Latent autoimmune diabetes in adults

Latent autoimmune diabetes in adults
Other namesLADA, late-onset autoimmune diabetes of adulthood,[1] adult-onset autoimmune diabetes
Universal blue circle symbol for diabetes[2]
Pronunciation
  • /daɪəbiːtiːs/
SpecialtyEndocrinology

Slowly evolving immune-mediated diabetes, or latent autoimmune diabetes in adults (LADA), is a form of diabetes that exhibits clinical features similar to both type 1 diabetes (T1D) and type 2 diabetes (T2D).[3][4] It is an autoimmune form of diabetes, similar to T1D, but patients with LADA often show insulin resistance, similar to T2D, and share some risk factors for the disease with T2D.[3] Studies have shown that LADA patients have certain types of antibodies against the insulin-producing cells, and that these cells stop producing insulin more slowly than in T1D patients.[3][5]

LADA appears to share genetic risk factors with both T1D and T2D but is genetically distinct from both.[6][7][8][9][4] Within the LADA patient group, a genetic and phenotypic heterogeneity has been observed with varying degrees of insulin resistance and autoimmunity.[5][10] With the knowledge we have today, LADA can thus be described as a hybrid form of T1D and T2D, showing phenotypic and genotypic similarities with both, as well as variation within LADA regarding the degree of autoimmunity and insulin resistance.

The concept of LADA was first introduced in 1993,[11] though The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus does not recognize the term, instead including it under the standard definition of diabetes mellitus type 1.[12]

Symptoms

The symptoms of latent autoimmune diabetes in adults are similar to those of other forms of diabetes: polydipsia (excessive thirst and drinking), polyuria (excessive urination), and often blurred vision.[13] Compared to juvenile type 1 diabetes, the symptoms develop comparatively slowly, over a period of at least six months.[14]

Diagnosis

A fasting blood sugar level of ≥ 7.0 mmol / L is used in the general diagnosis of diabetes.[15] There are no clear guidelines for the diagnosis of LADA, but the criteria often used are that the patient should develop the disease in adulthood, not need insulin treatment for the first 6 months after diagnosis and have autoantibodies in the blood.[5][3][4]

Glutamic acid decarboxylase autoantibody (GADA), islet cell autoantibody (ICA), insulinoma-associated (IA-2) autoantibody, and zinc transporter autoantibody (ZnT8) testing should be performed in order to correctly diagnose diabetes.[16]

Persons with LADA typically have low, although sometimes moderate, levels of C-peptide as the disease progresses. Those with insulin resistance or type 2 diabetes are more likely to have high levels of C-peptide due to an over production of insulin.[17][14]

Autoantibodies

Destruction of Glutamate decarboxylase (pictured here) via autoantibodies is strongly linked with LADA type 1 diabetes.

Glutamic acid decarboxylase autoantibodies (GADA), islet cell autoantibodies (ICA), insulinoma-associated (IA-2) autoantibodies, and zinc transporter autoantibodies (ZnT8) are all associated with LADA; GADAs are commonly found in cases of diabetes mellitus type 1.

The presence of islet cell complement fixing autoantibodies also aids in a differential diagnosis between LADA and type 2 diabetes. Persons with LADA often test positive for ICA, whereas type 2 diabetics only seldom do.[17]

Persons with LADA usually test positive for glutamic acid decarboxylase antibodies, whereas in type 1 diabetes these antibodies are more commonly seen in adults rather than in children.[17][18] In addition to being useful in making an early diagnosis for type 1 diabetes mellitus, GAD antibodies tests are used for differential diagnosis between LADA and type 2 diabetes[17][19][20] and may also be used for differential diagnosis of gestational diabetes, risk prediction in immediate family members for type 1, as well as a tool to monitor prognosis of the clinical progression of type 1 diabetes.

Prevalence

Since there is no regular autoantibody screening, patients with LADA are at risk of being diagnosed with type 2 diabetes, which makes it difficult to estimate the prevalence of LADA.[4] Globally, it is estimated that about 8.5% of adults suffer from some form of diabetes[15] and it is estimated that LADA accounts for about 3-12% of all adult diabetes cases.[21] Estimates from 2015 are saying that there could be as many as 10–20% of people with diabetes having LADA.

Risk factors

There is limited research on LADA and its etiology.[21][4] As with both T1D and T2D, the risk of LADA depends on both genetic and environmental factors.[21][15] Genetic risk factors for LADA are similar to T1D, i.e. is affected by the HLA complex, but also genetic variants associated with T2D have been identified in LADA.[21] LADA has several lifestyle risk factors in common with T2D, such as obesity, physical inactivity, smoking and consumption of sweetened beverages, all of which are linked to insulin resistance.[21]

Obesity has been shown to increase the risk of LADA in several studies, and one study showed that the risk was particularly high in combination with having diabetes in the family.[21][22][23] Physical activity also affects the risk of LADA, with less physical activity increasing the risk.[21] A Swedish study showed that low birth weight, in addition to increasing the risk of T2D, increases the risk of LADA.[24]

Although smoking has been shown to increase the risk of T2D while coffee consumption has been shown to reduce the risk of T2D, the results regarding these products and LADA are unclear.[21] However, results from two studies based on the same population seem to indicate that coffee consumption increases the risk of LADA.[25][26] Other foods that have been shown to increase the risk of LADA are sweetened beverages and processed red meat[27][28][29] while consumption of fatty fish has been shown to have a protective effect.[30]

Management

Diabetes is a chronic disease, i.e. it cannot be cured, but symptoms and complications can be minimized with proper treatment. Diabetes can lead to elevated blood sugar levels, which in turn can lead to damage to the heart, blood vessels, kidneys, eyes and nerves.[15] There are very few studies on how to treat LADA, specifically, which is probably due to difficulties in classifying and diagnosing the disease. LADA patients often do not need insulin treatment immediately after being diagnosed because their own insulin production decreases more slowly than T1D patients, but in the long run they will need it.[5][3] About 80% of all LADA patients initially misdiagnosed with type 2 (and who have GAD antibodies) will become insulin-dependent within 3 to 15 years (according to differing LADA sources).[31]

The treatment for Type 1 diabetes/LADA is exogenous insulin to control glucose levels, prevent further destruction of residual beta cells, reduce the possibility of diabetic complications, and prevent death from diabetic ketoacidosis (DKA). Although LADA may appear to initially respond to similar treatment (lifestyle and medications) as type 2 diabetes, it will not halt or slow the progression of beta cell destruction, and people with LADA will eventually become insulin-dependent.[32] People with LADA have insulin resistance similar to long-term type 1 diabetes; some studies showed that people with LADA have less insulin resistance, compared with those with type 2 diabetes; however, others have not found a difference.[33]

History

Although type 1 diabetes has been identified as an autoimmune disease since the 1970s,[34] the concept of latent autoimmune diabetes mellitus was not noted until 1993, when it was used to describe slow-onset type 1 autoimmune diabetes occurring in adults.[35] This followed the concept that GAD autoantibodies were a feature of type 1 diabetes and not type 2 diabetes.[36]

References

  1. ↑ Williams, Wilkins & Munden 2006, p. 20.
  2. ↑ "Diabetes Blue Circle Symbol". International Diabetes Federation. 17 March 2006. Archived from the original on 5 August 2007.
  3. 1 2 3 4 5 Carlsson, Sofia (2019). "Etiology and Pathogenesis of Latent Autoimmune Diabetes in Adults (LADA) Compared to Type 2 Diabetes". Frontiers in Physiology. 10: 320. doi:10.3389/fphys.2019.00320. ISSN 1664-042X. PMC 6444059. PMID 30971952.
  4. 1 2 3 4 5 Mishra, Rajashree; Hodge, Kenyaita M.; Cousminer, Diana L.; Leslie, Richard D.; Grant, Struan F. A. (2018-09-01). "A Global Perspective of Latent Autoimmune Diabetes in Adults". Trends in Endocrinology & Metabolism. 29 (9): 638–650. doi:10.1016/j.tem.2018.07.001. ISSN 1043-2760. PMID 30041834. S2CID 51715011.
  5. 1 2 3 4 Buzzetti, Raffaella; Zampetti, Simona; Maddaloni, Ernesto (November 2017). "Adult-onset autoimmune diabetes: current knowledge and implications for management". Nature Reviews Endocrinology. 13 (11): 674–686. doi:10.1038/nrendo.2017.99. ISSN 1759-5037. PMID 28885622. S2CID 3339346.
  6. ↑ Andersen, Mette K.; Lundgren, Virve; Turunen, Joni A.; Forsblom, Carol; Isomaa, Bo; Groop, Per-Henrik; Groop, Leif; Tuomi, Tiinamaija (2010-09-01). "Latent Autoimmune Diabetes in Adults Differs Genetically From Classical Type 1 Diabetes Diagnosed After the Age of 35 Years". Diabetes Care. 33 (9): 2062–2064. doi:10.2337/dc09-2188. ISSN 0149-5992. PMC 2928363. PMID 20805278.
  7. ↑ Andersen, Mette K.; Sterner, Maria; Forsén, Tom; Käräjämäki, Annemari; Rolandsson, Olov; Forsblom, Carol; Groop, Per-Henrik; Lahti, Kaj; Nilsson, Peter M.; Groop, Leif; Tuomi, Tiinamaija (2014-09-01). "Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes". Diabetologia. 57 (9): 1859–1868. doi:10.1007/s00125-014-3287-8. ISSN 1432-0428. PMID 24906951. S2CID 10477815.
  8. ↑ Cervin, Camilla; Lyssenko, Valeriya; Bakhtadze, Ekaterine; Lindholm, Eero; Nilsson, Peter; Tuomi, Tiinamaija; Cilio, Corrado M.; Groop, Leif (2008-05-01). "Genetic Similarities Between Latent Autoimmune Diabetes in Adults, Type 1 Diabetes, and Type 2 Diabetes". Diabetes. 57 (5): 1433–1437. doi:10.2337/db07-0299. ISSN 0012-1797. PMID 18310307.
  9. ↑ Cousminer, Diana L.; Ahlqvist, Emma; Mishra, Rajashree; Andersen, Mette K.; Chesi, Alessandra; Hawa, Mohammad I.; Davis, Asa; Hodge, Kenyaita M.; Bradfield, Jonathan P.; Zhou, Kaixin; Guy, Vanessa C. (2018-11-01). "First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes". Diabetes Care. 41 (11): 2396–2403. doi:10.2337/dc18-1032. ISSN 0149-5992. PMC 6196829. PMID 30254083.
  10. ↑ Pettersen, Elin; Skorpen, Frank; Kvaløy, Kirsti; Midthjell, Kristian; Grill, Valdemar (2010-01-01). "Genetic Heterogeneity in Latent Autoimmune Diabetes Is Linked to Various Degrees of Autoimmune Activity: Results From the Nord-Trøndelag Health Study". Diabetes. 59 (1): 302–310. doi:10.2337/db09-0923. ISSN 0012-1797. PMC 2797937. PMID 19833889.
  11. ↑ Vandewalle C.L.; Decraene, T.; Schuit, F.C.; De Leeuw, I.H.; Pipeleers, D.G.; F.K. Gorus (November 1993). "Insulin autoantibodies and high titre islet cell antibodies are preferentially associated with the HLA DQA1*0301-DQB1*0302 haplotype at clinical type 1 (insulin-dependent) diabetes mellitus before age 10 years, but not at onset between age 10 and 40 years". Diabetologia. 36 (11): 1155–62. doi:10.1007/bf00401060. PMID 8270130.
  12. ↑ American Diabetes, Association (January 2007). "Diagnosis and classification of diabetes mellitus". Diabetes Care. 30 Suppl 1: S42–7. doi:10.2337/dc07-S042. PMID 17192378.
  13. ↑ Flynn, Choi & Wooster 2013, p. 286.
  14. 1 2 Eisenbarth 2010, p. 316.
  15. 1 2 3 4 World Health Organization. (2016). Global Report on Diabetes. Geneva: World Health Organization.
  16. ↑ Landin-Olsson, Mona (April 2002). "Latent autoimmune diabetes in adults". