Potential positive and negative consequences of ZnT8 inhibition

in Journal of Endocrinology

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

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

Restricted access

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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  • AndrewsGKKageKPalmiter-ThomasPSarrasMP Jr. 1990 Metal ions induce expression of metallothionein in pancreatic exocrine and endocrine cells. Pancreas 5 548554. (https://doi.org/10.1097/00006676-199009000-00009)

    • Search Google Scholar
    • Export Citation
  • BoesgaardTWZilinskaiteJVanttinenMLaaksoMJanssonPAHammarstedtASmithUStefanNFritscheAHaringHet 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 816820. (https://doi.org/10.1007/s00125-008-0955-6)

    • Search Google Scholar
    • Export Citation
  • BosmaKJSyringKEOeserJKLeeJDBenningerRKPPamenterMEO’BrienRM 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 147151. (https://doi.org/10.1007/s00239-019-09898-0)

    • Search Google Scholar
    • Export Citation
  • BousteadJNMartinCCOeserJKSvitekCAHunterSIHuttonJCO’BrienRM 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 3353. (https://doi.org/10.1677/jme.0.0320033)

    • Search Google Scholar
    • Export Citation
  • ChausmerAB 1998 Zinc, insulin and diabetes. Journal of the American College of Nutrition 17 109115. (https://doi.org/10.1080/07315724.1998.10718735)

    • Search Google Scholar
    • Export Citation
  • CoulonVVeyruneJLTourkineNVieAHipskindRABlanchardJM 1999 A novel calcium signaling pathway targets the c-fos intragenic transcriptional pausing site. Journal of Biological Chemistry 274 3043930446. (https://doi.org/10.1074/jbc.274.43.30439)

    • Search Google Scholar
    • Export Citation
  • DavidsonHWWenzlauJMO’BrienRM 2014 Zinc transporter 8 (ZnT8) and beta cell function. Trends in Endocrinology and Metabolism 25 415424. (https://doi.org/10.1016/j.tem.2014.03.008)

    • Search Google Scholar
    • Export Citation
  • DeniroMAl-MohannaFA 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)

    • Search Google Scholar
    • Export Citation
  • DennyJCRitchieMDBasfordMAPulleyJMBastaracheLBrown-GentryKWangDMasysDRRodenDMCrawfordDC 2010 PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics 26 12051210. (https://doi.org/10.1093/bioinformatics/btq126)

    • Search Google Scholar
    • Export Citation
  • DennyJCCrawfordDCRitchieMDBielinskiSJBasfordMABradfordYChaiHSBastaracheLZuvichRPeissigPet 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 529542. (https://doi.org/10.1016/j.ajhg.2011.09.008)

    • Search Google Scholar
    • Export Citation
  • DennyJCBastaracheLRitchieMDCarrollRJZinkRMosleyJDFieldJRPulleyJMRamirezAHBowtonEet al. 2013 Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nature Biotechnology 31 11021110. (https://doi.org/10.1038/nbt.2749)

    • Search Google Scholar
    • Export Citation
  • DunnMF 2005 Zinc-ligand interactions modulate assembly and stability of the insulin hexamer – a review. Biometals 18 295303. (https://doi.org/10.1007/s10534-005-3685-y)

    • Search Google Scholar
    • Export Citation
  • DupuisJLangenbergCProkopenkoISaxenaRSoranzoNJacksonAUWheelerEGlazerNLBouatia-NajiNGloynALet al. 2010 New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nature Genetics 42 105116. (https://doi.org/10.1038/ng.520)

    • Search Google Scholar
    • Export Citation
  • DwivediOPLehtovirtaMHastoyBChandraVKrentzNAJKleinerSJainDRichardAMAbaituaFBeerNLet al. 2019 Loss of ZnT8 function protects against diabetes by enhanced insulin secretion. Nature Genetics 51 15961606. (https://doi.org/10.1038/s41588-019-0513-9)

    • Search Google Scholar
    • Export Citation
  • EckelRHKahnSEFerranniniEGoldfineABNathanDMSchwartzMWSmithRJSmithSR 2011 Obesity and type 2 diabetes: what can be unified and what needs to be individualized? Diabetes Care 34 14241430. (https://doi.org/10.2337/dc11-0447)

    • Search Google Scholar
    • Export Citation
  • EfratSLindeSKofodHSpectorDDelannoyMGrantSHanahanDBaekkeskovS 1988 Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene. PNAS 85 90379041. (https://doi.org/10.1073/pnas.85.23.9037)

    • Search Google Scholar
    • Export Citation
  • FanzoJCReavesSKCuiLZhuLWuJYWangYRLeiKY 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 C751C757. (https://doi.org/10.1152/ajpcell.2001.281.3.C751)

