Skip to main content

SLC30A8 mutations in type 2 diabetes

Abstract

SLC30A8 encodes the secretory granule-resident and largely endocrine pancreas-restricted zinc transporter ZnT8. Interest in this gene product was sparked amongst diabetologists in 2007 when the first genome-wide association study for type 2 diabetes identified polymorphisms in SLC30A8 as affecting disease risk. Thus, the common polymorphism rs13266634 was associated with lowered beta cell function and a 14% increase in diabetes abundance per risk (C) allele. This non-synonymous variant encodes a tryptophan-to-arginine switch at position 325 in the protein’s intracellular carboxy-terminal domain, resulting in reduced zinc transport activity and, consequently, decreased intragranular zinc levels. Whereas insulin secretion from isolated islets is most often increased in mice inactivated for Slc30a8, null animals usually show impaired glucose tolerance and lowered circulating insulin. Since Slc30a8 null animals display little, if any, zinc secretion from islets, the lower plasma insulin levels could be explained by increased hepatic clearance as a result of lowered local zinc levels, or less efficient insulin action on target tissues. Despite the emerging consensus on the role of ZnT8 in glucose homeostasis, a recent genetic study in humans has unexpectedly identified loss-of-function SLC30A8 mutants that are associated with protection from diabetes. Here, we attempt to reconcile these apparently contradictory findings, implicating (1) differing degrees of inhibition of ZnT8 activity in carriers of common variants vs rare loss-of-function forms, (2) effects dependent on age or hypoxic beta cell stress. We propose that these variables conspire to affect both the size and the direction of the effect of SLC30A8 risk alleles in man.

This is a preview of subscription content, access via your institution.

Fig. 1

Abbreviations

GWAS:

Genome-wide association study

LoF:

Loss-of-function

MT:

Metallothionein

PC:

Prohormone convertase

SNP:

Single nucleotide polymorphism

ZnT:

Zinc transporter

ZiP:

Zinc importer

References

  1. Maret W (2013) Zinc biochemistry: from a single zinc enzyme to a key element of life. Adv Nutr 4:82–91

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  2. Dodson G, Steiner D (1998) The role of assembly in insulin’s biosynthesis. Curr Opin Struct Biol 8:189–194

    CAS  PubMed  Article  Google Scholar 

  3. Emdin SO, Dodson GG, Cutfield JM, Cutfield SM (1980) Role of zinc in insulin biosynthesis. Some possible zinc-insulin interactions in the pancreatic B cell. Diabetologia 19:174–182

    CAS  PubMed  Article  Google Scholar 

  4. Hutton JC, Penn EJ, Peshavaria M (1983) Low-molecular-weight constituents of isolated insulin-secretory vesicles. Bivalent cations, adenine nucleotides and inorganic phosphate. Biochem J 210:297–305

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Vinkenborg JL, Nicolson TJ, Bellomo EA, Koay MS, Rutter GA, Merkx M (2009) Genetically encoded FRET sensors to monitor intracellular Zn2+ homeostasis. Nat Methods 6:737–740

    CAS  PubMed  Article  Google Scholar 

  6. Carroll RJ, Hammer RE, Chan SJ, Swift HH, Rubenstein AH, Steiner DF (1988) A mutant human proinsulin is secreted from islets of Langerhans in increased amounts via an unregulated pathway. Proc Natl Acad Sci U S A 85:8943–8947

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  7. Chausmer AB (1998) Zinc, insulin and diabetes. J Am Coll Nutr 17:109–115

    CAS  PubMed  Article  Google Scholar 

  8. Sladek R, Rocheleau G, Rung J et al (2007) A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445:881–885

    CAS  PubMed  Article  Google Scholar 

  9. Chimienti F, Devergnas S, Favier A, Seve M (2004) Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules. Diabetes 53:2330–2337

    CAS  PubMed  Article  Google Scholar 

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

    PubMed  Article  Google Scholar 

  11. Gerber PA, Bellomo EA, Hodson DJ et al (2014) Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Diabetologia 57:1635–1644

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  12. Boesgaard TW, Zilinskaite J, Vanttinen M 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

    CAS  PubMed  Article  Google Scholar 

  13. Cauchi S, Del GS, Choquet H et al (2010) Meta-analysis and functional effects of the SLC30A8 rs13266634 polymorphism on isolated human pancreatic islets. Mol Genet Metab 100:77–82

    CAS  PubMed  Article  Google Scholar 

  14. Kirchhoff K, Machicao F, Haupt A et al (2008) Polymorphisms in the TCF7L2, CDKAL1 and SLC30A8 genes are associated with impaired proinsulin conversion. Diabetologia 51:597–601

    CAS  PubMed  Article  Google Scholar 

  15. 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

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  16. 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 U S A 106:14872–14877

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  17. Tamaki M, Fujitani Y, Hara A et al (2013) The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest 123:4513–4524

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  18. Wenzlau JM, Juhl K, Yu L et al (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A 104:17040–17045

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  19. Wenzlau JM, Moua O, Sarkar SA et al (2008) SlC30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. Ann N Y Acad Sci 1150:256–259

  20. 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 2:33

    PubMed Central  PubMed  Article  Google Scholar 

  21. 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

    CAS  PubMed  Article  Google Scholar 

  22. Kim I, Kang ES, Yim YS et al (2010) A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion. Pharmacogenomics J 11:191–198

    PubMed  Article  Google Scholar 

  23. Davidson HW, Wenzlau JM, O’Brien RM (2014) Zinc transporter 8 (ZnT8) and beta cell function. Trends Endocrinol Metab 25:415–424

