Zinc Transporters in the Endocrine Pancreas

  • Mariea Dencey Bosco
  • Chris Drogemuller
  • Peter Zalewski
  • Patrick Toby CoatesEmail author
Reference work entry


The pancreas is composed of two types of cells: the exocrine (acinar) cells and endocrine (pancreatic islet) cells. Pancreatic islets have a high content of zinc (Zn) compared to exocrine tissue. Zinc is especially high in the pancreatic β cells, where it is involved in the maturation, synthesis, and secretion of insulin. Zn in the islet is regulated by zinc-buffering proteins such as metallothionein, membrane Zn transporters, and Zn-permeable ion channels such as TRPM3. There are two families of membrane protein Zn transporters: ZnT proteins lower cytosolic Zn by transporting it into organelles or out of cells while ZIP proteins increase cytosolic Zn by transporting zinc from the extracellular fluids or out of organelles into the cytosol. Some zinc transporters play specific roles in influencing insulin maturation, synthesis, and secretion. For example, ZnT8 is predominantly localized to the membranes of secretory granules in the pancreatic β cells where it is involved in incorporating Zn into crystalline structures of insulin. In both type 1 and 2 diabetes, Zn metabolism is altered and there are changes in ZnT8. A polymorphic variant of ZnT8 is associated with increase in the risk of type 2 diabetes while ZnT8 is an autoantigen in type 1 diabetes. The mechanisms by which ZnT8 is regulated and the role of other Zn transporters in pancreatic islet function are topics of much current interest, with potential implications as future therapeutic targets in diabetes.


Zinc Zinc transporters β cell α cell Type 2 diabetes Polymorphism 


  1. Achenbach P, Lampasona V, Landherr U et al (2009) Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia 52:1881–1888PubMedCrossRefGoogle Scholar
  2. Andrews GK, Geiser J (1999) Expression of the mouse metallothionein-I and -II genes provides a reproductive advantage during maternal dietary zinc deficiency. J Nutr 129:1643–1648PubMedGoogle Scholar
  3. Aydemir TB, Liuzzi JP, McClellan S, Cousins RJ (2009) Zinc transporter ZIP8 (SLC39A8) and zinc influence IFN-gamma expression in activated human T cells. J Leukoc Biol 86:337–348PubMedCrossRefPubMedCentralGoogle Scholar
  4. Beker Aydemir T, Chang SM, Guthrie GJ et al (2012) Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS One 7:e48679PubMedCrossRefPubMedCentralGoogle Scholar
  5. Bellomo EA, Meur G, Rutter GA (2011) Glucose regulates free cytosolic Zn2+ concentration, Slc39 (ZiP), and metallothionein gene expression in primary pancreatic islet β-cells. J Biol Chem 286:25778–25789PubMedCrossRefPubMedCentralGoogle Scholar
  6. Bosomworth HJ, Adlard PA, Ford D, Valentine RA (2013) Altered expression of ZnT10 in Alzheimer’s disease brain. PLoS One 8:e65475PubMedCrossRefPubMedCentralGoogle Scholar
  7. Camarata T, Krcmery J, Snyder D, Park S, Topczewski J, Simon HG (2010a) Pdlim7 (LMP4) regulation of Tbx5 specifies zebrafish heart atrio-ventricular boundary and valve formation. Dev Biol 337:233–245PubMedCrossRefPubMedCentralGoogle Scholar
  8. Camarata T, Snyder D, Schwend T, Klosowiak J, Holtrup B, Simon HG (2010b) Pdlim7 is required for maintenance of the mesenchymal/epidermal Fgf signaling feedback loop during zebrafish pectoral fin development. BMC Dev Biol 10:104PubMedCrossRefPubMedCentralGoogle Scholar
