Heterogeneity of autoimmune diabetes mellitus in adults: real-world clinical practice

BACKGROUND. To investigate the heterogeneity of autoimmune diabetes mellitus (DM) in adults and identify factors associated with delayed initiation of insulin therapy in real-world clinical practice.

MATERIALS AND METHODS. A retrospective analysis was conducted on clinical and laboratory data from 717 patients with DM onset after the age of 18 who were tested for antibodies against β-cell antigens (GAD, IA-2, ICA, ZnT8, insulin) at the National Medical Research Center for Endocrinology (NMRCE) between 2017 and 2022. Data were obtained from the electronic medical records of the NMRCE database and questionnaires from the nationwide clinical and epidemiological diabetes monitoring system in the Russian Federation. Patients with elevated vs normal antibody titers were compared, as well as patients with autoimmune DM based on the timing of insulin therapy initiation.

RESULTS. Elevated antibodies to β-cell antigens were identified in 370 patients (51.6%). A combination of two or more antibodies at DM onset was found in 63.7% of cases. The most frequently elevated antibodies were ZnT8, GAD, and IA-2. There was no significant difference in age at onset between patients with positive and negative antibodies; however, those with positive antibodies had lower body mass index (BMI), a higher incidence of ketoacidosis, and lower levels of C-peptide, uric acid, and triglycerides at disease onset. Among antibody-positive patients, 36.8% did not require insulin therapy until at least 6 months after disease onset (median: 2 [1; 3] years). During onset and the first 5 years, these patients demonstrated higher BMI, triglycerides, and C-peptide levels. Notably, 8.9% of patients with elevated antibodies were managed exclusively with oral glucose-lowering agents and/or glucagon like peptide 1 (GLP-1) receptor agonists for a median of 3 [2; 7.5] years after disease onset, maintaining an HbA1c level of 6.7 [6.2; 7.75]%.

CONCLUSION. Autoimmune DM in adults demonstrates heterogeneity in the rate of β-cell function decline and the development of insulin dependence. Later initiation of insulin therapy in autoimmune DM is associated with older age at onset, higher BMI, triglycerides, and C-peptide levels at diagnosis and during follow-up. The use of oral antidiabetic drugs and/or GLP-1 receptor agonists may be considered for patients with preserved C-peptide levels, provided that carbohydrate metabolism and C-peptide levels are regularly monitored. Nonetheless, insulin replacement therapy remains the primary pathogenetic treatment for autoimmune DM.

1. Gregory GA, Robinson TIG, Linklater SE, et al. Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study [published correction appears in Lancet Diabetes Endocrinol. 2022 Nov;10(11):e11. doi: https://doi.org/10.1016/S2213-8587(22)00280-7.]. Lancet Diabetes Endocrinol. 2022;10(10):741-760. doi: https://doi.org/10.1016/S2213-8587(22)00218-2

2. Ogrotis I, Koufakis T, Kotsa K. Changes in the Global Epidemiology of Type 1 Diabetes in an Evolving Landscape of Environmental Factors: Causes, Challenges, and Opportunities. Medicina (Kaunas). 2023;59(4):668. doi: https://doi.org/10.3390/medicina59040668

3. International Diabetes Federation. IDF Diabetes Atlas, 11th edn. Brussels, Belgium; 2025 [cited 10.02.2025]. Available from: https://diabetesatlas.org/resources/idf-diabetes-atlas-2025/

4. Kotova EG, Kobyakova OS, Starodubov VI, et al. Zabolevaemost’ vzroslogo naseleniya Rossii v 2022 godu s diagnozom, ustanovlennym vpervye v zhizni: statisticheskie materialy. — M.: FGBU «TsNIIOIZ» Minzdrava Rossii; 2023. (In Russ.) doi: https://doi.org/10.21045/978-5-94116-113-3-2023

5. Kotova EG, Kobyakova OS, Starodubov VI, et al. Zabolevaemost’ detskogo naseleniya Rossii (0-14 let) v 2022 godu s diagnozom, ustanovlennym vpervye v zhizni: statisticheskie materialy. — M.: FGBU «TsNIIOIZ» Minzdrava Rossii; 2023. (In Russ.) doi: https://doi.org/10.21045/978-5-94116-115-7-2023

6. Insel RA, Dunne JL, Atkinson MA, et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care. 2015;38(10):1964-1974. doi: https://doi.org/10.2337/dc15-1419

7. Kobayashi T, Sugimoto T, Itoh T, et al. The prevalence of islet cell antibodies in Japanese insulin-dependent and noninsulin-dependent diabetic patients studied by indirect immunofluorescence and by a new method. Diabetes. 1986;35(3):335-340. doi: https://doi.org/10.2337/diab.35.3.335

8. Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group [published correction appears in Lancet 1998 Jan 31;351(9099):376]. Lancet. 1997;350(9087):1288-1293. doi: https://doi.org/10.1016/s0140-6736(97)03062-6