  24. Valentine RA, Jackson KA, Christie GR, Mathers JC, Taylor PM, Ford D (2007) ZnT5 variant B is a bidirectional zinc transporter and mediates zinc uptake in human intestinal Caco-2 cells. J Biol Chem 282:14389–14393

    CAS  PubMed  Article  Google Scholar 

  25. Hoch E, Lin W, Chai J, Hershfinkel M, Fu D, Sekler I (2012) Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity. Proc Natl Acad Sci U S A 109:7202–7207

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  26. Pound LD, Sarkar SA, Benninger RK et al (2009) Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem J 421:371–376

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  27. Pound LD, Sarkar SA, Ustione A 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

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  28. Wijesekara N, Dai FF, Hardy AB et al (2010) Beta cell specific ZnT8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53:1656–1668

    CAS  PubMed  Article  Google Scholar 

  29. Hardy AB, Wijesekara N, Genkin I et al (2012) Effects of high-fat diet feeding on Znt8-null mice: differences between beta-cell and global knockout of Znt8. Am J Physiol Endocrinol Metab 302:E1084–E1096

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  30. Rutter GA (2010) Think zinc: new roles for zinc in the control of insulin secretion. Islets 2:1–2

    Article  Google Scholar 

  31. Quarterman J, Mills CF, Humphries WR (1966) The reduced secretion of, and sensitivity to insulin in zinc-deficient rats. Biochem Biophys Res Commun 25:354–358

    CAS  PubMed  Article  Google Scholar 

  32. Coulston L, Dandona P (1980) Insulin-like effect of zinc on adipocytes. Diabetes 29:665–667

    CAS  PubMed  Article  Google Scholar 

  33. Haase H, Maret W (2005) Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. Biometals 18:333–338

    CAS  PubMed  Article  Google Scholar 

  34. Flannick J, Thorleifsson G, Beer NL et al (2014) Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet 46:357–363

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  35. Kang ES, Kim MS, Kim YS et al (2008) A polymorphism in the zinc transporter gene SLC30A8 confers resistance against posttransplantation diabetes mellitus in renal allograft recipients. Diabetes 57:1043–1047

    CAS  PubMed  Article  Google Scholar 

  36. Kim BJ, Kim YH, Kim S et al (2000) Zinc as a paracrine effector in pancreatic islet cell death. Diabetes 49:367–372

    CAS  PubMed  Article  Google Scholar 

  37. Chimienti F, Jourdan E, Favier A, Seve M (2001) Zinc resistance impairs sensitivity to oxidative stress in HeLa cells: protection through metallothioneins expression. Free Radic Biol Med 31:1179–1190

    CAS  PubMed  Article  Google Scholar 

  38. Zeggini E, Weedon MN, Lindgren CM et al (2007) Replication of genome-wide association signals in U.K. samples reveals risk loci for type 2 diabetes. Science 316:1336–1341

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  39. Scott LJ, Mohlke KL, Bonnycastle LL et al (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316:1341–1345

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  40. da Silva Xavier G, Bellomo EA, McGinty JA, French PM, Rutter GA (2013) Animal models of GWAS-identified type 2 diabetes genes. J Diabetes Res 2013:906590

    PubMed Central  PubMed  Article  Google Scholar 

  41. Kahn SE, Zraika S, Utzschneider KM, Hull RL (2009) The beta cell lesion in type 2 diabetes: there has to be a primary functional abnormality. Diabetologia 52:1003–1012

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  42. van Hoek M, Dehghan A, Witteman JC et al (2008) Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study. Diabetes 57:3122–3128

    PubMed Central  PubMed  Article  Google Scholar 

  43. Lango H, Palmer CN, Morris AD et al (2008) Assessing the combined impact of 18 common genetic variants of modest effect sizes on type 2 diabetes risk. Diabetes 57:3129–3135

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  44. Nature Medicine (2013) Of men, not mice. Nat Med 19:379

    Article  Google Scholar 

  45. da Silva Xavier G, Loder MK, McDonald A et al (2009) TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes 58:894–905

    PubMed Central  PubMed  Article  Google Scholar 

  46. da Silva Xavier G, Mondragon A, Sun G et al (2012) Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2 null mice. Diabetologia 55:2667–2676

    CAS  PubMed  Article  Google Scholar 

  47. White CR, Seymour RS (2003) Mammalian basal metabolic rate is proportional to body mass2/3. Proc Natl Acad Sci U S A 100:4046–4049

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  48. Tamaki M, Fujitani Y, Uchida T, Hirose T, Kawamori R, Watada H (2009) Downregulation of ZnT8 expression in pancreatic beta-cells of diabetic mice. Islets 1:124–128

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

We thank Professor Mark McCarthy (University of Oxford, UK) for useful discussion.

Funding

GAR thanks the MRC (UK) for Programme grant MR/J0003042/1, the BBSRC (UK) for a Project grant (BB/J015873/1) the Royal Society for a Wolfson Research Merit Award and the Wellcome Trust for a Senior Investigator Award (WT098424AIA). The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 155005 (IMIDIA), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution (to GAR).

Duality of interest

There is no duality of interest associated with this manuscript.

Contribution statement

Both authors were responsible for the conception and design of the manuscript, drafting the article and revising it critically for important intellectual content. Both authors approved the version to be published.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Guy A. Rutter.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00125-014-3405-7

Keywords

  • Diabetes genetics
  • GWAS
  • Insulin secretion
  • Review
  • SLC30A8
  • Zinc transport
  • ZnT8