Journal of Molecular Evolution

, Volume 86, Issue 9, pp 613–617 | Cite as

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

  • Kristen E. Syring
  • Karin J. Bosma
  • James K. Oeser
  • Masakazu Shiota
  • Richard M. O’BrienEmail author
Letter to the Editor


In most mammals pancreatic islet beta cells have very high zinc levels that promote the crystallization and storage of insulin. Guinea pigs are unusual amongst mammals in that their islets have very low zinc content. The selectionist theory of insulin evolution proposes that low environmental zinc led to the selection of a mutation in Guinea pig insulin that negated the requirement for zinc binding. In mice deletion of the Slc30a8 gene, that encodes the zinc transporter ZnT8, markedly reduces islet zinc content. We show here that SLC30A8 is a pseudogene in Guinea pigs. We hypothesize that inactivation of the SLC30A8 gene led to low islet zinc content that allowed for the evolution of insulin that no longer bound zinc.



Glucose-stimulated insulin secretion


Type 2 diabetes


Single nucleotide polymorphism


Genome-wide association studies



This research was supported by the following grants: RO’B, DK92589; MS, DK60667. KES and KJB were supported by the Vanderbilt Molecular Endocrinology Training Program Grant 5T32 DK07563.

Author Contributions

KES, KJB, JKO all contributed to gene expression analyses and wrote parts of the manuscript. MS 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.


  1. Beintema JJ, Campagne RN (1987) Molecular evolution of rodent insulins. Mol Biol Evol 4:10PubMedGoogle 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. Gorbunova V, Seluanov A (2009) Coevolution of telomerase activity and body mass in mammals: from mice to beavers. Mech Ageing Dev 130:3CrossRefGoogle Scholar
  10. 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
  11. 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
  12. Jackson IJ (1991) A reappraisal of non-consensus mRNA splice sites. Nucleic Acids Res 19:3795CrossRefGoogle Scholar
  13. 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
  14. 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
  15. Rutter GA, Chimienti F (2015) SLC30A8 mutations in type 2 diabetes. Diabetologia 58:31CrossRefGoogle Scholar
  16. Smith LF (1966) Species variation in the amino acid sequence of insulin. Am J Med 40:662CrossRefGoogle Scholar
  17. 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 157:4534CrossRefGoogle Scholar
  18. Tsirigos KD, Peters C, Shu N, Kall L, Elofsson A (2015) The TOPCONS web server for consensus prediction of membrane protein topology and signal peptides. Nucleic Acids Res 43:W401CrossRefGoogle Scholar
  19. 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
  20. Zimmerman AE, Yip CC (1974) Guinea pig insulin. I. Purification and physical properties. J Biol Chem 249:4021PubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular Physiology and BiophysicsVanderbilt University School of MedicineNashvilleUSA

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