  9. Chao Y, Fu D (2004) Thermodynamic studies of the mechanism of metal binding to the Escherichia coli zinc transporter YiiP. J Biol Chem 279:17173–17180PubMedCrossRefGoogle Scholar
  10. Chen H, Carlson EC, Pellet L, Moritz JT, Epstein PN (2001) Overexpression of metallothionein in pancreatic β-cells reduces streptozotocin-induced DNA damage and diabetes. Diabetes 50:2040–2046PubMedCrossRefGoogle Scholar
  11. Chimienti F, Devergnas S, Pattou F et al (2006) In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. J Cell Sci 119:4199–4206PubMedCrossRefGoogle Scholar
  12. Claus J, Chavarria-Krauser A (2012) Modeling regulation of zinc uptake via ZIP transporters in yeast and plant roots. PLoS One 7:e37193PubMedCrossRefPubMedCentralGoogle Scholar
  13. Coudray N, Valvo S, Hu M et al (2013) Inward-facing conformation of the zinc transporter YiiP revealed by cryoelectron microscopy. Proc Natl Acad Sci U S A 110:2140–2145PubMedCrossRefPubMedCentralGoogle Scholar
  14. Cousins RJ, Lee-Ambrose LM (1992) Nuclear zinc uptake and interactions and metallothionein gene expression are influenced by dietary zinc in rats. J Nutr 122:56–64PubMedGoogle Scholar
  15. Cousins RJ, Liuzzi JP, Lichten LA (2006) Mammalian zinc transport, trafficking, and signals. J Biol Chem 281:24085–24089PubMedCrossRefGoogle Scholar
  16. Desouki MM, Geradts J, Milon B, Franklin RB, Costello LC (2007) hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands. Mol Cancer 6:37PubMedCrossRefPubMedCentralGoogle Scholar
  17. Devergnas S, Chimienti F, Naud N et al (2004) Differential regulation of zinc efflux transporters ZnT-1, ZnT-5 and ZnT-7 gene expression by zinc levels: a real-time RT-PCR study. Biochem Pharmacol 68:699–709PubMedCrossRefGoogle Scholar
  18. Dufner-Beattie J, Kuo YM, Gitschier J, Andrews GK (2004) The adaptive response to dietary zinc in mice involves the differential cellular localization and zinc regulation of the zinc transporters ZIP4 and ZIP5. J Biol Chem 279:49082–49090PubMedCrossRefGoogle Scholar
  19. Egefjord L, Petersen AB, Rungby J (2010) Zinc, α cells and glucagon secretion. Curr Diabetes Rev 6:52–57PubMedCrossRefGoogle Scholar
  20. El Muayed M, Raja MR, Zhang X et al (2012) Accumulation of cadmium in insulin-producing β cells. Islets 4:405–416PubMedCrossRefPubMedCentralGoogle Scholar
  21. Emdin SO, Dodson GG, Cutfield JM, Cutfield SM (1980) Role of zinc in insulin biosynthesis. Diabetologia 19:174–182PubMedCrossRefGoogle Scholar
  22. Foster MC, Leapman RD, Li MX, Atwater I (1993) Elemental composition of secretory granules in pancreatic islets of Langerhans. Biophys J 64:525–532PubMedCrossRefPubMedCentralGoogle Scholar
  23. Franklin I, Gromada J, Gjinovci A, Theander S, Wollheim CB (2005) β-cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release. Diabetes 54:1808–1815PubMedCrossRefGoogle Scholar
  24. Fukada T, Civic N, Furuichi T et al (2008) The zinc transporter SLC39A13/ZIP13 is required for connective tissue development; its involvement in BMP/TGF-? Signaling pathways. PLoS One 3:e3642PubMedCrossRefPubMedCentralGoogle Scholar
  25. Grass G, Franke S, Taudte N et al (2005) The metal permease ZupT from escherichia coli is a transporter with a broad substrate spectrum. J Bacteriol 187:1604–1611PubMedCrossRefPubMedCentralGoogle Scholar
