Skip to main content
SpringerLink
Log in

Zinc Transporters in the Endocrine Pancreas

  • Reference work entry
  • First Online:
Islets of Langerhans

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 699.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Achenbach P, Lampasona V, Landherr U et al (2009) Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia 52:1881–1888

    Article  PubMed  CAS  Google Scholar 

  • 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 129:1643–1648

    PubMed  CAS  Google Scholar 

  • 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 86:337–348

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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:e48679

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 286:25778–25789

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bosomworth HJ, Adlard PA, Ford D, Valentine RA (2013) Altered expression of ZnT10 in Alzheimer’s disease brain. PLoS One 8:e65475

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 337:233–245

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 10:104

    Article  PubMed  PubMed Central  Google Scholar 

  • Chao Y, Fu D (2004) Thermodynamic studies of the mechanism of metal binding to the Escherichia coli zinc transporter YiiP. J Biol Chem 279:17173–17180

    Article  PubMed  CAS  Google Scholar 

  • 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 50:2040–2046

    Article  PubMed  CAS  Google Scholar 

  • 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 119:4199–4206

    Article  PubMed  CAS  Google Scholar 

  • Claus J, Chavarria-Krauser A (2012) Modeling regulation of zinc uptake via ZIP transporters in yeast and plant roots. PLoS One 7:e37193

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 110:2140–2145

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Cousins RJ, Lee-Ambrose LM (1992) Nuclear zinc uptake and interactions and metallothionein gene expression are influenced by dietary zinc in rats. J Nutr 122:56–64

    PubMed  CAS  Google Scholar 

  • Cousins RJ, Liuzzi JP, Lichten LA (2006) Mammalian zinc transport, trafficking, and signals. J Biol Chem 281:24085–24089

    Article  PubMed  CAS  Google Scholar 

  • 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 6:37

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 68:699–709

    Article  PubMed  CAS  Google Scholar 

  • 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 279:49082–49090

    Article  PubMed  CAS  Google Scholar 

  • Egefjord L, Petersen AB, Rungby J (2010) Zinc, α cells and glucagon secretion. Curr Diabetes Rev 6:52–57

    Article  PubMed  CAS  Google Scholar 

  • El Muayed M, Raja MR, Zhang X et al (2012) Accumulation of cadmium in insulin-producing β cells. Islets 4:405–416

    Article  PubMed  PubMed Central  Google Scholar 

  • Emdin SO, Dodson GG, Cutfield JM, Cutfield SM (1980) Role of zinc in insulin biosynthesis. Diabetologia 19:174–182

    Article  PubMed  CAS  Google Scholar 

  • Foster MC, Leapman RD, Li MX, Atwater I (1993) Elemental composition of secretory granules in pancreatic islets of Langerhans. Biophys J 64:525–532

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 54:1808–1815

    Article  PubMed  CAS  Google Scholar 

  • 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:e3642

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 187:1604–1611

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 107:2818–2823

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 11:780–786

    Article  PubMed  CAS  Google Scholar 

  • Hijova E (2004) Metallothioneins and zinc: their functions and interactions. Bratisl Lek Listy 105:230–234

    PubMed  CAS  Google Scholar 

  • Hill GM, Link JE (2009) Transporters in the absorption and utilization of zinc and copper. J Anim Sci 87:E85–E89

    Article  PubMed  CAS  Google Scholar 

  • Huang L, Kirschke CP, Gitschier J (2002) Functional characterization of a novel mammalian zinc transporter, ZnT6. J Biol Chem 277:26389–26395

    Article  PubMed  CAS  Google Scholar 

  • 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 316:2630–2643

    Article  PubMed  CAS  Google Scholar 

  • 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 287:33883–33896

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 281:17743–17750

    Article  PubMed  CAS  Google Scholar 

  • Jenkitkasemwong S, Wang CY, Mackenzie B, Knutson MD (2012) Physiologic implications of metal-ion transport by ZIP14 and ZIP8. Biometals 25:643–655

    Article  PubMed  CAS  Google Scholar 

  • Kambe T (2012) Molecular architecture and function of ZnT transporters. Curr Top Membr 69:199–220

    Article  PubMed  CAS  Google Scholar 

  • Kelleher SL, McCormick NH, Velasquez V, Lopez V (2011) Zinc in specialized secretory tissues: roles in the pancreas, prostate, and mammary gland. Adv Nutr 2:101–111

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Khadeer MA, Sahu SN, Bai G, Abdulla S, Gupta A (2005) Expression of the zinc transporter ZIP1 in osteoclasts. Bone 37:296–304

    Article  PubMed  CAS  Google Scholar 

  • Kimura T, Itoh N (2008) Function of metallothionein in gene expression and signal transduction: newly found protective role of metallothionein. J Health Sci 54:251–260

    Article  CAS  Google Scholar 

  • Kirschke CP, Huang L (2003) ZnT7, a novel Mammalian zinc transporter, accumulates zinc in the Golgi apparatus. J Biol Chem 278:4096–4102

