabetes. Journal of the American College of Nutrition 17 109–115. (https://doi.org/10.1080/07315724.1998.10718735)

  • Coulon V, Veyrune JL, Tourkine N, Vie A, Hipskind RA & Blanchard JM 1999 A novel calcium signaling pathway targets the c-fos intragenic transcriptional pausing site. Journal of Biological Chemistry 274 30439–30446. (https://doi.org/10.1074/jbc.274.43.30439)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Davidson HW, Wenzlau JM & O’Brien RM 2014 Zinc transporter 8 (ZnT8) and beta cell function. Trends in Endocrinology and Metabolism 25 415–424. (https://doi.org/10.1016/j.tem.2014.03.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Deniro M & Al-Mohanna FA 2012 Zinc transporter 8 (ZnT8) expression is reduced by ischemic insults: a potential therapeutic target to prevent ischemic retinopathy. PLoS One 7 e50360. (https://doi.org/10.1371/journal.pone.0050360)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Denny JC, Ritchie MD, Basford MA, Pulley JM, Bastarache L, Brown-Gentry K, Wang D, Masys DR, Roden DM & Crawford DC 2010 PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics 26 1205–1210. (https://doi.org/10.1093/bioinformatics/btq126)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Denny JC, Crawford DC, Ritchie MD, Bielinski SJ, Basford MA, Bradford Y, Chai HS, Bastarache L, Zuvich R, Peissig P, et al. 2011 Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies. American Journal of Human Genetics 89 529–542. (https://doi.org/10.1016/j.ajhg.2011.09.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Denny JC, Bastarache L, Ritchie MD, Carroll RJ, Zink R, Mosley JD, Field JR, Pulley JM, Ramirez AH, Bowton E, et al. 2013 Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nature Biotechnology 31 1102–1110. (https://doi.org/10.1038/nbt.2749)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dunn MF 2005 Zinc-ligand interactions modulate assembly and stability of the insulin hexamer – a review. Biometals 18 295–303. (https://doi.org/10.1007/s10534-005-3685-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, et al. 2010 New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics 42 105–116. (https://doi.org/10.1038/ng.520)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dwivedi OP, Lehtovirta M, Hastoy B, Chandra V, Krentz NAJ, Kleiner S, Jain D, Richard AM, Abaitua F, Beer NL, et al. 2019 Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nature Genetics 51 1596–1606. (https://doi.org/10.1038/s41588-019-0513-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Eckel RH, Kahn SE, Ferrannini E, Goldfine AB, Nathan DM, Schwartz MW, Smith RJ & Smith SR 2011 Obesity and type 2 diabetes: what can be unified and what needs to be individualized? Diabetes Care 34 1424–1430. (https://doi.org/10.2337/dc11-0447)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Efrat S, Linde S, Kofod H, Spector D, Delannoy M, Grant S, Hanahan D & Baekkeskov S 1988 Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene. PNAS 85 9037–9041. (https://doi.org/10.1073/pnas.85.23.9037)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fanzo JC, Reaves SK, Cui L, Zhu L, Wu JY, Wang YR & Lei KY 2001 Zinc status affects p53, gadd45, and c-fos expression and caspase-3 activity in human bronchial epithelial cells. American Journal of Physiology: Cell Physiology 281 C751–C757. (https://doi.org/10.1152/ajpcell.2001.281.3.C751)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Figlewicz DP, Forhan SE, Hodgson AT & Grodsky GM 1984 65Zinc and endogenous zinc content and distribution in islets in relationship to insulin content. Endocrinology 115 877–881. (https://doi.org/10.1210/endo-115-3-877)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, et al. 2014 Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nature Genetics 46 357–363. (https://doi.org/10.1038/ng.2915)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Flannick J, Mercader JM, Fuchsberger C, Udler MS, Mahajan A, Wessel