Diagnosing and Managing LADA: A Review of the Overlooked Diabetes Subtype
DOI:
https://doi.org/10.12775/QS.2025.37.57142Keywords
LADA diabetes, GADA antibodies, type 1 diabetes, type 2 diabetes, insulin resistance, insulin therapyAbstract
LADA (latent autoimmune diabetes in adults) is a dual form of diabetes, combining the autoimmune features typical of type 1 diabetes and the clinical and metabolic aspects of type 2 diabetes. Due to the slow development of symptoms and often late age of onset, LADA is frequently misdiagnosed as type 2 diabetes, which can lead to a delay in appropriate treatment. It is estimated that LADA affects between 4% and 12% of adults initially diagnosed with type 2 diabetes, making it a more common disease entity than previously thought. This paper examines current data on the epidemiology, pathogenesis, genetic factors and diagnostic criteria of LADA. Particular attention was given to the immunological and genetic aspects of the disease, which allow a more accurate differentiation of LADA from type 2 diabetes. The review also discusses the significance of early insulin therapy aimed at beta-cell preservation and the role of alternative treatments, such as DPP-4 inhibitors, which may influence disease progression. Diagnostic and therapeutic challenges stemming from the phenotypic similarities between LADA and type 2 diabetes are highlighted, along with potential benefits of early detection.
References
1. Sun H, Saeedi P, Karuranga S, et al. IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045 [published correction appears in Diabetes Res Clin Pract. 2023 Oct;204:110945. doi: 10.1016/j.diabres.2023.110945]. Diabetes Res Clin Pract. 2022;183:109119. doi:10.1016/j.diabres.2021.109119
2. Magliano DJ, Boyko EJ; IDF Diabetes Atlas 10th edition scientific committee . IDF DIABETES ATLAS [Internet]. 10th edition. Brussels: International Diabetes Federation; 2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK581934/
3. Carlsson S. Etiology and Pathogenesis of Latent Autoimmune Diabetes in Adults (LADA) Compared to Type 2 Diabetes. Front Physiol. 2019;10:320. Published 2019 Mar 26. doi:10.3389/fphys.2019.00320
4. Pozzilli P, Pieralice S: Latent autoimmune diabetes in adults: current status and new horizons . Endocrinol Metab (Seoul). 2018, 33:147-59. 10.3803/EnM.2018.33.2.147
5. Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R, et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care. 2013;36:908–913. doi: 10.2337/dc12-0931.
6. Hawa MI, Kolb H, Schloot N, et al.: Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action LADA 7. Diabetes Care. 2013; 36:908-13. doi:10.2337/dc12-0931
7. Buzzetti R, Di Pietro S, Giaccari A, Petrone A, Locatelli M, Suraci C, et al. High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care. 2007;30:932–938. doi: 10.2337/dc06-1696.
8. Qiu J, Xiao Z, Zhang Z, Luo S, Zhou Z. Latent autoimmune diabetes in adults in China. Frontiers in Immunology. 2022; 13:977413. doi:10.3389/fimmu.2022.977413
9. Buzzetti R, Di Pietro S, Giaccari A, Petrone A, Locatelli M, Suraci C, Capizzi M, Arpi ML, Bazzigaluppi E, Dotta F, Bosi E; for the Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study Group. High Titer of Autoantibodies to GAD Identifies a Specific Phenotype of Adult-Onset Autoimmune Diabetes. Diabetes Care. 2007; 30(4):932-938. doi:10.2337/dc06-1693
10. Xiang Y, Huang G, Shan Z, Pan L, Luo S, Yang L, Shi L, Li Q, Leslie RD, Zhou Z. 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. 2015 Dec;52(6):1121-7.
11. Strenstrõm G., Gottsäter A., Bakhtadze E. i wsp. Latent autoimmune diabetes in adults. Definition, prevalence, b-cell function, and treatment. Diabetes 2005; 54 (supl. 2): S68–S72.
12. Chiu HK, Tsai EC, Juneja R, Stoever J, Brooks-Worrell B, Goel A, Palmer JP. Equivalent insulin resistance in latent autoimmune diabetes in adults (LADA) and type 2 diabetic patients. Diabetes Res Clin Pract. 2007 Aug;77(2):237-44.