    • Search Google Scholar
    • Export Citation
  • FiglewiczDPForhanSEHodgsonATGrodskyGM 1984 65Zinc and endogenous zinc content and distribution in islets in relationship to insulin content. Endocrinology 115 877881. (https://doi.org/10.1210/endo-115-3-877)

    • Search Google Scholar
    • Export Citation
  • FlannickJThorleifssonGBeerNLJacobsSBGrarupNBurttNPMahajanAFuchsbergerCAtzmonGBenediktssonRet al. 2014 Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nature Genetics 46 357363. (https://doi.org/10.1038/ng.2915)

    • Search Google Scholar
    • Export Citation
  • FlannickJMercaderJMFuchsbergerCUdlerMSMahajanAWesselJTeslovichTMCaulkinsLKoestererRBarajas-OlmosFet al. 2019 Exome sequencing of 20,791 cases of type 2 diabetes and 24,440 controls. Nature 570 7176. (https://doi.org/10.1038/s41586-019-1231-2)

    • Search Google Scholar
    • Export Citation
  • FrigeriCMartinCCSvitekCAOeserJKHuttonJCGannonMO’BrienRM 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 17541764. (https://doi.org/10.2337/diabetes.53.7.1754)

    • Search Google Scholar
    • Export Citation
  • FuYTianWPrattEBDirlingLBShyngSLMeshulCKCohenDM 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)

    • Search Google Scholar
    • Export Citation
  • GiacconiRMalavoltaMChiodiLBoccoliGCostarelliLBonfigliARGaleazziRPiacenzaFBassoAGaspariniNet al. 2018 ZnT8 Arg325Trp polymorphism influences zinc transporter expression and cytokine production in PBMCs from patients with diabetes. Diabetes Research and Clinical Practice 144 102110. (https://doi.org/10.1016/j.diabres.2018.08.001)

    • Search Google Scholar
    • Export Citation
  • HardyABSerinoASWijesekaraNChimientiFWheelerMB 2011 Regulation of glucagon secretion by zinc: lessons from the beta cell-specific Znt8 knockout mouse model. Diabetes Obesity and Metabolism 13 (Supplement 1) 112117. (https://doi.org/10.1111/j.1463-1326.2011.01451.x)

    • Search Google Scholar
    • Export Citation
  • HardyABWijesekaraNGenkinIPrenticeKJBhattacharjeeAKongDChimientiFWheelerMB 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 E1084E1096. (https://doi.org/10.1152/ajpendo.00448.2011)

    • Search Google Scholar
    • Export Citation
  • HesseLELonerganZRBeaversWNSkaarEP 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)

    • Search Google Scholar
    • Export Citation
  • KirchhoffKMachicaoFHauptASchaferSATschritterOStaigerHStefanNHaringHUFritscheA 2008 Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51 597601. (https://doi.org/10.1007/s00125-008-0926-y)

    • Search Google Scholar
    • Export Citation
  • KleinerSGomezDMegraBNaEBhavsarRCavinoKXinYRojasJDominguez-GutierrezGZambrowiczBet al. 2018 Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity. PNAS 115 E7642E7649. (https://doi.org/10.1073/pnas.1721418115)

    • Search Google Scholar
    • Export Citation
  • LemaireKRavierMASchraenenACreemersJWVan de PlasRGranvikMVan LommelLWaelkensEChimientiFRutterGAet al. 2009 Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. PNAS 106 1487214877. (https://doi.org/10.1073/pnas.0906587106)

    • Search Google Scholar
    • Export Citation
  • LiLBaiSShelineCT 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 551559. (https://doi.org/10.2337/db16-0323)

    • Search Google Scholar
    • Export Citation
  • LiuBYJiangYLuZLiSLuDChenB 2011 Down-regulation of zinc transporter 8 in the pancreas of db/db mice is rescued by exendin-4 administration. Molecular Medicine Reports 4 4752. (https://doi.org/10.3892/mmr.2011.435)

    • Search Google Scholar
    • Export Citation
  • LivakKJSchmittgenTD 2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25 402408. (https://doi.org/10.1006/meth.2001.1262)

    • Search Google Scholar
    • Export Citation
  • LoosRJFJanssensA 2017 Predicting polygenic obesity using genetic information. Cell Metabolism 25 535543. (https://doi.org/10.1016/j.cmet.2017.02.013)

    • Search Google Scholar
    • Export Citation
  • LuYDayFRGustafssonSBuchkovichMLNaJBatailleVCousminerDLDastaniZDrongAWEskoTet 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)

    • Search Google Scholar
    • Export Citation
  • MarmugiAParnisJChenXCarmichaelLHardyJMannanNMarchettiPPiemontiLBoscoDJohnsonPet al. 2016 Sorcin links pancreatic beta-cell lipotoxicity to ER Ca2+ stores. Diabetes 65 10091021. (https://doi.org/10.2337/db15-1334)