J, Teslovich TM, Caulkins L, Koesterer R, Barajas-Olmos F, et al. 2019 Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature 570 71–76. (https://doi.org/10.1038/s41586-019-1231-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Frigeri C, Martin CC, Svitek CA, Oeser JK, Hutton JC, Gannon M & O’Brien RM 2004 The proximal islet-specific glucose-6-phosphatase catalytic subunit related protein (IGRP) autoantigen promoter is sufficient to initiate but not maintain transgene expression in mouse islets in vivo. Diabetes 53 1754–1764. (https://doi.org/10.2337/diabetes.53.7.1754)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fu Y, Tian W, Pratt EB, Dirling LB, Shyng SL, Meshul CK & Cohen DM 2009 Down-regulation of ZnT8 expression in INS-1 rat pancreatic beta cells reduces insulin content and glucose-inducible insulin secretion. PLoS One 4 e5679. (https://doi.org/10.1371/journal.pone.0005679)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Giacconi R, Malavolta M, Chiodi L, Boccoli G, Costarelli L, Bonfigli AR, Galeazzi R, Piacenza F, Basso A, Gasparini N, et al. 2018 ZnT8 Arg325Trp polymorphism influences zinc transporter expression and cytokine production in PBMCs from patients with diabetes. Diabetes Research and Clinical Practice 144 102–110. (https://doi.org/10.1016/j.diabres.2018.08.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hardy AB, Serino AS, Wijesekara N, Chimienti F & Wheeler MB 2011 Regulation of glucagon secretion by zinc: lessons from the beta cell-specific Znt8 knockout mouse model. Diabetes, Obesity and Metabolism 13 (Supplement 1) 112–117. (https://doi.org/10.1111/j.1463-1326.2011.01451.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hardy AB, Wijesekara N, Genkin I, Prentice KJ, Bhattacharjee A, Kong D, Chimienti F & Wheeler MB 2012 Effects of high-fat diet feeding on Znt8-null mice: differences between beta-cell and global knockout of Znt8. American Journal of Physiology: Endocrinology and Metabolism 302 E1084–E1096. (https://doi.org/10.1152/ajpendo.00448.2011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hesse LE, Lonergan ZR, Beavers WN & Skaar EP 2019 The Acinetobacter baumannii znu system overcomes host-imposed nutrient zinc limitation. Infection and Immunity 87 :e00746–e00819. (https://doi.org/10.1128/IAI.00746-19)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kirchhoff K, Machicao F, Haupt A, Schafer SA, Tschritter O, Staiger H, Stefan N, Haring HU & Fritsche A 2008 Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51 597–601. (https://doi.org/10.1007/s00125-008-0926-y)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kleiner S, Gomez D, Megra B, Na E, Bhavsar R, Cavino K, Xin Y, Rojas J, Dominguez-Gutierrez G, Zambrowicz B, et al. 2018 Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity. PNAS 115 E7642–E7649. (https://doi.org/10.1073/pnas.1721418115)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lemaire K, Ravier MA, Schraenen A, Creemers JW, Van de Plas R, Granvik M, Van Lommel L, Waelkens E, Chimienti F, Rutter GA, et al. 2009 Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. PNAS 106 14872–14877. (https://doi.org/10.1073/pnas.0906587106)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Li L, Bai S & Sheline CT 2016 hZnT8 (slc30a8) transgenic mice which overexpress the R325W polymorph have reduced islet Zn2+ and proinsulin levels, increased glucose tolerance after a high-fat diet, and altered levels of pancreatic zinc binding proteins. Diabetes 66 551–559. (https://doi.org/10.2337/db16-0323)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Liu BY, Jiang Y, Lu Z, Li S, Lu D & Chen B 2011 Down-regulation of zinc transporter 8 in the pancreas of db/db mice is rescued by exendin-4 administration. Molecular Medicine Reports 4 47–52. (https://doi.org/10.3892/mmr.2011.435)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Livak KJ & Schmittgen TD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25 402–408. (https://doi.org/10.1006/meth.2001.1262)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Loos RJF & Janssens A 2017 Predicting polygenic obesity using genetic information. Cell Metabolism 25 535–543. (https://doi.org/10.1016/j.cmet.2017.02.013)