  26. Guo L, Lichten LA, Ryu M-S, Liuzzi JP, Wang F, Cousins RJ (2010) STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells. Proc Natl Acad Sci 107:2818–2823PubMedCrossRefPubMedCentralGoogle Scholar
  27. Heise CC, King JC, Costa FM, Kitzmiller JL (1988) Hyperzincuria in IDDM women. Relationship to measures of glycemic control, renal function, and tissue catabolism. Diabetes Care 11:780–786PubMedCrossRefGoogle Scholar
  28. Hijova E (2004) Metallothioneins and zinc: their functions and interactions. Bratisl Lek Listy 105:230–234PubMedGoogle Scholar
  29. Hill GM, Link JE (2009) Transporters in the absorption and utilization of zinc and copper. J Anim Sci 87:E85–E89PubMedCrossRefGoogle Scholar
  30. Huang L, Kirschke CP, Gitschier J (2002) Functional characterization of a novel mammalian zinc transporter, ZnT6. J Biol Chem 277:26389–26395PubMedCrossRefGoogle Scholar
  31. Huang L, Yan M, Kirschke CP (2010) Over-expression of ZnT7 increases insulin synthesis and secretion in pancreatic β-cells by promoting insulin gene transcription. Exp Cell Res 316:2630–2643PubMedCrossRefGoogle Scholar
  32. Huang L, Kirschke CP, Lay YA, Levy LB, Lamirande DE, Zhang PH (2012) Znt7-null mice are more susceptible to diet-induced glucose intolerance and insulin resistance. J Biol Chem 287:33883–33896PubMedCrossRefPubMedCentralGoogle Scholar
  33. Ishihara K, Yamazaki T, Ishida Y et al (2006) Zinc transport complexes contribute to the homeostatic maintenance of secretory pathway function in vertebrate cells. J Biol Chem 281:17743–17750PubMedCrossRefGoogle Scholar
  34. Jenkitkasemwong S, Wang CY, Mackenzie B, Knutson MD (2012) Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25:643–655PubMedCrossRefGoogle Scholar
  35. Kambe T (2012) Molecular architecture and function of ZnT transporters. Curr Top Membr 69:199–220PubMedCrossRefGoogle Scholar
  36. Kelleher SL, McCormick NH, Velasquez V, Lopez V (2011) Zinc in specialized secretory tissues: roles in the pancreas, prostate, and mammary gland. Adv Nutr 2:101–111PubMedCrossRefPubMedCentralGoogle Scholar
  37. Khadeer MA, Sahu SN, Bai G, Abdulla S, Gupta A (2005) Expression of the zinc transporter ZIP1 in osteoclasts. Bone 37:296–304PubMedCrossRefGoogle Scholar
  38. Kimura T, Itoh N (2008) Function of metallothionein in gene expression and signal transduction: newly found protective role of metallothionein. J Health Sci 54:251–260CrossRefGoogle Scholar
  39. Kirschke CP, Huang L (2003) ZnT7, a novel Mammalian zinc transporter, accumulates zinc in the Golgi apparatus. J Biol Chem 278:4096–4102PubMedCrossRefGoogle Scholar
  40. Lemaire K, Ravier MA, Schraenen A et al (2009) Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc Natl Acad Sci 106:14872–14877PubMedCrossRefPubMedCentralGoogle Scholar
  41. Lichten LA, Cousins RJ (2009) Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr 29:153–176PubMedCrossRefGoogle Scholar
  42. Liuzzi JP, Bobo JA, Lichten LA, Samuelson DA, Cousins RJ (2004) Responsive transporter genes within the murine intestinal-pancreatic axis form a basis of zinc homeostasis. Proc Natl Acad Sci USA 101:14355–14360PubMedCrossRefPubMedCentralGoogle Scholar
  43. Lu M, Fu D (2007) Structure of the zinc transporter YiiP. Science 317:1746–1748PubMedCrossRefGoogle Scholar
  44. Maret W, Krezel A (2007) Cellular zinc and redox buffering capacity of metallothionein/thionein in health and disease. Mol Med 13:371–375PubMedCrossRefPubMedCentralGoogle Scholar