    • Search Google Scholar
    • Export Citation
  • MartinCCOeserJKSvitekCAHunterSIHuttonJCO’BrienRM 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 205222. (https://doi.org/10.1677/jme.0.0290205)

    • Search Google Scholar
    • Export Citation
  • MerrimanCFuD 2019 Down-regulation of the islet-specific zinc transporter-8 (ZnT8) protects human insulinoma cells against inflammatory stress. Journal of Biological Chemistry 294 1699217006. (https://doi.org/10.1074/jbc.RA119.010937)

    • Search Google Scholar
    • Export Citation
  • MerrimanCHuangQRutterGAFuD 2016 Lipid-tuned zinc transport activity of human ZnT8 protein correlates with risk for type-2 diabetes. Journal of Biological Chemistry 291 2695026957. (https://doi.org/10.1074/jbc.M116.764605)

    • Search Google Scholar
    • Export Citation
  • MurgiaCDevirgiliisCManciniEDonadelGZalewskiPPerozziG 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 431439. (https://doi.org/10.1016/j.numecd.2008.09.004)

    • Search Google Scholar
    • Export Citation
  • NicolsonTJBellomoEAWijesekaraNLoderMKBaldwinJMGyulkhandanyanAVKoshkinVTarasovAICarzanigaRKronenbergerKet 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 20702083. (https://doi.org/10.2337/db09-0551)

    • Search Google Scholar
    • Export Citation
  • O’BrienRM 2013 Moving on from GWAS: functional studies on the G6PC2 gene implicated in the regulation of fasting blood glucose. Current Diabetes Reports 13 768777. (https://doi.org/10.1007/s11892-013-0422-8)

    • Search Google Scholar
    • Export Citation
  • OverbeckSUciechowskiPAcklandMLFordDRinkL 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 368380. (https://doi.org/10.1189/jlb.0307148)

    • Search Google Scholar
    • Export Citation
  • PareGChasmanDIParkerANNathanDMMiletichJPZeeRYRidkerPM 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)

    • Search Google Scholar
    • Export Citation
  • PetersenABSmidtKMagnussonNEMooreFEgefjordLRungbyJ 2011 siRNA-mediated knock-down of ZnT3 and ZnT8 affects production and secretion of insulin and apoptosis in INS-1E cells. APMIS 119 93102. (https://doi.org/10.1111/j.1600-0463.2010.02698.x)

    • Search Google Scholar
    • Export Citation
  • PoundLDOeserJKO’BrienTPWangYFaulmanCJDadiPKJacobsonDAHuttonJCMcGuinnessOPShiotaMet al. 2013 G6PC2: a negative regulator of basal glucose-stimulated insulin secretion. Diabetes 62 15471556. (https://doi.org/10.2337/db12-1067)

    • Search Google Scholar
    • Export Citation
  • PoundLDSarkarSBenningerRKWangYSuwanichkulAShadoanMKPrintzRLOeserJKLeeCEPistonDWet al. 2009 Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochemical Journal 421 371376. (https://doi.org/10.1042/BJ20090530)

    • Search Google Scholar
    • Export Citation
  • PoundLDSarkarSAUstioneADadiPKShadoanMKLeeCEWaltersJAShiotaMMcGuinnessOPJacobsonDAet 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)

    • Search Google Scholar
    • Export Citation
  • PulleyJClaytonEBernardGRRodenDMMasysDR 2010 Principles of human subjects protections applied in an opt-out, de-identified biobank. Clinical and Translational Science 3 4248. (https://doi.org/10.1111/j.1752-8062.2010.00175.x)

    • Search Google Scholar
    • Export Citation
  • RitchieMDDennyJCZuvichRLCrawfordDCSchildcroutJSBastaracheLRamirezAHMosleyJDPulleyJMBasfordMAet al. 2013 Genome- and phenome-wide analyses of cardiac conduction identifies markers of arrhythmia risk. Circulation 127 13771385. (https://doi.org/10.1161/CIRCULATIONAHA.112.000604)

    • Search Google Scholar
    • Export Citation
  • RobertsonRPZhouHSluccaM 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) 106111. (https://doi.org/10.1111/j.1463-1326.2011.01448.x)

    • Search Google Scholar
    • Export Citation
  • RodenDMPulleyJMBasfordMABernardGRClaytonEWBalserJRMasysDR 2008 Development of a large-scale de-identified DNA biobank to enable personalized medicine. Clinical Pharmacology & Therapeutics 84 362369. (https://doi.org/10.1038/clpt.2008.89)

    • Search Google Scholar
    • Export Citation
  • RutterGAChimientiF 2015 SLC30A8 mutations in type 2 diabetes. Diabetologia 58 3136. (https://doi.org/10.1007/s00125-014-3405-7)