  • Lu Y, Day FR, Gustafsson S, Buchkovich ML, Na J, Bataille V, Cousminer DL, Dastani Z, Drong AW, Esko T, et al. 2016 New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk. Nature Communications 7 10495. (https://doi.org/10.1038/ncomms10495)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Marmugi A, Parnis J, Chen X, Carmichael L, Hardy J, Mannan N, Marchetti P, Piemonti L, Bosco D, Johnson P, et al. 2016 Sorcin links pancreatic beta-cell lipotoxicity to ER Ca2+ stores. Diabetes 65 1009–1021. (https://doi.org/10.2337/db15-1334)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Martin CC, Oeser JK, Svitek CA, Hunter SI, Hutton JC & O’Brien RM 2002 Identification and characterization of a human cDNA and gene encoding a ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein. Journal of Molecular Endocrinology 29 205–222. (https://doi.org/10.1677/jme.0.0290205)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Merriman C & Fu D 2019 Down-regulation of the islet-specific zinc transporter-8 (ZnT8) protects human insulinoma cells against inflammatory stress. Journal of Biological Chemistry 294 16992–17006. (https://doi.org/10.1074/jbc.RA119.010937)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Merriman C, Huang Q, Rutter GA & Fu D 2016 Lipid-tuned zinc transport activity of human ZnT8 protein correlates with risk for type-2 diabetes. Journal of Biological Chemistry 291 26950–26957. (https://doi.org/10.1074/jbc.M116.764605)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Murgia C, Devirgiliis C, Mancini E, Donadel G, Zalewski P & Perozzi G 2009 Diabetes-linked zinc transporter ZnT8 is a homodimeric protein expressed by distinct rodent endocrine cell types in the pancreas and other glands. Nutrition, Metabolism & Cardiovascular Diseases 19 431–439. (https://doi.org/10.1016/j.numecd.2008.09.004)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nicolson TJ, Bellomo EA, Wijesekara N, Loder MK, Baldwin JM, Gyulkhandanyan AV, Koshkin V, Tarasov AI, Carzaniga R, Kronenberger K, et al. 2009 Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58 2070–2083. (https://doi.org/10.2337/db09-0551)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • O’Brien RM 2013 Moving on from GWAS: functional studies on the G6PC2 gene implicated in the regulation of fasting blood glucose. Current Diabetes Reports 13 768–777. (https://doi.org/10.1007/s11892-013-0422-8)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Overbeck S, Uciechowski P, Ackland ML, Ford D & Rink L 2008 Intracellular zinc homeostasis in leukocyte subsets is regulated by different expression of zinc exporters ZnT-1 to ZnT-9. Journal of Leukocyte Biology 83 368–380. (https://doi.org/10.1189/jlb.0307148)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pare G, Chasman DI, Parker AN, Nathan DM, Miletich JP, Zee RY & Ridker PM 2008 Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women’s Genome Health Study. PLoS Genetics 4 e1000312. (https://doi.org/10.1371/journal.pgen.1000312)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Petersen AB, Smidt K, Magnusson NE, Moore F, Egefjord L & Rungby J 2011 siRNA-mediated knock-down of ZnT3 and ZnT8 affects production and secretion of insulin and apoptosis in INS-1E cells. APMIS 119 93–102. (https://doi.org/10.1111/j.1600-0463.2010.02698.