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Autoimmunity in latent autoimmune diabetes in adults

U.O.C di Medicina Generale 2, Azienda Ospedaliero-Universitaria di Sassari, Sassari, Italy

Latent autoimmune diabetes in adults (LADA) is clinically characterized by onset after age 30, absence of ketoacidosis, insulin independence for at least 6 months after diagnosis, and presence of circulating islet-cell antibodies. These include glutamic acid decarboxylase (GADA) autoantibodies, tyrosine phosphatase-2 autoantibodies, or zinc-transporter 8 autoantibodies. In particular, GADA are the most frequent autoantibody in LADA and can be detected in serum for many years post diagnosis. High concentrations of GADA have been considered as a marker of faster islet-cell exhaustion in these patients. Moreover, LADA patients have other circulating non islet antibodies, such as antibodies against thyroperoxidase and antibodies against gastric parietal cells, that reflect the presence of a high intensity of immune processes. Although the presence of each antibody taken individually shows scarce predictive value for the progression of the disease, their simultaneous presence might predict the insulin dependence in this LADA subgroup. The occurrence of islet autoantibodies in these patients might identify specific phenotypes of LADA with more homogeneous characteristics that are prone to faster exhaustion of β cell function. The high prevalence of these autoantibodies is clinically relevant and their measurement should be introduced as screening in clinical practice in order to identify the clinical presence of other organ specific autoimmune diseases.
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1. Bluestone JA, Herold K, Eisenbarth G (2010) Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464: 1293–1300.    

2. Zampetti S, Capizzi M, Spoletini M, et al. (2012) GADA titer-related risk for organ-specific autoimmunity in LADA subjects subdivided according to gender (NIRAD study 6). J Clin Endocrinol Metab 97: 3759–3765.    

3. Huang G, Wang X, Li Z, et al. (2012) Insulin autoantibody could help to screen latent autoimmune diabetes in adults in phenotypic type 2 diabetes mellitus in Chinese. Acta Diabetol 49: 327–331.    

4. Hawa MI, Kolb H, Schloot N, et al. (2013) Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care 36: 908–913.    

5. Delitala AP, Pes GM, Fanciulli G, et al. (2016) Organ-specific antibodies in LADA patients for the prediction of insulin dependence. Endocr Res 41: 207–212.    

6. Irvine WJ, McCallum CJ, Gray RS, et al. (1977) Clinical and pathogenic significance of pancreatic-islet-cell antibodies in diabetics treated with oral hypoglycaemic agents. Lancet 1: 1025–1027.

7. Pieralice S, Pozzilli P (2018) Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management. Diabetes Metab J 42: 451–464.    

8. Pozzilli P, Pieralice S (2018) Latent Autoimmune Diabetes in Adults: Current Status and New Horizons. Endocrinol Metab (Seoul) 33: 147–159.    

9. Zimmet PZ, Tuomi T, Mackay IR, et al. (1994) Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med 11: 299–303.    

10. Kantarova D, Buc M (2007) Genetic susceptibility to type 1 diabetes mellitus in humans. Physiol Res 56: 255–266.

11. Bell GI, Horita S, Karam JH (1984) A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33: 176–183.    

12. Zampetti S, Spoletini M, Petrone A, et al. (2010) Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD Study 5). Diabet Med 27: 701–704.    

13. Lukacs K, Hosszufalusi N, Dinya E, et al. (2012) The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity: a meta-analysis and an individual study. Diabetologia 55: 689–693.    

14. Laugesen E, Ostergaard JA, Leslie RD, et al. (2015) Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Diabet Med 32: 843–852.    

15. Lohmann T, Kellner K, Verlohren HJ, et al. (2001) Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia 44: 1005–1010.    

16. Maruyama T, Nakagawa T, Kasuga A, et al. (2011) Heterogeneity among patients with latent autoimmune diabetes in adults. Diabetes Metab Res Rev 27: 971–974.    

17. Hawa MI, Thivolet C, Mauricio D, et al. (2009) Metabolic syndrome and autoimmune diabetes: action LADA 3. Diabetes Care 32: 160–164.    

18. Pes GM, Delitala AP, Delitala G, et al. (2014) Phenotypic heterogeneity of latent autoimmune diabetes in adults identified by body composition analysis. Diabetol Metab Syndr 6: 128.    

19. Genovese S, Bazzigaluppi E, Goncalves D, et al. (2006) Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes. Eur J Endocrinol 154: 441–447.    

20. Buzzetti R, Di Pietro S, Giaccari A, et al. (2007) High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care 30: 932–938.    

