, Volume 27, Issue 3, pp 453–464 | Cite as

Zinc and its regulators in pancreas

  • Tianjiao Zhao
  • Qiongfang Huang
  • Yangni Su
  • Wuyi Sun
  • Qiong HuangEmail author
  • Wei WeiEmail author
Review Article


Studies have demonstrated that susceptibility to type 2 diabetes (T2D) is influenced by common polymorphism in the zinc transporter 8 gene SLC30A8, providing novel insight into the role of zinc in diabetes. Intriguingly, zinc participates in every step of the process, including insulin synthesis, crystallization, storage, secretion and signaling. Zinc deficiency or overload is associated with various disorders, such as diabetes, cardiovascular disease and obesity. Zinc supplementation is considered as an effective means of treating or preventing T2D in people with certain SLC30A8 genotypes. Three important protein families—zinc transporters (ZnTs), zinc importers (ZiPs) and metallothionein (MT)—participate in maintaining zinc homeostasis. Here, we review research on the physiological characteristics of zinc and its role in the pancreas and homeostasis regulation mechanisms, along with the latest research on the structure and function of ZnT/ZiP and MT. In addition, we summarize the advancements in research on SLC30A8 gene polymorphism in search of a mechanism to explain the relationship between the R risk allele and zinc transporter activity.


Zinc Zinc regulators Diabetes ZnT8 Pancreas 



Funding was provided by National Natural Science Foundation of China (Grant nos.: 81673492/81202596/81330081).


  1. Bafaro E, Liu Y, Xu Y, Dempski RE (2017) The emerging role of zinc transporters in cellular homeostasis and cancer. Signal Transduct Target Ther 2:17029CrossRefGoogle Scholar
  2. Baltaci AK, Yuce K (2018) Zinc transporter proteins. Neurochem Res 43:517–530CrossRefGoogle Scholar
  3. Bellomo EA, Meur G, Rutter GA (2011) Glucose regulates free cytosolic Zn(2)(+) concentration, Slc39 (ZiP), and metallothionein gene expression in primary pancreatic islet beta-cells. J Biol Chem 286:25778–25789CrossRefGoogle Scholar
  4. Boesgaard TW, Zilinskaite J, Vanttinen M, Laakso M, Jansson PA, Hammarstedt A, Smith U, Stefan N, Fritsche A, Haring H, Hribal M, Sesti G, Zobel DP, Pedersen O, Hansen T (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 51:816–820CrossRefGoogle Scholar
  5. Cai Y, Kirschke CP, Huang L (2018) SLC30A family expression in the pancreatic islets of humans and mice: cellular localization in the beta-cells. J Mol Histol 49:133–145CrossRefGoogle Scholar
  6. Carpene E, Andreani G, Isani G (2007) Metallothionein functions and structural characteristics. J Trace Elem Med Biol 21(Suppl 1):35–39CrossRefGoogle Scholar
  7. Carvalho S, Molina-Lopez J, Parsons D, Corpe C, Maret W, Hogstrand C (2017) Differential cytolocation and functional assays of the two major human SLC30A8 (ZnT8) isoforms. J Trace Elem Med Biol 44:116–124CrossRefGoogle Scholar
  8. Cauchi S, Proenca C, Choquet H, Gaget S, DeGraeve F, Marre M, Balkau B, Tichet J, Meyre D, Vaxillaire M, Froguel P (2008) Analysis of novel risk loci for type 2 diabetes in a general French population: the D.E.S.I.R. Study. J Mol Med (Berl) 86:341–348CrossRefGoogle Scholar
  9. Cauchi S, Del GS, Choquet H, D’Aleo V, Groves CJ, Lupi R, McCarthy MI, Froguel P, Marchetti P (2010) Meta-analysis and functional effects of the SLC30A8 rs13266634 polymorphism on isolated human pancreatic islets. Mol Genet Metab 100:77–82CrossRefGoogle Scholar