  45. McCormick NH, Kelleher SL (2012) ZnT4 provides zinc to zinc-dependent proteins in the trans-Golgi network critical for cell function and Zn export in mammary epithelial cells. Am J Physiol Cell Physiol 303:C291–C297PubMedCrossRefPubMedCentralGoogle Scholar
  46. Myers SA, Nield A, Myers M (2012) Zinc transporters, mechanisms of action and therapeutic utility: implications for type 2 diabetes mellitus. J Nutr Metab 2012:173712PubMedCrossRefPubMedCentralGoogle Scholar
  47. Nicolson TJ, Bellomo EA, Wijesekara N 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 58:2070–2083PubMedCrossRefPubMedCentralGoogle Scholar
  48. Palmiter RD, Huang L (2004) Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch 447:744–751PubMedCrossRefGoogle Scholar
  49. Palmiter RD, Cole TB, Quaife CJ, Findley SD (1996) ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci U S A 93:14934–14939PubMedCrossRefPubMedCentralGoogle Scholar
  50. Petersen AB, Smidt K, Magnusson NE, Moore F, Egefjord L, Rungby J (2010) siRNA-mediated knock-down of ZnT3 and ZnT8 affects production and secretion of insulin and apoptosis in INS-1E cells. APMIS 119:93–102PubMedCrossRefGoogle Scholar
  51. Ravier MA, Rutter GA (2005) Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic α-cells. Diabetes 54:1789–1797PubMedCrossRefGoogle Scholar
  52. Ruttkay-Nedecky B, Nejdl L, Gumulec J et al (2013) The role of metallothionein in oxidative stress. Int J Mol Sci 14:6044–6066PubMedCrossRefPubMedCentralGoogle Scholar
  53. Scott DA, Fisher AM (1938) The insulin and the zinc content of normal and diabetic pancreas. J Clin Invest 17:725–728PubMedCrossRefPubMedCentralGoogle Scholar
  54. Sekler I, Sensi SL, Hershfinkel M, Silverman WF (2007) Mechanism and regulation of cellular zinc transport. Mol Med 13:337–343PubMedCrossRefPubMedCentralGoogle Scholar
  55. Sheline CT, Shi C, Takata T et al (2012) Dietary zinc reduction, pyruvate supplementation, or zinc transporter 5 knockout attenuates β-cell death in nonobese diabetic mice, islets, and insulinoma cells. J Nutr 142:2119–2127PubMedCrossRefPubMedCentralGoogle Scholar
  56. Simon SF, Taylor CG (2001) Dietary zinc supplementation attenuates hyperglycemia in db/db mice. Exp Biol Med (Maywood) 226:43–51Google Scholar
  57. Skelin M, Rupnik M, Cencic A (2010) Pancreatic β cell lines and their applications in diabetes mellitus research. Altex 27:105–113PubMedGoogle Scholar
  58. Sondergaard LG, Stoltenberg M, Flyvbjerg A et al (2003) Zinc ions in β-cells of obese, insulin-resistant, and type 2 diabetic rats traced by autometallography. APMIS 111:1147–1154PubMedCrossRefGoogle Scholar
  59. Suhy DA, Simon KD, Linzer DIH, O’Halloran TV (1999) Metallothionein is part of a zinc-scavenging mechanism for cell survival under conditions of extreme zinc deprivation. J Biol Chem 274:9183–9192PubMedCrossRefGoogle Scholar
  60. Taniguchi M, Fukunaka A, Hagihara M et al (2013) Essential role of the zinc transporter ZIP9/SLC39A9 in regulating the activations of Akt and Erk in β-cell receptor signaling pathway in DT40 cells. PLoS One 8:e58022PubMedCrossRefPubMedCentralGoogle Scholar
  61. Taylor KM, Nicholson RI (2003) The LZT proteins; the LIV-1 subfamily of zinc transporters. Biochim Biophys Acta 1611:16–30PubMedCrossRefGoogle Scholar