    Article  PubMed  CAS  Google Scholar 

  • 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 106:14872–14877

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lichten LA, Cousins RJ (2009) Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr 29:153–176

    Article  PubMed  Google Scholar 

  • 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 101:14355–14360

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Lu M, Fu D (2007) Structure of the zinc transporter YiiP. Science 317:1746–1748

    Article  PubMed  CAS  Google Scholar 

  • Maret W, Krezel A (2007) Cellular zinc and redox buffering capacity of metallothionein/thionein in health and disease. Mol Med 13:371–375

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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–C297

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Myers SA, Nield A, Myers M (2012) Zinc transporters, mechanisms of action and therapeutic utility: implications for type 2 diabetes mellitus. J Nutr Metab 2012:173712

    Article  PubMed  PubMed Central  Google Scholar 

  • 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 58:2070–2083

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Palmiter RD, Huang L (2004) Efflux and compartmentalization of zinc by members of the SLC30 family of solute carriers. Pflugers Arch 447:744–751

    Article  PubMed  CAS  Google Scholar 

  • 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 93:14934–14939

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 119:93–102

    Article  PubMed  Google Scholar 

  • Ravier MA, Rutter GA (2005) Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic α-cells. Diabetes 54:1789–1797

    Article  PubMed  CAS  Google Scholar 

  • Ruttkay-Nedecky B, Nejdl L, Gumulec J et al (2013) The role of metallothionein in oxidative stress. Int J Mol Sci 14:6044–6066

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Scott DA, Fisher AM (1938) The insulin and the zinc content of normal and diabetic pancreas. J Clin Invest 17:725–728

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Sekler I, Sensi SL, Hershfinkel M, Silverman WF (2007) Mechanism and regulation of cellular zinc transport. Mol Med 13:337–343

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 142:2119–2127

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Simon SF, Taylor CG (2001) Dietary zinc supplementation attenuates hyperglycemia in db/db mice. Exp Biol Med (Maywood) 226:43–51

    CAS  Google Scholar 

  • Skelin M, Rupnik M, Cencic A (2010) Pancreatic β cell lines and their applications in diabetes mellitus research. Altex 27:105–113

    PubMed  Google Scholar 

  • 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 111:1147–1154

    Article  PubMed  CAS  Google Scholar 

  • 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 274:9183–9192

    Article  PubMed  CAS  Google Scholar 

  • 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:e58022

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Taylor KM, Nicholson RI (2003) The LZT proteins; the LIV-1 subfamily of zinc transporters. Biochim Biophys Acta 1611:16–30

    Article  PubMed  CAS  Google Scholar 

  • 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:ra11

    PubMed  PubMed Central  Google Scholar 

  • Thiel G, Muller I, Rossler OG (2013) Signal transduction via TRPM3 channels in pancreatic β-cells. J Mol Endocrinol 50:R75–R83

    Article  PubMed  CAS  Google Scholar 

  • Tomita T (2000) Metallothionein in pancreatic endocrine neoplasms. Mod Pathol 13:389–395

    Article  PubMed  CAS  Google Scholar 

  • 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–1466S

    PubMed  CAS  Google Scholar 

  • 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 14:1223–1233

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 460:755–765

    Article  CAS  Google Scholar 

  • 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 388:1301–1312

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 2:33

    Article  PubMed  PubMed Central  Google Scholar 

  • Wijesekara N, Chimienti F, Wheeler MB (2009) Zinc, a regulator of islet function and glucose homeostasis. Diabetes Obes Metab 11(Suppl 4):202–214

    Article  PubMed  CAS  Google Scholar 

  • 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 53:1656–68

    Article  PubMed  CAS  Google Scholar 

  • 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 85:1357–1362

    Article  PubMed  CAS  Google Scholar 

  • 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:e42939

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • 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 42:877–884

    Article  PubMed  CAS  Google Scholar 

  • 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 40:509–520

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Basil Hetzel Institute at The Queen Elizabeth Hospital, Centre for Clinical and Experimental Transplantation Laboratory, Discipline of Medicine, University of Adelaide, Adelaide, SA, Australia

    Mariea Dencey Bosco

  2. Centre for Clinical and Experimental Transplantation (CCET), University of Adelaide, Royal Adelaide Hospital, Australian Islet Consortium, Adelaide, SA, Australia

    Chris Drogemuller & Patrick Toby Coates

  3. Department of Medicine, Basil Hetzel Institute at the Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA, Australia

    Peter Zalewski

Authors
  1. Mariea Dencey Bosco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chris Drogemuller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Zalewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Patrick Toby Coates
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick Toby Coates .

Editor information

Editors and Affiliations

  1. Department of Clinical Sciences and Education, Sodersjukhuset, Karolinska Institutet, Stockholm, Sweden

    Md. Shahidul Islam

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Bosco, M.D., Drogemuller, C., Zalewski, P., Coates, P.T. (2015). Zinc Transporters in the Endocrine Pancreas. In: Islam, M. (eds) Islets of Langerhans. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6686-0_42

Download citation

Publish with us

Policies and ethics

Search

Navigation