  10. Chabosseau P, Rutter GA (2016) Zinc and diabetes. Arch Biochem Biophys 611:79–85CrossRefGoogle Scholar
  11. Chabosseau P, Woodier J, Cheung R, Rutter GA (2018) Sensors for measuring subcellular zinc pools. Metallomics 10:229–239CrossRefGoogle Scholar
  12. Chimienti F (2013) Zinc, pancreatic islet cell function and diabetes: new insights into an old story. Nutr Res Rev 26:1–11CrossRefGoogle Scholar
  13. Cipriano C, Malavolta M, Costarelli L, Giacconi R, Muti E, Gasparini N, Cardelli M, Monti D, Mariani E, Mocchegiani E (2006) Polymorphisms in MT1a gene coding region are associated with longevity in Italian central female population. Biogerontology 7:357–365CrossRefGoogle Scholar
  14. Cruz K, de Oliveira A, Morais J, Severo JS, Mendes P, de Sousa MS, de Sousa GS, Marreiro D (2018) Zinc and insulin resistance: biochemical and molecular aspects. Biol Trace Elem Res 186:407–412CrossRefGoogle Scholar
  15. Davidson HW, Wenzlau JM, O’Brien RM (2014) Zinc transporter 8 (ZnT8) and beta cell function. Trends Endocrinol Metab 25:415–424CrossRefGoogle Scholar
  16. Egefjord L, Petersen AB, Rungby J (2010) Zinc, alpha cells and glucagon secretion. Curr Diabetes Rev 6:52–57CrossRefGoogle Scholar
  17. Fan M, Li W, Wang L, Gu S, Dong S, Chen M, Yin H, Zheng J, Wu X, Jin J, Jiang X, Cai J, Liu P, Zheng C (2016) Association of SLC30A8 gene polymorphism with type 2 diabetes, evidence from 46 studies: a meta-analysis. Endocrine 53:381–394CrossRefGoogle Scholar
  18. Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsen T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jorgensen T, Jorgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee JY, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel-Madsen R, Richard AM, Rolph T, Salomaa V, Segre AV, Skarstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njolstad PR, Pedersen O, Groop L, Cox DR, Stefansson K, Altshuler D (2014) Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet 46:357–363CrossRefGoogle Scholar
  19. Foster M, Samman S (2010) Zinc and redox signaling: perturbations associated with cardiovascular disease and diabetes mellitus. Antioxid Redox Signal 13:1549–1573CrossRefGoogle Scholar
  20. 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:e5679CrossRefGoogle Scholar
  21. Fukunaka A, Fujitani Y (2018) Role of zinc homeostasis in the pathogenesis of diabetes and obesity. Int J Mol Sci 19:476CrossRefGoogle Scholar
  22. Gerber PA, Bellomo EA, Hodson DJ, Meur G, Solomou A, Mitchell RK, Hollinshead M, Chimienti F, Bosco D, Hughes SJ, Johnson PR, Rutter GA (2014) Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Diabetologia 57:1635–1644CrossRefGoogle Scholar
  23. Gunther V, Lindert U, Schaffner W (2012) The taste of heavy metals: gene regulation by MTF-1. Biochim Biophys Acta 1823:1416–1425CrossRefGoogle Scholar
  24. Gyulkhandanyan AV, Lee SC, Bikopoulos G, Dai F, Wheeler MB (2006) The Zn2+-transporting pathways in pancreatic beta-cells: a role for the L-type voltage-gated Ca2+ channel. J Biol Chem 281:9361–9372CrossRefGoogle Scholar
  25. Gyulkhandanyan AV, Lu H, Lee SC, Bhattacharjee A, Wijesekara N, Fox JE, MacDonald PE, Chimienti F, Dai FF, Wheeler MB (2008) Investigation of transport mechanisms and regulation of intracellular Zn2+ in pancreatic alpha-cells. J Biol Chem 283:10184–10197CrossRefGoogle Scholar