13. Andersen, M.K. New Insights into the Genetics of Latent Autoimmune Diabetes in Adults. Curr Diab Rep 20, 43 (2020). https://doi.org/10.1007/s11892-020-01330-y
14. Raffaella Buzzetti, Tiinamaija Tuomi, Didac Mauricio, Massimo Pietropaolo, Zhiguang Zhou, Paolo Pozzilli, Richard David Leslie; Management of Latent Autoimmune Diabetes in Adults: A Consensus Statement From an International Expert Panel. Diabetes 1 October 2020; 69 (10): 2037–2047. https://doi.org/10.2337/dbi20-0017
15. Leighton E, Sainsbury CA, Jones GC. A Practical Review of C-Peptide Testing in Diabetes. Diabetes Ther. 2017 Jun;8(3):475-487
16. Rajkumar V, Levine SN. Latent Autoimmune Diabetes. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557897/
17. Tuomi, T., Santoro, N., Caprio, S., Cai, M., Weng, J., & Groop, L. (2014). The many faces of diabetes: a disease with increasing heterogeneity. The Lancet, 383(9922), 1084–1094. doi:10.1016/s0140-6736(13)62219-9
18. Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, 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. Lancet (1997) 350(9087):1288–93. doi: 10.1016/S0140-6736(97) 03062-6
19. Yin W, Luo S, Xiao Z, Zhang Z, Liu B and Zhou Z (2022) Latent autoimmune diabetes in adults: a focus on b-cell protection and therapy. Front. Endocrinol. 13:959011. doi: 10.3389/fendo.2022.959011
20. Hjort R, Ahlqvist E, Carlsson PO, Grill V, Groop L, Martinell M, et al. Overweight, obesity and the risk of LADA: Results from a Swedish case-control study and the Norwegian HUNT study. Diabetologia (2018) 61(6):1333–43. doi: 10.1007/s00125-018-4596-0
21. Zaharia OP, Bobrov P, Strassburger K, Bódis K, Karusheva Y, Scholz M, et al. Metabolic characteristics of recently diagnosed adult-onset autoimmune diabetes mellitus. J Clin Endocrinol Metab (2018) 103(2):429–37. doi: 10.1210/ jc.2017-01706
22. Hernandez M, Mollo A, Marsal JR, Esquerda A, Capel I, Puig-Domingo M, et al. Insulin secretion in patients with latent autoimmune diabetes (LADA): Half way between type 1 and type 2 diabetes: Action LADA 9. BMC endocrine Disord (2015) 15:1. doi: 10.1186/1472-6823-15-1
23. Page, C., Fitzgerald, B. & Hawes, E.M. Latent autoimmune diabetes of adulthood: case report. Clin Diabetes Endocrinol 3, 11 (2017). https://doi.org/10.1186/s40842-017-0049-9
24. Pieralice S, Pozzilli P. Latent Autoimmune Diabetes in Adults: A Review on Clinical Implications and Management. Diabetes Metab J. 2018;42(6):451-464. doi:10.4093/dmj.2018.0190
25. Campbell-Thompson M, Fu A, Kaddis JS, Wasserfall C, Schatz DA, Pugliese A, et al. Insulitis and β-Cell Mass in the natural history of type 1 diabetes. Diabetes. 2016;65:719–31.
26. Kobayashi T, Maruyama T, Shimada A, Kasuga A, Kanatsuka A, Takei I, et al. Insulin intervention to preserve beta cells in slowly progressive insulindependent (Type 1) diabetes mellitus. Ann New York Acad Sci (2002) 958:117–30. doi: 10.1111/j.1749-6632.2002.tb02954.x
27. Brophy S, Davies H, Mannan S, Brunt H, Williams R. Interventions for latent autoimmune diabetes (LADA) in adults. Cochrane Database Syst Rev. 2011;2011(9):CD006165. Published 2011 Sep 7. doi:10.1002/14651858.CD006165.pub3
28. Zampetti, S., Campagna, G., Tiberti, C., Songini, M., Arpi, M. L., De Simone, G., … __. (2014). High GADA titer increases the risk of insulin requirement in LADA patients: a 7-year follow-up (NIRAD study 7). European Journal of Endocrinology, 171(6), 697–704. doi:10.1530/eje-14-0342
29. Alonso N, Julián MT, Carrascal J, Colobran R, Pujol-Autonell I, Rodriguez-Fernández S, Teniente A, Fernández MA, Miñarro A, Ruiz de Villa MC, Vives-Pi M, Puig-Domingo M. Type 1 Diabetes Prevention in NOD Mice by Targeting DPPIV/CD26 Is Associated with Changes in CD8⁺T Effector Memory Subset. PLoS One. 2015;10(11):e0142186.
30. Cree-Green M, Bergman BC, Cengiz E, et al.: Metformin improves peripheral insulin sensitivity in youth with type 1 diabetes. J Clin Endocrinol Metab. 2019, 104:3265-78. 10.1210/jc.2019-00129
31. Chen W, Chen X, Zhang M, Huang Z. The association of human leukocyte antigen class II (HLA II) haplotypes with the risk of latent autoimmune diabetes of adults (LADA): Evidence based on available data. Gene (2021) 767:145177. doi: 10.1016/j.gene.2020.145177
32. Zampetti S, Spoletini M, Petrone A, Capizzi M, Arpi ML, Tiberti C, et al. Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD Study 5). Diabet Medicine: J Br Diabet Association. 2010;27:701–4.
33. Cervin C, Lyssenko V, Bakhtadze E, Lindholm E, Nilsson P, Tuomi T, et al. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Diabetes. 2008;57:1433–1437. doi: 10.2337/db07-0299.
34. Hernández M, Nóvoa-Medina Y, Faner R, et al. Genetics: Is LADA just late onset type 1 diabetes?. Front Endocrinol (Lausanne). 2022;13:916698. Published 2022 Aug 10. doi:10.3389/fendo.2022.916698
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Copyright (c) 2025 Maciej Wojszczyk, Julia Kulbacka, Karol Dziedzic, Filip Arczewski, Michalina Wójcikiewicz, Marta Chuncia-Ileczko, Julia Kacperczyk, Witold Czyż, Piotr Pasek, Julia Ryniecka
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