  • SerrezeDVChapmanHDVarnumDSHansonMSReifsnyderPCRichardSDFlemingSALeiterEHShultzLD 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 20492053. (https://doi.org/10.1084/jem.184.5.2049)

    • Search Google Scholar
    • Export Citation
  • ShameerKDennyJCDingKJouniHCrosslinDRde AndradeMChuteCGPeissigPPachecoJALiRet 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 95109. (https://doi.org/10.1007/s00439-013-1355-7)

    • Search Google Scholar
    • Export Citation
  • SladekRRocheleauGRungJDinaCShenLSerreDBoutinPVincentDBelisleAHadjadjSet al. 2007 A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445 881885. (https://doi.org/10.1038/nature05616)

    • Search Google Scholar
    • Export Citation
  • SmidtKPedersenSBBrockBSchmitzOFiskerSBendixJWogensenLRungbyJ 2007 Zinc-transporter genes in human visceral and subcutaneous adipocytes: lean versus obese. Molecular and Cellular Endocrinology 264 6873. (https://doi.org/10.1016/j.mce.2006.10.010)

    • Search Google Scholar
    • Export Citation
  • StaigerHMachicaoFStefanNTschritterOThamerCKantartzisKSchaferSAKirchhoffKFritscheAHaringHU 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)

    • Search Google Scholar
    • Export Citation
  • SurwitRSKuhnCMCochraneCMcCubbinJAFeinglosMN 1988 Diet-induced type II diabetes in C57BL/6J mice. Diabetes 37 11631167. (https://doi.org/10.2337/diab.37.9.1163)

    • Search Google Scholar
    • Export Citation
  • SyringKEBosmaKJOeserJKShiotaMO’BrienRM 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 613617. (https://doi.org/10.1007/s00239-018-9873-5)

    • Search Google Scholar
    • Export Citation
  • SyringKEBoortzKAOeserJKUstioneAPlattKAShadoanMKMcGuinnessOPPistonDWPowellDRO’BrienRM 2016 Combined deletion of Slc30a7 and Slc30a8 unmasks a critical role for ZnT8 in glucose-stimulated insulin secretion. Endocrinology 157 45344541. (https://doi.org/10.1210/en.2016-1573)

    • Search Google Scholar
    • Export Citation
  • TamakiMFujitaniYHaraAUchidaTTamuraYTakenoKKawaguchiMWatanabeTOgiharaTFukunakaAet al. 2013 The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. Journal of Clinical Investigation 123 45134524. (https://doi.org/10.1172/JCI68807)

    • Search Google Scholar
    • Export Citation
  • TreftsEHugheyCCLantierLLarkDSBoydKLPozziAZentRWassermanDH 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 E1118E1135. (https://doi.org/10.1152/ajpendo.00496.2018)

    • Search Google Scholar
    • Export Citation
  • WangYFlemmingBPMartinCCAllenSRWaltersJOeserJKHuttonJCO’BrienRM 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 133141. (https://doi.org/10.2337/db07-0092)

    • Search Google Scholar
    • Export Citation
  • WangYOeserJKYangCSarkarSHacklSIHastyAHMcGuinnessOPParadeeWHuttonJCPowellDRet 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 3998239989. (https://doi.org/10.1074/jbc.M605858200)

    • Search Google Scholar
    • Export Citation
  • WijesekaraNDaiFFHardyABGiglouPRBhattacharjeeAKoshkinVChimientiFGaisanoHYRutterGAWheelerMB 2010 Beta cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53 16561668. (https://doi.org/10.1007/s00125-010-1733-9)

    • Search Google Scholar
    • Export Citation
  • WongWPAllenNBMeyersMSLinkEOZhangXMacRenarisKWEl MuayedM 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)

    • Search Google Scholar
    • Export Citation
  • XuGKangDZhangCLouHSunCYangQLuLXuGTZhangJWangF 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 81668178. (https://doi.org/10.1167/iovs.15-18093)

    • Search Google Scholar
    • Export Citation
  • XuKZhaMWuXYuZYuRXuXChenHYangT 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 195202. (https://doi.org/10.1016/j.diabres.2010.11.012)

    • Search Google Scholar
    • Export Citation
  • ZhangXGuanTYangBChiZWangZYGuHF 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 4050. (https://doi.org/10.1016/j.metabol.2018.09.002)

    • Search Google Scholar
    • Export Citation
  • ZhongMLChiZHShanZYTengWPWangZY 2012 Widespread expression of zinc transporter ZnT (SLC30) family members in mouse endocrine cells. Histochemistry and Cell Biology 138 605616. (https://doi.org/10.1007/s00418-012-0979-3)

    • Search Google Scholar
    • Export Citation