  26. 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 Obes Metab 13(Suppl 1):112–117CrossRefGoogle Scholar
  27. Hardyman JE, Tyson J, Jackson KA, Aldridge C, Cockell SJ, Wakeling LA, Valentine RA, Ford D (2016) Zinc sensing by metal-responsive transcription factor 1 (MTF1) controls metallothionein and ZnT1 expression to buffer the sensitivity of the transcriptome response to zinc. Metallomics 8:337–343CrossRefGoogle Scholar
  28. Haupt A, Guthoff M, Schafer SA, Kirchhoff K, Machicao F, Gallwitz B, Staiger H, Stefan N, Fritsche A, Haring HU (2009) The inhibitory effect of recent type 2 diabetes risk loci on insulin secretion is modulated by insulin sensitivity. J Clin Endocrinol Metab 94:1775–1780CrossRefGoogle Scholar
  29. Ishihara H, Maechler P, Gjinovci A, Herrera PL, Wollheim CB (2003) Islet beta-cell secretion determines glucagon release from neighbouring alpha-cells. Nat Cell Biol 5:330–335CrossRefGoogle Scholar
  30. Kambe T, Hashimoto A, Fujimoto S (2014) Current understanding of ZIP and ZnT zinc transporters in human health and diseases. Cell Mol Life Sci 71:3281–3295CrossRefGoogle Scholar
  31. Kambe T, Matsunaga M, Takeda TA (2017) Understanding the contribution of zinc transporters in the function of the early secretory pathway. Int J Mol Sci 18:2179CrossRefGoogle Scholar
  32. Kleiner S, Gomez D, Megra B, Na E, Bhavsar R, Cavino K, Xin Y, Rojas J, Dominguez-Gutierrez G, Zambrowicz B, Carrat G, Chabosseau P, Hu M, Murphy AJ, Yancopoulos GD, Rutter GA, Gromada J (2018) Mice harboring the human SLC30A8 R138X loss-of-function mutation have increased insulin secretory capacity. Proc Natl Acad Sci USA 115:E7642–E7649CrossRefGoogle Scholar
  33. Krezel A, Maret W (2017) The functions of metamorphic metallothioneins in zinc and copper metabolism. Int J Mol Sci 18:1237CrossRefGoogle Scholar
  34. Kulkarni H, Mamtani M, Peralta JM, Diego V, Dyer TD, Goring H, Almasy L, Mahaney MC, Williams-Blangero S, Duggirala R, Curran JE, Blangero J (2016) Lack of association between SLC30A8 variants and type 2 diabetes in Mexican American families. J Diabetes Res 2016:6463214CrossRefGoogle Scholar
  35. Lemaire K, Ravier MA, Schraenen A, Creemers JW, Van de Plas R, Granvik M, Van Lommel L, Waelkens E, Chimienti F, Rutter GA, Gilon P, In’T VP, Schuit FC (2009) Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc Natl Acad Sci USA 106:14872–14877CrossRefGoogle Scholar
  36. Lewis JP, Palmer ND, Hicks PJ, Sale MM, Langefeld CD, Freedman BI, Divers J, Bowden DW (2008) Association analysis in african americans of European-derived type 2 diabetes single nucleotide polymorphisms from whole-genome association studies. Diabetes 57:2220–2225CrossRefGoogle Scholar
  37. Li YV (2014) Zinc and insulin in pancreatic beta-cells. Endocrine 45:178–189CrossRefGoogle Scholar
  38. Li L, Bai S, Sheline CT (2017) HZnT8 (Slc30a8) transgenic mice that overexpress the R325 W 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 66:551–559CrossRefGoogle Scholar
  39. Lu M, Chai J, Fu D (2009) Structural basis for autoregulation of the zinc transporter YiiP. Nat Struct Mol Biol 16:1063–1067CrossRefGoogle Scholar
  40. Maret W (2015) Analyzing free zinc(II) ion concentrations in cell biology with fluorescent chelating molecules. Metallomics 7:202–211CrossRefGoogle Scholar
  41. Maret W (2017) Zinc in cellular regulation: the nature and significance of “zinc signals”. Int J Mol Sci 18:2285CrossRefGoogle Scholar
