Emerging Role of Zinc Transporter-8 Autoantibodies (ZnT8A) in Type 1 Diabetes Mellitus- A Review

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Afreen Bhatty
Saeeda Baig
Zil-e-Rubab .
Moazzam Ali Shahid


Zinc, an important micronutrient for the storage, structural stabilization, secretion and action of insulin, is present in highest concentration in pancreas. The transport of zinc occurs through the zinc transporter-8 (ZnT8) to the insulin secretory vesicles. Zinc Transporter-8 Autoantibodies (ZnT8A) has been found to be associated with Type 2 Diabetes Mellitus. Recently it is recognized as a new autoantigen in Type 1 Diabetes Mellitus (T1DM) and its autoantibodies have been found in 50-60% of individuals with T1DM. Moreover, ZnT8A exhibit humoral auto reactivity which is not displayed by any of the other islet autoantigen like glutamine decarboxylase (GAD), insulin or tyrosine phosphate-related molecules (IA-2). Immunity against ZnT8 is dependent on clinical characteristics, which may provide evidence for early recognition highlighting the importance of this transporter in the pathogenesis of T1DM.

Information regarding this article was retrieved through PubMed, Google Scholar and other search engines available in the University by using the keywords zinc, ZnT, ZnT8, SLC30A8 (Solute carrier 30 member 8) and Type 1 Diabetes Mellitus. Information was gathered through original researches, reviews and epidemiological studies published up to August 2019.The aim of this review is to summarize the emerging role of ZnT8A in diagnosis and understanding the genetic basis of Type 1 Diabetes Mellitus.

Diabetes mellitus, type 1, insulin, zinc.

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How to Cite
Bhatty, A., Baig, S., ., Z.- e-R., & Shahid, M. A. (2019). Emerging Role of Zinc Transporter-8 Autoantibodies (ZnT8A) in Type 1 Diabetes Mellitus- A Review. Journal of Advances in Medicine and Medical Research, 31(6), 1-10. https://doi.org/10.9734/jammr/2019/v31i630304
Review Article


Kawasaki E. ZnT8 and type 1 diabetes. Endocrine Journal. 2012;59(7):531-7.

Michels A, Zhang L, Khadra A, Kushner JA, Redondo MJ, Pietropaolo M. Prediction and prevention of type 1 diabetes: Update on success of prediction and struggles at prevention. Pediatric diabetes. 2015;16(7): 465-84.

Wenzlau JM, Hutton JC. Novel diabetes autoantibodies and prediction of type 1 diabetes. Current Diabetes Reports. 2013;13(5):608-15.

Andersson C, Larsson K, Vaziri-Sani F, Lynch K, Carlsson A, Cedervall E, Jönsson B, Neiderud J, Månsson M, Nilsson A, Lernmark Å. The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes. Autoimmunity. 2011; 44(5):394-405.

Rogowicz-Frontczak A, Pilacinski S, Wyka K, Wierusz-Wysocka B, Zozulinska-Ziolkiewicz D. Zinc transporter 8 autoantibodies (ZnT8-ab) are associated with higher prevalence of multiple diabetes-related autoantibodies in adults with type 1 diabetes. Diabetes Research and Clinical Practice. 2018;146:313-20.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2005;28(1):S37.

Gomes KF, Semzezem C, Batista R, Fukui RT, Santos AS, Correia MR, Passos-Bueno MR, da Silva ME. Importance of zinc transporter 8 autoantibody in the diagnosis of type 1 diabetes in Latin Americans. Scientific Reports. 2017; 7(1):207.

Precechtelova J, Borsanyiova M, Sarmirova S, Bopegamage S. Type I diabetes mellitus: Genetic factors and presumptive enteroviral etiology or protection. Journal of Pathogens. 2014; 2014.

Abdel-Moneim A, El-Senousy WM, Abdel-Latif M, Khalil RG, Arafa AA. Increased incidence of Anti-IgG of Coxsackievirus and cytomegalovirus among diabetic children in Egypt. International Journal of Bioassays. 2017;6(9):5489-93.

Federation ID. IDF diabetes atlas eighth edition; 2017.
(Accessed 13 October 2019)

Parkkola A, Härkönen T, Ryhänen SJ, Ilonen J, Knip M. Finnish pediatric diabetes register. Extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children. Diabetes Care. 2013;36(2):348-54.

Redondo MJ, Fain PR, Krischer JP, Yu L, Cuthbertson D, Winter WE, Eisenbarth GS. DPT-1 Study group. Expression of beta-cell autoimmunity does not differ between potential dizygotic twins and siblings of patients with type 1 diabetes. Journal of autoimmunity. 2004;23(3):275-9.

Regnell SE, Lernmark Å. Early prediction of autoimmune (type 1) diabetes. Diabeto-logia. 2017;60(8):1370-81.

Li SW, Koya V, Li Y, Donelan W, Lin P, Reeves WH, Yang LJ. Pancreatic duodenal homeobox 1 protein is a novel β-cell-specific autoantigen for type I diabetes. Laboratory Investigation. 2010; 90(1):31.