9. Buzzetti R, Tuomi T, Mauricio D, et al. Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel. Diabetes. 2020;69(10):2037-2047. doi: https://doi.org/10.2337/dbi20-0017

10. Battaglia M, Ahmed S, Anderson MS, et al. Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes. Diabetes Care. 2020;43(1):5-12. doi: https://doi.org/10.2337/dc19-0880

11. Jiang Z, Ren W, Liang H, et al. HLA class I genes modulate disease risk and age at onset together with DR-DQ in Chinese patients with insulin-requiring type 1 diabetes. Diabetologia. 2021;64(9):2026-2036. doi: https://doi.org/10.1007/s00125-021-05476-6

12. Mikk ML, Pfeiffer S, Kiviniemi M, et al. HLA-DR-DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity. Pediatr Diabetes. 2020;21(7):1218-1226. doi: https://doi.org/10.1111/pedi.13073

13. Ilonen J, Laine AP, Kiviniemi M, et al. Associations between deduced first islet specific autoantibody with sex, age at diagnosis and genetic risk factors in young children with type 1 diabetes. Pediatr Diabetes. 2022;23(6):693-702. doi: https://doi.org/10.1111/pedi.13340

14. Arif S, Leete P, Nguyen V, et al. Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes [published correction appears in Diabetes. 2015 Sep;64(9):3334. doi: 10.2337/db15-er09a.]. Diabetes. 2014;63(11):3835-3845. doi: https://doi.org/10.2337/db14-0365

15. Leete P, Willcox A, Krogvold L, et al. Differential Insulitic Profiles Determine the Extent of β-Cell Destruction and the Age at Onset of Type 1 Diabetes. Diabetes. 2016;65(5):1362-1369. doi: https://doi.org/10.2337/db15-1615

16. Nikonova TV, Apanovich PV, Pekareva EV, et al. Immunogenetic characteristics of LADA. Diabetes mellitus. 2011;14(1):28-34. (In Russ.) doi: https://doi.org/10.14341/2072-0351-6247

17. Nikonova TV, Apanovich PV, Pekareva EV, et al. The role of regulatory CD4+CD25+high T-lymphocytes and their functional activity in the development of type 1 diabetes mellitus. Diabetes mellitus. 2010;13(3):25-31. (In Russ.) doi: https://doi.org/10.14341/2072-0351-5483

18. Nikonova TV. Sakharnyi diabet 1 tipa i latentnyi autoimmunnyi diabet vzroslykh (LADA): klinicheskie, immunogeneticheskie i gormonal’no-metabolicheskie aspekty. Diss. ... dokt. med. nauk. — Moskva; 2011. (In Russ.)

19. Lohmann T, Kellner K, Verlohren HJ, et al. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia. 2001;44(8):1005-1010. doi: https://doi.org/10.1007/s001250100602

20. Shimada A, Kawasaki E, Abiru N, et al. New diagnostic criteria (2023) for slowly progressive type 1 diabetes (SPIDDM): Report from Committee on Type 1 Diabetes of the Japan Diabetes Society (English version) [published correction appears in J Diabetes Investig. 2024 May;15(5):643. doi: 10.1111/jdi.14190.]. J Diabetes Investig. 2024;15(2):254-257. doi: https://doi.org/10.1111/jdi.14121

21. Zampetti S, Campagna G, Tiberti C, et al. High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7). Eur J Endocrinol. 2014;171(6):697-704. doi: https://doi.org/10.1530/EJE-14-0342

22. Rajkumar V, Levine SN. Latent Autoimmune Diabetes. In: StatPearls. Treasure Island (FL): StatPearls Publishing; March 1, 2024.

23. Maioli M, Pes GM, Delitala G, et al. 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. 2010;163(4):541-549. doi: https://doi.org/10.1530/EJE-10-0427

24. Golodnikov II, Rusyaeva NV, Nikonova TV, et al. Modern understanding of latent autoimmune diabetes in adults. Diabetes mellitus. 2023;26(3):262-274. (In Russ.) doi: https://doi.org/10.14341/DM12994

25. Cervin C, Lyssenko V, Bakhtadze E, et al. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes. 2008;57(5):1433-1437. doi: https://doi.org/10.2337/db07-0299

26. Andersen MK, Sterner M, Forsén T, et al. Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes. Diabetologia. 2014;57(9):1859-1868. doi: https://doi.org/10.1007/s00125-014-3287-8

27. Wang W, Huang F, Han C. Efficacy of regimens in the treatment of latent autoimmune diabetes in adults: a network meta-analysis. Diabetes Ther. 2023;14(10):1723-1752. doi: https://doi.org/10.1007/s13300-023-01459-5

28. Zhao Y, Yang L, Xiang Y, et al. Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in patients with recentonset latent autoimmune diabetes in adults: one year prospective study. J Clin Endocrinol Metab. 2014;99(5):E876-E880. doi: https://doi.org/10.1210/jc.2013-3633