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

  • Karin J. Bosma
  • Kristen E. Syring
  • James K. Oeser
  • Jason D. Lee
  • Richard K. P. Benninger
  • Matthew E. Pamenter
  • Richard M. O’BrienEmail author
Letter to the Editor


Pancreatic islet zinc levels vary widely between species. Very low islet zinc levels in Guinea pigs were thought to be driven by evolution of the INS gene that resulted in the generation of an isoform lacking a histidine at amino acid 10 in the B chain of insulin that is unable to bind zinc. However, we recently showed that the SLC30A8 gene, that encodes the zinc transporter ZnT8, is a pseudogene in Guinea pigs, providing an alternate mechanism to potentially explain the low zinc levels. We show here that the SLC30A8 gene is also inactivated in sheep, cows, chinchillas and naked mole rats but in all four species a histidine is retained at amino acid 10 in the B chain of insulin. Zinc levels are known to be very low in sheep and cow islets. These data suggest that evolution of SLC30A8 rather than INS drives variation in pancreatic islet zinc content in multiple species.


Islet Zinc Diabetes Insulin Evolution 



We thank Dr. Martien A.M. Groenen for comments on the pig genome project and Dr. Daniel Tollin and Wolfgang Schleicher for providing chinchilla DNA. This research was supported by the following grant: R.O’B, DK92589. K. J. B. and K. E. S. were supported by the Vanderbilt Molecular Endocrinology Training Program grant 5T32 DK07563.

Author Contributions

KJB, KES, JKO, JL all contributed to gene expression analyses and wrote parts of the manuscript. RKPB, MEP and RO’B designed experiments and wrote parts of the manuscript.

Compliance with Ethical Standards

Conflict of interest

The authors have no financial interests that would result in a conflict of interest with respect to this work.

Supplementary material

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Supplementary material 1 (DOCX 146 kb)
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Supplementary material 2 (DOCX 222 kb)
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Supplementary material 3 (DOCX 25 kb)


  1. Beintema JJ, Campagne RN (1987) Molecular evolution of rodent insulins. Mol Biol Evol 4:10Google Scholar
  2. Blundell TL, Cutfield JF, Cutfield SM, Dodson EJ, Dodson GG, Hodgkin DC, Mercola DA (1972) Three-dimensional atomic structure of insulin and its relationship to activity. Diabetes 21:492CrossRefGoogle Scholar
  3. Chan SJ, Episkopou V, Zeitlin S, Karathanasis SK, MacKrell A, Steiner DF, Efstratiadis A (1984) Guinea pig preproinsulin gene: an evolutionary compromise? Proc Natl Acad Sci USA 81:5046CrossRefGoogle Scholar
  4. Chausmer AB (1998) Zinc, insulin and diabetes. J Am Coll Nutr 17:109CrossRefGoogle Scholar
  5. 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 53:2330CrossRefGoogle Scholar
  6. Davidson HW, Wenzlau JM, O’Brien RM (2014) Zinc transporter 8 (ZnT8) and beta cell function. Trends Endocrinol Metab 25:415CrossRefGoogle Scholar
  7. Dunn MF (2005) Zinc-ligand interactions modulate assembly and stability of the insulin hexamer—a review. Biometals 18:295CrossRefGoogle Scholar
  8. 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 46:357CrossRefGoogle Scholar
  9. Galabova R, Gospodinov C, Ogneva V, Petkov P (1971) Histochemistry of the islands of Langerhans in the pancreas of the sheep (Ovis aries). Ann Histochim 16:91Google Scholar
  10. Gorbunova V, Seluanov A (2009) Coevolution of telomerase activity and body mass in mammals: from mice to beavers. Mech Ageing Dev 130:3CrossRefGoogle Scholar
  11. 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):112CrossRefGoogle Scholar
  12. Havu N, Lundgren G, Falkmer S (1977) Zinc and manganese contents of micro-dissected pancreatic islets of some rodents. A microchemical study in adult and newborn guinea pigs, rats, Chinese hamsters and spiny mice. Acta Endocrinol (Copenh) 86:570CrossRefGoogle Scholar
  13. Jackson IJ (1991) A reappraisal of non-consensus mRNA splice sites. Nucleic Acids Res 19:3795CrossRefGoogle Scholar
  14. Petkov P, Galabova R (1969) Distribution of zinc in the pancreas of some mammals. Acta Histochem 32:93Google Scholar
  15. Petkov PE, Gospodinov C, Galabova R (1970) Histochemistry of Langerhans’ islets in the pancreas of cattle (Bos taurus L.). Histochemie 23:127CrossRefGoogle Scholar
  16. Pound LD, Sarkar S, Benninger RK, Wang Y, Suwanichkul A, Shadoan MK, Printz RL, Oeser JK, Lee CE, Piston DW, McGuinness OP, Hutton JC, Powell DR, O’Brien RM (2009) Deletion of the mouse Slc30a8 gene encoding zinc transporter-8 results in impaired insulin secretion. Biochem J 421:371CrossRefGoogle Scholar
  17. 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):106CrossRefGoogle Scholar
  18. Rutter GA, Chimienti F (2015) SLC30A8 mutations in type 2 diabetes. Diabetologia 58:31CrossRefGoogle Scholar
  19. Schweiger M, Steffl M, Amselgruber WM (2013) The zinc transporter ZnT8 (slc30A8) is expressed exclusively in beta cells in porcine islets. Histochem Cell Biol 140:677CrossRefGoogle Scholar
  20. 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 445:881CrossRefGoogle Scholar
  21. Smith LF (1966) Species variation in the amino acid sequence of insulin. Am J Med 40:662CrossRefGoogle Scholar
  22. Syring KE, Bosma KJ, Oeser JK, Shiota M, O’Brien RM (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. J Mol Evol 86:613CrossRefGoogle Scholar
  23. Wood SP, Blundell TL, Wollmer A, Lazarus NR, Neville RW (1975) The relation of conformation and association of insulin to receptor binding; x-ray and circular-dichroism studies on bovine and hystricomorph insulins. Eur J Biochem 55:531CrossRefGoogle Scholar
  24. Xu Y, Yan Y, Seeman D, Sun L, Dubin PL (2012) Multimerization and aggregation of native-state insulin: effect of zinc. Langmuir 28:579CrossRefGoogle Scholar
  25. Ynsa MD, Ren MQ, Rajendran R, Sidhapuriwala JN, van Kan JA, Bhatia M, Watt F (2009) Zinc mapping and density imaging of rabbit pancreas endocrine tissue sections using nuclear microscopy. Microsc Microanal 15:345CrossRefGoogle Scholar
  26. Zimmerman AE, Yip CC (1974) Guinea pig insulin. I. Purification and physical properties. J Biol Chem 249:4021Google Scholar

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Authors and Affiliations

  1. 1.Department of Molecular Physiology and BiophysicsVanderbilt University School of MedicineNashvilleUSA
  2. 2.Department of BioengineeringUniversity of Colorado Anschutz Medical CampusAuroraUSA
  3. 3.Department of BiologyUniversity of OttawaOttawaCanada
  4. 4.University of Ottawa Brain and Mind Research InstituteOttawaCanada

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