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pound LD, Oeser JK, O’Brien TP, Wang Y, Faulman CJ, Dadi PK, Jacobson DA, Hutton JC, McGuinness OP, Shiota M, et al. 2013 G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Diabetes 62 1547–1556. (https://doi.org/10.2337/db12-1067)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pound LD, Sarkar S, Benninger RK, Wang Y, Suwanichkul A, Shadoan MK, Printz RL, Oeser JK, Lee CE, Piston DW, et al. 2009 Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochemical Journal 421 371–376. (https://doi.org/10.1042/BJ20090530)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pound LD, Sarkar SA, Ustione A, Dadi PK, Shadoan MK, Lee CE, Walters JA, Shiota M, McGuinness OP, Jacobson DA, et al. 2012 The physiological effects of deleting the mouse slc30a8 gene encoding zinc transporter-8 are influenced by gender and genetic background. PLoS One 7 e40972. (https://doi.org/10.1371/journal.pone.0040972)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pulley J, Clayton E, Bernard GR, Roden DM & Masys DR 2010 Principles of human subjects protections applied in an opt-out, de-identified biobank. Clinical and Translational Science 3 42–48. (https://doi.org/10.1111/j.1752-8062.2010.00175.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ritchie MD, Denny JC, Zuvich RL, Crawford DC, Schildcrout JS, Bastarache L, Ramirez AH, Mosley JD, Pulley JM, Basford MA, et al. 2013 Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk. Circulation 127 1377–1385. (https://doi.org/10.1161/CIRCULATIONAHA.112.000604)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Robertson RP, Zhou H & Slucca M 2011 A role for zinc in pancreatic islet beta-cell cross-talk with the alpha-cell during hypoglycaemia. Diabetes, Obesity and Metabolism 13 (Supplement 1) 106–111. (https://doi.org/10.1111/j.1463-1326.2011.01448.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Roden DM, Pulley JM, Basford MA, Bernard GR, Clayton EW, Balser JR & Masys DR 2008 Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clinical Pharmacology & Therapeutics 84 362–369. (https://doi.org/10.1038/clpt.2008.89)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rutter GA & Chimienti F 2015 SLC30A8 mutations in type 2 diabetes. Diabetologia 58 31–36. (https://doi.org/10.1007/s00125-014-3405-7)

  • Serreze DV, Chapman HD, Varnum DS, Hanson MS, Reifsnyder PC, Richard SD, Fleming SA, Leiter EH & Shultz LD 1996 B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new “speed congenic” stock of NOD.Ig mu null mice. Journal of Experimental Medicine 184 2049–2053. (https://doi.org/10.1084/jem.184.5.2049)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shameer K, Denny JC, Ding K, Jouni H, Crosslin DR, de Andrade M, Chute CG, Peissig P, Pacheco JA, Li R, et al. 2014 A genome- and phenome-wide association study to identify genetic variants influencing platelet count and volume and their pleiotropic effects. Human Genetics 133 95–109. (https://doi.org/10.1007/s00439-013-1355-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, et al. 2007 A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445 881–885. (https://doi.org/10.1038/nature05616)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Smidt K, Pedersen SB, Brock B, Schmitz O, Fisker S, Bendix J, Wogensen L & Rungby J 2007 Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese. Molecular and Cellular Endocrinology 264 68–73. (https://doi.org/10.1016/j.mce.2006.10.010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Staiger H, Machicao F, Stefan N, Tschritter O, Thamer C, Kantartzis K, Schafer SA, Kirchhoff K, Fritsche A & Haring HU 2007 Polymorphisms within novel risk loci for type 2 diabetes determine beta-cell function. PLoS One 2 e832. (https://doi.org/10.1371/journal.pone.0000832)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Surwit RS, Kuhn CM, Cochrane C, McCubbin JA & Feinglos MN 1988 Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37 1163–1167. (https://doi.org/10.2337/diab.37.9.1163)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Syring KE, Bosma KJ, Oeser JK, Shiota M & O’Brien RM 2018 The diabetes susceptibility gene SLC30A8 that encodes the zinc transporter ZnT8 is a pseudogene in guinea pigs potentially contributing to low guinea pig islet zinc content. Journal of Molecular Evolution 86 