  42. Maruthur NM, Clark JM, Fu M, Linda KW, Shuldiner AR (2015) Effect of zinc supplementation on insulin secretion: interaction between zinc and SLC30A8 genotype in old order amish. Diabetologia 58:295–303CrossRefGoogle Scholar
  43. 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. J Biol Chem 291:26950–26957CrossRefGoogle Scholar
  44. 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. Mol Endocrinol 30:77–91CrossRefGoogle Scholar
  45. Navarro JA, Schneuwly S (2017) Copper and zinc homeostasis: lessons from Drosophila melanogaster. Front Genet 8:223CrossRefGoogle Scholar
  46. Ng MC, Park KS, Oh B, Tam CH, Cho YM, Shin HD, Lam VK, Ma RC, So WY, Cho YS, Kim HL, Lee HK, Chan JC, Cho NH (2008) Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians. Diabetes 57:2226–2233CrossRefGoogle Scholar
  47. Nicolson TJ, Bellomo EA, Wijesekara N, Loder MK, Baldwin JM, Gyulkhandanyan AV, Koshkin V, Tarasov AI, Carzaniga R, Kronenberger K, Taneja TK, Da SXG, Libert S, Froguel P, Scharfmann R, Stetsyuk V, Ravassard P, Parker H, Gribble FM, Reimann F, Sladek R, Hughes SJ, Johnson PR, Masseboeuf M, Burcelin R, Baldwin SA, Liu M, Lara-Lemus R, Arvan P, Schuit FC, Wheeler MB, Chimienti F, Rutter GA (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 58:2070–2083CrossRefGoogle Scholar
  48. Norouzi S, Adulcikas J, Sohal SS, Myers S (2017) Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease. J Biomed Sci 24:87CrossRefGoogle Scholar
  49. Norouzi S, Adulcikas J, Sohal SS, Myers S (2018) Zinc stimulates glucose oxidation and glycemic control by modulating the insulin signaling pathway in human and mouse skeletal muscle cell lines. PLoS ONE 13:e191727CrossRefGoogle Scholar
  50. Omori S, Tanaka Y, Takahashi A, Hirose H, Kashiwagi A, Kaku K, Kawamori R, Nakamura Y, Maeda S (2008) Association of CDKAL1, IGF2BP2, CDKN2A/B, HHEX, SLC30A8, and KCNJ11 with susceptibility to type 2 diabetes in a Japanese population. Diabetes 57:791–795CrossRefGoogle Scholar
  51. Park L, Min D, Kim H, Chung HY, Lee CH, Park IS, Kim Y, Park Y (2011) Tat-enhanced delivery of metallothionein can partially prevent the development of diabetes. Free Radic Biol Med 51:1666–1674CrossRefGoogle Scholar
  52. Pearson E (2014) Zinc transport and diabetes risk. Nat Genet 46:323–324CrossRefGoogle Scholar
  53. Pertusa J, Leon-Quinto T, Berna G, Tejedo JR, Hmadcha A, Bedoya FJ, Martin F, Soria B (2017) Zn2 + chelation by serum albumin improves hexameric Zn2 + -insulin dissociation into monomers after exocytosis. PLoS ONE 12:e187547CrossRefGoogle Scholar
  54. Pound LD, Sarkar SA, Ustione A, Dadi PK, Shadoan MK, Lee CE, Walters JA, Shiota M, McGuinness OP, Jacobson DA, Piston DW, Hutton JC, Powell DR, O’Brien RM (2012) The physiological effects of deleting the mouse SLC30A8 gene encoding zinc transporter-8 are influenced by gender and genetic background. PLoS One 7:e40972CrossRefGoogle Scholar
  55. Prost AL, Bloc A, Hussy N, Derand R, Vivaudou M (2004) Zinc is both an intracellular and extracellular regulator of KATP channel function. J Physiol 559:157–167CrossRefGoogle Scholar
  56. Raudenska M, Gumulec J, Podlaha O, Sztalmachova M, Babula P, Eckschlager T, Adam V, Kizek R, Masarik M (2014) Metallothionein polymorphisms in pathological processes. Metallomics 6:55–68CrossRefGoogle Scholar
