Clinical and immunological characteristics of diabetes mellitus in patients with autoimmune polyglandular syndrome type 1 in Russia

Background. Autoimmune polyglandular syndrome type 1 (APS type 1) is a rare inherited autoimmune disease caused by mutations in AIRE gene (autoimmune regulator) and characterized by list of components. Diabetes mellitus (DM) can be one of components of this disease.

Aims. To show frequency of DM in patients with APS type 1 in Russia, to describe clinical and immunological aspects of DM in patients with APS type 1

Materials and methods. 113 patients have been enrolled in the study, 16 of them had DM (15/16) or impaired glucose tolerance (1/16). Antibodies against glutamate decarboxylase, tyrosine phosphatase, zinc transporter-8, insulin and β-cells of pancreas were investigated in 30 patients with APS type 1 without DM and in 11 patients with APS type 1 and DM. ELISA test was used for detection autoantibodies.

Results. Frequency of DM in patients with APS type 1 in Russia is 14.1% (16/113). Some patients had slow-progressive DM – 19%(3/16). Antibodies against insulin and β-cells were not specific and also were not sensitive markers for DM in APS type 1. Antibodies against tyrosine phosphatase and zinc transporter-8 test showed high specificity (100% и 97%), but low sensitivity (42% и 33,3%). Antibodies against glutamate decarboxylase were less specific (70%) and had very low sensitivity (58,3%).

Conclusions. Frequency of DM in patients with APS type 1 in Russia is high to compare to other countries. 20% of Russian patients had slow-progressive course of DM. Antibodies against tyrosine phosphatase and zinc transporter-8 were the most specific for DM in patients with APS type 1, but sensitivity of these antibodies was low.

autoimmune polyglandular syndrome type 1, AIRE, diabetes mellitus, antibodies, glutamate decarboxylase, tyrosine phosphatase, zinc transporter-8, insulin, β-cells of pancreas

1. Finnish-German AC. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat Genet. 1997;17(4):399-403. doi: 10.1038/ng1297-399

2. Liston A, Lesage S, Wilson J, et al. Aire regulates negative selection of organ-specific T cells. Nat Immunol. 2003;4(4):350-354. doi: 10.1038/ni906

3. Orlova EM, Bukina AM, Kuznetsova ES, et al. Autoimmune polyglandular syndrome type 1 in Russian patients: clinical variants and autoimmune regulator mutations. Horm Res Paediatr. 2010;73(6):449-457. doi: 10.1159/000313585

4. Meager A, Visvalingam K, Peterson P, et al. Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1. PLoS Med. 2006;3(7):e289. doi: 10.1371/journal.pmed.0030289

5. Perheentupa J. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2006;91(8):2843-2850. doi: 10.1210/jc.2005-2611

6. Betterle C, Greggio NA, Volpato M. Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. 1998;83(4):1049-1055. doi: 10.1210/jcem.83.4.4682

7. Breunig A, Lee MS, Miller BS, et al. Autoimmune retinopathy in a patient with autoimmune polyendocrine syndrome type I. Ocul Immunol Inflamm. 2013;21(2):153-157. doi: 10.3109/09273948.2012.754906

8. Orlova EM, Kareva MA, Melikyan MA, et al. Response of pure red cell aplasia to cyclophosphamide after failure of mycofenolate mofetil in a patient with polyglandular syndrome type I. J Pediatr Hematol Oncol. 2013;35(8):e338-340. doi: 10.1097/MPH.0b013e3182755c52

9. Wolff AS, Erichsen MM, Meager A, et al. Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene. J Clin Endocrinol Metab. 2007;92(2):595-603. doi: 10.1210/jc.2006-1873

10. Kisand K, Peterson P. Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy: known and novel aspects of the syndrome. Ann N Y Acad Sci. 2011;1246:77-91. doi: 10.1111/j.1749-6632.2011.06308.x

11. Gylling M, Tuomi T, Bjorses P, et al. ss-cell autoantibodies, human leukocyte antigen II alleles, and type 1 diabetes in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. J Clin Endocrinol Metab. 2000;85(12):4434-4440. doi: 10.1210/jcem.85.12.7120

12. Proust-Lemoine E, Saugier-Veber P, Wemeau JL. Polyglandular autoimmune syndrome type I. Presse Med. 2012;41(12 P 2):e651-662. doi: 10.1016/j.lpm.2012.10.005

13. Proust-Lemoine E, Saugier-Veber P, Lefranc D, et al. Autoimmune polyendocrine syndrome type 1 in north-western France: AIRE gene mutation specificities and severe forms needing immunosuppressive therapies. Horm Res Paediatr. 2010;74(4):275-284. doi: 10.1159/000297714

14. Craig ME, Jefferies C, Dabelea D, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes. 2014;15(Suppl 20):4-17. doi: 10.1111/pedi.12186

15. Patterson CC, Dahlquist GG, Gyürüs E, et al. Incidence trends for childhood type 1 diabetes in Europe during 1989–2003 and predicted new cases 2005–20: a multicentre prospective registration study. Lancet. 2009;373(9680):2027-2033. doi: 10.1016/s0140-6736(09)60568-7

16. Howson JM, Stevens H, Smyth DJ, et al. Evidence that HLA class I and II associations with type 1 diabetes, autoantibodies to GAD and autoantibodies to IA-2, are distinct. Diabetes. 2011;60(10):2635-2644. doi: 10.2337/db11-0131

17. Wenzlau JM, Hutton JC. Novel diabetes autoantibodies and prediction of type 1 diabetes. Curr Diab Rep. 2013;13(5):608-615. doi: 10.1007/s11892-013-0405-9

18. Landin-Olsson M, Karlsson A, Dahlquist G, et al. Islet cell and other organ-specific autoantibodies in all children developing Type 1 (insulin-dependent) diabetes mellitus in Sweden during one year and in matched control children. Diabetologia. 1989;32(6):387-395. doi: 10.1007/bf00277264

19. Hagopian WA, Sanjeevi CB, Kockum I, et al. Glutamate decarboxylase-, insulin-, and islet cell-antibodies and HLA typing to detect diabetes in a general population-based study of Swedish children. J Clin Invest. 1995;95(4):1505-1511. doi: 10.1172/JCI117822

20. Davidson HW, Wenzlau JM, O'Brien RM. Zinc transporter 8 (ZnT8) and beta cell function. Trends Endocrinol Metab. 2014;25(8):415-424. doi: 10.1016/j.tem.2014.03.008

21. Paquette J, Varin DS, Hamelin CE, et al. Risk of autoimmune diabetes in APECED: association with short alleles of the 5'insulin VNTR. Genes Immun. 2010;11(7):590-597. doi: 10.1038/gene.2010.33

22. Abdul-Rasoul M, Habib H, Al-Khouly M. 'The honeymoon phase' in children with type 1 diabetes mellitus: frequency, duration, and influential factors. Pediatr Diabetes. 2006;7(2):101-107. doi: 10.1111/j.1399-543X.2006.00155.x

23. Poudel RR. Latent autoimmune diabetes of adults: From oral hypoglycemic agents to early insulin. Indian J Endocrinol Metab. 2012;16(Suppl 1):S41-46. doi: 10.4103/2230-8210.94257