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
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.
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.
- 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
- 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