Stadinski BD, Delong T, Reisdorph N, Reisdorph R, Powell RL, Armstrong M, Piganelli JD, Barbour G, Bradley B, Crawford F, Marrack P. Chromogranin A is an autoantigen in type 1 diabetes. Nature Immunology. 2010;11(3):225.

Wan H, Merriman C, Atkinson MA, Wasserfall CH, Mcgrail KM, Liang Y, Fu D, Dai H. Proteoliposome-based full-length ZnT8 self-antigen for type 1 diabetes diagnosis on a plasmonic platform. Proceedings of the National Academy of Sciences. 2017;114(38):10196-201.

Myers SA, Nield A, Myers M. Zinc transporters, mechanisms of action and therapeutic utility: Implications for type 2 diabetes mellitus. Journal of Nutrition and Metabolism; 2012.

Wenzlau JM, Liu Y, Yu L, Moua O, Fowler KT, Rangasamy S, Walters J, Eisenbarth GS, Davidson HW, Hutton JC. A common nonsynonymous single nucleotide poly-morphism in the SLC30A8 gene determines ZnT8 autoantibody specificity in type 1 diabetes. Diabetes. 2008;57(10): 2693-7.

Jeong J, Eide DJ. The SLC39 family of zinc transporters. Molecular Aspects of Medicine. 2013;34(2-3):612-9.

Fukada T, Yamasaki S, Nishida K, Murakami M, Hirano T. Zinc homeostasis and signaling in health and diseases. JBIC Journal of Biological Inorganic Chemistry. 2011;16(7):1123-34.

Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME. Zinc and human health: An update. Archives of toxicology. 2012;86(4):521-34.

Kambe T. An overview of a wide range of functions of ZnT and Zip zinc transporters in the secretory pathway. Bioscience, Biotechnology and Biochemistry. 2011; 75(6):1036-43.

Bin BH, Seo J, Kim ST. Function, Structure, and Transport Aspects of ZIP and ZnT Zinc Transporters in Immune Cells. Journal of Immunology Research; 2018.

Han S, Donelan W, Wang H, Reeves W, Yang LJ. Novel autoantigens in type 1 diabetes. American Journal of Trans-lational Research. 2013;5(4):379.

Rorsman P, Ashcroft FM. Pancreatic β-cell electrical activity and insulin secretion: Of mice and men. Physiological Reviews. 2017;98(1):117-214.

Liu M, Weiss MA, Arunagiri A, Yong J, Rege N, Sun J, Haataja L, Kaufman RJ, Arvan P. Biosynthesis, structure and folding of the insulin precursor protein. Diabetes, Obesity and Metabolism. 2018; 20:28-50.

Thirunavukkarasu R, Asirvatham AJ, Chitra A, Jayalakshmi M. SLC30A8 Gene rs13266634 C/T Polymorphism in Children with Type 1 Diabetes in Tamil Nadu, India. Journal of Clinical Research in Pediatric Endocrinology. 2019;11(1):55.

Noble JA. Immunogenetics of type 1 diabetes: A comprehensive review. Journal of Autoimmunity. 2015;64:101-12.

Pociot F, Lernmark Å. Genetic risk factors for type 1 diabetes. The Lancet. 2016; 387(10035):2331-9.

Seve M, Chimienti F, Devergnas S, Favier A. In silico identification and expression of SLC30 family genes: An expressed sequence tag data mining strategy for the characterization of zinc transporters' tissue expression. BMC genomics. 2004;5(1):32.

Xu K, Zha M, Wu X, Yu Z, Yu R, Xu X, Chen H, Yang T. Association between rs13266634 C/T polymorphisms of solute carrier family 30 member 8 (SLC30A8) and type 2 diabetes, impaired glucose tolerance, type 1 diabetes—a meta-analysis. Diabetes Research and Clinical Practice. 2011;91(2):195-202.

Achenbach P, Lampasona V, Landherr U, Koczwara K, Krause S, Grallert H, Winkler C, Pflüger M, Illig T, Bonifacio E, Ziegler AG. Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk. Diabetologia. 2009;52(9): 1881-8.

Yi B, Huang G, Zhou ZG. Current and future clinical applications of zinc transporter-8 in type 1 diabetes mellitus. Chinese Medical Journal. 2015;128(17): 2387.

Dereke J, Palmqvist S, Nilsson C, Landin–Olsson M, Hillman M. The prevalence and predictive value of the SLC30A8 R325W polymorphism and zinc transporter 8 autoantibodies in the development of GDM and postpartum type 1 diabetes. Endocrine. 2016;53(3):740-6.

Sanna A, Firinu D, Zavattari P, Valera P. Zinc status and autoimmunity: A systematic review and meta-analysis. Nutrients. 2018;10(1):68.

Maares M, Haase H. Zinc and immunity: An essential interrelation. Archives of Biochemistry and Biophysics. 2016; 611:58-65.