  57. Ravier MA, Rutter GA (2005) Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic alpha-cells. Diabetes 54:1789–1797CrossRefGoogle Scholar
  58. 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 Obes Metab 13(Suppl 1):106–111CrossRefGoogle Scholar
  59. Rutter GA, Chimienti F (2015) SLC30A8 mutations in type 2 diabetes. Diabetologia 58:31–36CrossRefGoogle Scholar
  60. Rutter GA, Chabosseau P, Bellomo EA, Maret W, Mitchell RK, Hodson DJ, Solomou A, Hu M (2016) Intracellular zinc in insulin secretion and action: a determinant of diabetes risk? Proc Nutr Soc 75:61–72CrossRefGoogle Scholar
  61. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PI, Chen H, Roix JJ, Kathiresan S, Hirschhorn JN, Daly MJ, Hughes TE, Groop L, Altshuler D, Almgren P, Florez JC, Meyer J, Ardlie K, Bengtsson BK, Isomaa B, Lettre G, Lindblad U, Lyon HN, Melander O, Newton-Cheh C, Nilsson P, Orho-Melander M, Rastam L, Speliotes EK, Taskinen MR, Tuomi T, Guiducci C, Berglund A, Carlson J, Gianniny L, Hackett R, Hall L, Holmkvist J, Laurila E, Sjogren M, Sterner M, Surti A, Svensson M, Svensson M, Tewhey R, Blumenstiel B, Parkin M, Defelice M, Barry R, Brodeur W, Camarata J, Chia N, Fava M, Gibbons J, Handsaker B, Healy C, Nguyen K, Gates C, Sougnez C, Gage D, Nizzari M, Gabriel SB, Chirn GW, Ma Q, Parikh H, Richardson D, Ricke D, Purcell S (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336CrossRefGoogle Scholar
  62. Schweiger M, Steffl M, Amselgruber WM (2016) Co-localization of the zinc transporter ZnT8 (slc30A8) with ghrelin and motilin in the gastrointestinal tract of pigs. Histol Histopathol 31:205–211Google Scholar
  63. Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, Erdos MR, Stringham HM, Chines PS, Jackson AU, Prokunina-Olsson L, Ding CJ, Swift AJ, Narisu N, Hu T, Pruim R, Xiao R, Li XY, Conneely KN, Riebow NL, Sprau AG, Tong M, White PP, Hetrick KN, Barnhart MW, Bark CW, Goldstein JL, Watkins L, Xiang F, Saramies J, Buchanan TA, Watanabe RM, Valle TT, Kinnunen L, Abecasis GR, Pugh EW, Doheny KF, Bergman RN, Tuomilehto J, Collins FS, Boehnke M (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345CrossRefGoogle Scholar
  64. Shan Z, Bao W, Zhang Y, Rong Y, Wang X, Jin Y, Song Y, Yao P, Sun C, Hu FB, Liu L (2014) Interactions between zinc transporter-8 gene (SLC30A8) and plasma zinc concentrations for impaired glucose regulation and type 2 diabetes. Diabetes 63:1796–1803CrossRefGoogle Scholar
  65. Sladek R, Rocheleau G, Rung J, Dina C, Shen L, Serre D, Boutin P, Vincent D, Belisle A, Hadjadj S, Balkau B, Heude B, Charpentier G, Hudson TJ, Montpetit A, Pshezhetsky AV, Prentki M, Posner BI, Balding DJ, Meyre D, Polychronakos C, Froguel P (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885CrossRefGoogle Scholar
  66. Slepchenko KG, Daniels NA, Guo A, Li YV (2015) Autocrine effect of Zn(2)(+) on the glucose-stimulated insulin secretion. Endocrine 50:110–122CrossRefGoogle Scholar
  67. Slucca M, Harmon JS, Oseid EA, Bryan J, Robertson RP (2010) ATP-sensitive K+ channel mediates the zinc switch-off signal for glucagon response during glucose deprivation. Diabetes 59:128–134CrossRefGoogle Scholar
  68. Smidt K, Larsen A, Bronden A, Sorensen KS, Nielsen JV, Praetorius J, Martensen PM, Rungby J (2016) The zinc transporter ZNT3 co-localizes with insulin in INS-1E pancreatic beta cells and influences cell survival, insulin secretion capacity, and ZNT8 expression. Biometals 29:287–298CrossRefGoogle Scholar