21. Tuomi T, Carlsson A, Li H, et al. (1999) Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48: 150–157.    

22. Zhou Z, Xiang Y, Ji L, et al. (2013) Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a nationwide, multicenter, clinic-based cross-sectional study. Diabetes 62: 543–550.    

23. Desai M, Cull CA, Horton VA, et al. (2007) GAD autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77. Diabetologia 50: 2052–2060.    

24. Tuomi T, Groop LC, Zimmet PZ, et al. (1993) Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42: 359–362.    

25. Tiberti C, Giordano C, Locatelli M, et al. (2008) Identification of tyrosine phosphatase 2 (256–760) construct as a new, sensitive marker for the detection of islet autoimmunity in type 2 diabetic patients: the non-insulin requiring autoimmune diabetes (NIRAD) study 2. Diabetes 57: 1276–1283.    

26. Lampasona V, Petrone A, Tiberti C, et al. (2010) Zinc transporter 8 antibodies complement GAD and IA-2 antibodies in the identification and characterization of adult-onset autoimmune diabetes: Non Insulin Requiring Autoimmune Diabetes (NIRAD) 4. Diabetes Care 33: 104–108.    

27. Xiang Y, Huang G, Shan Z, et al. (2015) Glutamic acid decarboxylase autoantibodies are dominant but insufficient to identify most Chinese with adult-onset non-insulin requiring autoimmune diabetes: LADA China study 5. Acta Diabetol 52: 1121–1127.    

28. Perros P, McCrimmon RJ, Shaw G, et al. (1995) Frequency of thyroid dysfunction in diabetic patients: value of annual screening. Diabet Med 12: 622–627.    

29. Falorni A, Brozzetti A (2005) Diabetes-related antibodies in adult diabetic patients. Best Pract Res Clin Endocrinol Metab 19: 119–133.    

30. Triolo TM, Armstrong TK, McFann K, et al. (2011) Additional autoimmune disease found in 33% of patients at type 1 diabetes onset. Diabetes Care 34: 1211–1213.    

31. Gambelunghe G, Forini F, Laureti S, et al. (2000) Increased risk for endocrine autoimmunity in Italian type 2 diabetic patients with GAD65 autoantibodies. Clin Endocrinol (Oxf) 52: 565–573.    

32. Maioli M, Pes GM, Delitala G, et al. (2010) Number of autoantibodies and HLA genotype, more than high titers of glutamic acid decarboxylase autoantibodies, predict insulin dependence in latent autoimmune diabetes of adults. Eur J Endocrinol 163: 541–549.    

33. Delitala AP, Fanciulli G, Zoledziewska M, et al. (2015) Allelic variant in CTLA4 is associated with thyroid failure and faster beta-cell exhaustion in latent autoimmune diabetes in adults. J Diabetes 7: 68–73.    

34. Levin L, Tomer Y (2003) The etiology of autoimmune diabetes and thyroiditis: evidence for common genetic susceptibility. Autoimmun Rev 2: 377–386.    

35. Kobayashi T, Tanaka S, Shimada A, et al. (2007) High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes: response to Buzzetti et al. Diabetes Care 30: e126.    

36. De Graaff LC, Smit JW, Radder JK (2007) Prevalence and clinical significance of organ-specific autoantibodies in type 1 diabetes mellitus. Neth J Med 65: 235–247.

37. Reijonen H, Daniels TL, Lernmark A, et al. (2000) GAD65-specific autoantibodies enhance the presentation of an immunodominant T-cell epitope from GAD65. Diabetes 49: 1621–1626.    

38. Tian J, Zekzer D, Lu Y, et al. (2006) B cells are crucial for determinant spreading of T cell autoimmunity among beta cell antigens in diabetes-prone nonobese diabetic mice. J Immunol 176: 2654–2661.    

39. Strollo R, Vinci C, Napoli N, et al. (2019) Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies. Diabetes Metab Res Rev, e3132.

40. Strollo R, Vinci C, Napoli N, et al. (2017) Antibodies to post-translationally modified insulin as a novel biomarker for prediction of type 1 diabetes in children. Diabetologia 60: 1467–1474.    

41. Strollo R, Vinci C, Arshad MH, et al. (2015) Antibodies to post-translationally modified insulin in type 1 diabetes. Diabetologia 58: 2851–2860.    

42. Buzzetti R, Spoletini M, Zampetti S, et al. (2015) Tyrosine phosphatase-related islet antigen 2 (256–760) autoantibodies, the only marker of islet autoimmunity that increases by increasing the degree of BMI in obese subjects with type 2 diabetes. Diabetes Care 38: 513–520.    

© 2019 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

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