613–617. (https://doi.org/10.1007/s00239-018-9873-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Syring KE, Boortz KA, Oeser JK, Ustione A, Platt KA, Shadoan MK, McGuinness OP, Piston DW, Powell DR & O’Brien RM 2016 Combined deletion of Slc30a7 and Slc30a8 unmasks a critical role for ZnT8 in glucose-stimulated insulin secretion. Endocrinology 157 4534–4541. (https://doi.org/10.1210/en.2016-1573)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, Takeno K, Kawaguchi M, Watanabe T, Ogihara T, Fukunaka A, et al. 2013 The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. Journal of Clinical Investigation 123 4513–4524. (https://doi.org/10.1172/JCI68807)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Trefts E, Hughey CC, Lantier L, Lark DS, Boyd KL, Pozzi A, Zent R & Wasserman DH 2019 Energy metabolism couples hepatocyte integrin-linked kinase to liver glucoregulation and postabsorptive responses of mice in an age-dependent manner. American Journal of Physiology: Endocrinology and Metabolism 316 E1118–E1135. (https://doi.org/10.1152/ajpendo.00496.2018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang Y, Flemming BP, Martin CC, Allen SR, Walters J, Oeser JK, Hutton JC & O’Brien RM 2008 Long-range enhancers are required to maintain expression of the autoantigen islet-specific glucose-6-phosphatase catalytic subunit-related protein in adult mouse islets in vivo. Diabetes 57 133–141. (https://doi.org/10.2337/db07-0092)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wang Y, Oeser JK, Yang C, Sarkar S, Hackl SI, Hasty AH, McGuinness OP, Paradee W, Hutton JC, Powell DR, et al. 2006 Deletion of the gene encoding the ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein (UGRP)/glucose-6-phosphatase catalytic subunit-beta results in lowered plasma cholesterol and elevated glucagon. Journal of Biological Chemistry 281 39982–39989. (https://doi.org/10.1074/jbc.M605858200)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wijesekara N, Dai FF, Hardy AB, Giglou PR, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano HY, Rutter GA & Wheeler MB 2010 Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53 1656–1668. (https://doi.org/10.1007/s00125-010-1733-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wong WP, Allen NB, Meyers MS, Link EO, Zhang X, MacRenaris KW & El Muayed M 2017 Exploring the association between demographics, SLC30A8 genotype, and human islet content of zinc, cadmium, copper, iron, manganese and nickel. Scientific Reports 7 473. (https://doi.org/10.1038/s41598-017-00394-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xu G, Kang D, Zhang C, Lou H, Sun C, Yang Q, Lu L, Xu GT, Zhang J & Wang F 2015 Erythropoietin protects retinal cells in diabetic rats through upregulating ZnT8 via activating ERK pathway and inhibiting HIF-1alpha expression. Investigative Ophthalmology & Visual Science 56 8166–8178. (https://doi.org/10.1167/iovs.15-18093)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xu K, Zha M, Wu X, Yu Z, Yu R, Xu X, Chen H & Yang T 2011 Association between rs13266634 C/T polymorphisms of solute carrier family 30 member 8 (SLC30A8) and type 2 diabetes, impaired glucose tolerance, type 1 diabetes – a meta-analysis. Diabetes Research and Clinical Practice 91 195–202. (https://doi.org/10.1016/j.diabres.2010.11.012)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang X, Guan T, Yang B, Chi Z, Wang ZY & Gu HF 2018 A novel role for zinc transporter 8 in the facilitation of zinc accumulation and regulation of testosterone synthesis in leydig cells of human and mouse testicles. Metabolism 88 40–50. (https://doi.org/10.1016/j.metabol.2018.09.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhong ML, Chi ZH, Shan ZY, Teng WP & Wang ZY 2012 Widespread expression of zinc transporter ZnT (SLC30) family members in mouse endocrine cells. Histochemistry and Cell Biology 138 605–616. (https://doi.org/10.1007/s00418-012-0979-3)

    • PubMed
    • Search Google Scholar
    • Export Citation