  69. Solomou A, Meur G, Bellomo E, Hodson DJ, Tomas A, Li SM, Philippe E, Herrera PL, Magnan C, Rutter GA (2015) The zinc transporter Slc30a8/ZnT8 is required in a subpopulation of pancreatic alpha-cells for hypoglycemia-induced glucagon secretion. J Biol Chem 290:21432–21442CrossRefGoogle Scholar
  70. Sun W, Yang J, Wang W, Hou J, Cheng Y, Fu Y, Xu Z, Cai L (2018) The beneficial effects of Zn on Akt-mediated insulin and cell survival signaling pathways in diabetes. J Trace Elem Med Biol 46:117–127CrossRefGoogle Scholar
  71. 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 157:4534–4541CrossRefGoogle Scholar
  72. Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, Takeno K, Kawaguchi M, Watanabe T, Ogihara T, Fukunaka A, Shimizu T, Mita T, Kanazawa A, Imaizumi MO, Abe T, Kiyonari H, Hojyo S, Fukada T, Kawauchi T, Nagamatsu S, Hirano T, Kawamori R, Watada H (2013) The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Investig 123:4513–4524CrossRefGoogle Scholar
  73. Votsi C, Toufexis C, Michailidou K, Antoniades A, Skordis N, Karaolis M, Pattichis CS, Christodoulou K (2017) Type 2 diabetes susceptibility in the Greek-cypriot population: replication of associations with TCF7L2, FTO, HHEX, SLC30A8 and IGF2BP2 polymorphisms. Genes (Basel) 8:16CrossRefGoogle Scholar
  74. Weijers RN (2010) Three-dimensional structure of beta-cell-specific zinc transporter, ZnT-8, predicted from the type 2 diabetes-associated gene variant SLC30A8 R325W. Diabetol Metab Syndr 2:33CrossRefGoogle Scholar
  75. 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 53:1656–1668CrossRefGoogle Scholar
  76. Wong WP, Allen NB, Meyers MS, Link EO, Zhang X, MacRenaris KW, El MM (2017) Exploring the association between demographics, SLC30A8 genotype, and human islet content of zinc, cadmium, copper, iron, manganese and nickel. Sci Rep 7:473CrossRefGoogle Scholar
  77. Wu W, Wang X, Zhang W, Reed W, Samet JM, Whang YE, Ghio AJ (2003) Zinc-induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. J Biol Chem 278:28258–28263CrossRefGoogle Scholar
  78. Wu Y, Li H, Loos RJ, Yu Z, Ye X, Chen L, Pan A, Hu FB, Lin X (2008) Common variants in CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, and HHEX/IDE genes are associated with type 2 diabetes and impaired fasting glucose in a Chinese Han population. Diabetes 57:2834–2842CrossRefGoogle Scholar
  79. Yu T, Jiang Z, Liu L, Fan Z (2018) Decrease of gamma-aminobutyric acid and zinc ions in the islet periportal circulation stimulates glucagon secretion during hypoglycemia. Exp Ther Med 15:2507–2511Google Scholar
  80. Zeggini E, Weedon MN, Lindgren CM, Frayling TM, Elliott KS, Lango H, Timpson NJ, Perry JR, Rayner NW, Freathy RM, Barrett JC, Shields B, Morris AP, Ellard S, Groves CJ, Harries LW, Marchini JL, Owen KR, Knight B, Cardon LR, Walker M, Hitman GA, Morris AD, Doney AS, McCarthy MI, Hattersley AT (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341CrossRefGoogle Scholar
  81. Zhou H, Zhang T, Harmon JS, Bryan J, Robertson RP (2007) Zinc, not insulin, regulates the rat alpha-cell response to hypoglycemia in vivo. Diabetes 56:1107–1112CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Key Laboratory of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune MedicineAnhui Medical University, Ministry of EducationHefeiChina

Personalised recommendations