Elmaoğulları S, Uçaktürk SA, Elbeg Ş, Döğer E, Tayfun M, Gürbüz F, Bideci A. Prevalence of ZnT8 antibody in Turkish children and adolescents with new onset type 1 diabetes. Journal of Clinical Research in Pediatric Endocrinology. 2018;10(2):108.

Chimienti F, Devergnas S, Pattou F, Schuit F, Garcia-Cuenca R, Vandewalle B, Kerr-Conte J, Van Lommel L, Grunwald D, Favier A, Seve M. In vivo expression and functional characterization of the zinc transporter ZnT8 in glucose-induced insulin secretion. Journal of Cell Science. 2006;119(20):4199-206.

Huang L, Kirschke CP. Down-regulation of zinc transporter 8 (SLC30A8) in pancreatic beta-cells promotes cell survival. Austin J Endocrinol Diabetes. 2016;3(1):1037.

Egefjord L, Jensen JL, Bang-Berthelsen CH, Petersen AB, Smidt K, Schmitz O, Karlsen AE, Pociot F, Chimienti F, Rungby J, Magnusson NE. Zinc transporter gene expression is regulated by pro-inflammatory cytokines: a potential role for zinc transporters in beta-cell apoptosis?. BMC Endocrine Disorders. 2009;9(1): 7.

Kawasaki E, Nakamura K, Kuriya G, Satoh T, Kobayashi M, Kuwahara H, Abiru N, Yamasaki H, Matsuura N, Miura J, Uchigata Y. Differences in the humoral autoreactivity to zinc transporter 8 between childhood-and adult-onset type 1 diabetes in Japanese patients. Clinical Immunology. 2011;138(2):146-53.

Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proceedings of the National Academy of Sciences. 2007;104(43): 17040-5.

Wenzlau JM, Frisch LM, Hutton JC, Fain PR, Davidson HW. Changes in zinc transporter 8 autoantibodies following type 1 diabetes onset: The Type 1 Diabetes Genetics Consortium Autoantibody Workshop. Diabetes Care. 2015;38 (Supplement 2):S14-20.

Yang L, Luo S, Huang G, Peng J, Li X, Yan X, Lin J, Wenzlau JM, Davidson HW, Hutton JC, Zhou Z. The diagnostic value of zinc transporter 8 autoantibody (ZnT8A) for type 1 diabetes in Chinese. Diabetes/ Metabolism Research and Reviews. 2010;26(7):579-84.

Niechciał E, Rogowicz-Frontczak A, Piłaciński S, Fichna M, Skowrońska B, Fichna P, Zozulińska-Ziółkiewicz D. Autoantibodies against zinc transporter 8 are related to age and metabolic state in patients with newly diagnosed autoimmune diabetes. Acta diabetologica. 2018; 55(3):287-94.

Boudiaf AL, Bouziane D, Smara M, Meddour Y, Haffaf EM, Oudjit B, Mamouzi SC, Bouguerra SA. Could ZnT8 antibodies replace ICA, GAD, IA2 and insulin antibodies in the diagnosis of type 1 diabetes? Current research in translational medicine. 2018;66(1):1-7.

Garnier L, Marchand L, Benoit M, Nicolino M, Bendelac N, Wright C, Moulin P, Lombard C, Thivolet C, Fabien N. Screening of ZnT8 autoantibodies in the diagnosis of autoimmune diabetes in a large French cohort. Clinica Chimica Acta. 2018;478:162-5.

Alkanani AK, Rewers M, Dong F, Waugh K, Gottlieb PA, Zipris D. Dysregulated toll-like receptor–induced interleukin-1β and interleukin-6 responses in subjects at risk for the development of Type 1 diabetes. Diabetes. 2012;61(10):2525-33.

Gao S, Wang X. Predicting type 1 diabetes candidate genes using human protein-protein interaction networks. Journal of Computer Science and Systems Biology. 2009;2.

Medina IR, Lubovac-Pilav Z. Gene co-expression network analysis for identifying modules and functionally enriched pathways in type 1 diabetes. PloS One. 2016;11(6):e0156006.

Carbonetto P, Stephens M. Integrated enrichment analysis of variants and pathways in genome-wide association studies indicates central role for IL-2 signaling genes in type 1 diabetes, and cytokine signaling genes in Crohn's disease. PLoS Genetics. 2013;9(10): e1003770.

Jensen LJ, Kuhn M, Stark M, Chaffron S, Creevey C, Muller J, Doerks T, Julien P, Roth A, Simonovic M, Bork P. String 8—A global view on proteins and their functional interactions in 630 organisms. Nucleic acids research. 2008;37(Suppl_1):D412- 6.

Bergholdt R, Brorsson C, Palleja A, Berchtold LA, Fløyel T, Bang-Berthelsen CH, Frederiksen KS, Jensen LJ, Størling J, Pociot F. Identification of novel type 1 diabetes candidate genes by integrating genome-wide association data, protein-protein interactions, and human pancreatic islet gene expression. Diabetes. 2012; 61(4):954-62.