  62. Taylor KM, Hiscox S, Nicholson RI, Hogstrand C, Kille P (2012) Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. Sci Signal 5:ra11PubMedPubMedCentralGoogle Scholar
  63. Thiel G, Muller I, Rossler OG (2013) Signal transduction via TRPM3 channels in pancreatic β-cells. J Mol Endocrinol 50:R75–R83PubMedCrossRefGoogle Scholar
  64. Tomita T (2000) Metallothionein in pancreatic endocrine neoplasms. Mod Pathol 13:389–395PubMedCrossRefGoogle Scholar
  65. Truong-Tran AQ, Ho LH, Chai F, Zalewski PD (2000) Cellular zinc fluxes and the regulation of apoptosis/gene-directed cell death. J Nutr 130:1459S–1466SPubMedGoogle Scholar
  66. Vert G, Grotz N, Dedaldechamp F et al (2002) IRT1, an Arabidopsis transporter essential for iron uptake from the soil and for plant growth. Plant Cell 14:1223–1233PubMedCrossRefPubMedCentralGoogle Scholar
  67. Wagner TJ, Drews A, Loch S et al (2010) TRPM3 channels provide a regulated influx pathway for zinc in pancreatic β cells. Pflugers Arch Eur J Physiol 460:755–765CrossRefGoogle Scholar
  68. Weaver BP, Dufner-Beattie J, Kambe T, Andrews GK (2007) Novel zinc-responsive post-transcriptional mechanisms reciprocally regulate expression of the mouse Slc39a4 and Slc39a5 zinc transporters (Zip4 and Zip5). Biol Chem 388:1301–1312PubMedCrossRefPubMedCentralGoogle Scholar
  69. Weijers RN (2010) Three-dimensional structure of β-cell-specific zinc transporter, ZnT-8, predicted from the type 2 diabetes-associated gene variant SLC30A8 R325W. Diabetol Metab Syndr 2:33PubMedCrossRefPubMedCentralGoogle Scholar
  70. Wijesekara N, Chimienti F, Wheeler MB (2009) Zinc, a regulator of islet function and glucose homeostasis. Diabetes Obes Metab 11(Suppl 4):202–214PubMedCrossRefGoogle Scholar
  71. Wijesekara N, Dai F, Hardy A et al (2010) β cell-specific Znt8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53:1656–68PubMedCrossRefGoogle Scholar
  72. Wu JP, Ma BY, Ren HW, Zhang LP, Xiang Y, Brown MA (2007) Characterization of metallothioneins (MT-I and MT-II) in the yak. J Anim Sci 85:1357–1362PubMedCrossRefGoogle Scholar
  73. Yan G, Zhang Y, Yu J et al (2012) Slc39a7/zip7 plays a critical role in development and zinc homeostasis in zebrafish. PLoS One 7:e42939PubMedCrossRefPubMedCentralGoogle Scholar
  74. Zalewski P, Millard S, Forbes I et al (1994) Video image analysis of labile zinc in viable pancreatic islet cells using a specific fluorescent probe for zinc. J Histochem Cytochem 42:877–884PubMedCrossRefGoogle Scholar
  75. Zalewski PD, Truong-Tran A, Lincoln SF et al (2006) Use of a zinc fluorophore to measure labile pools of zinc in body fluids and cell-conditioned media. Biotechniques 40:509–520PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Mariea Dencey Bosco
    • 1
  • Chris Drogemuller
    • 2
  • Peter Zalewski
    • 3
  • Patrick Toby Coates
    • 2
    Email author
  1. 1.Basil Hetzel Institute at The Queen Elizabeth Hospital, Centre for Clinical and Experimental Transplantation Laboratory, Discipline of MedicineUniversity of AdelaideAdelaideAustralia
  2. 2.Centre for Clinical and Experimental Transplantation (CCET)University of Adelaide, Royal Adelaide Hospital, Australian Islet ConsortiumAdelaideAustralia
  3. 3.Department of Medicine, Basil Hetzel Institute at the Queen Elizabeth HospitalUniversity of AdelaideAdelaideAustralia

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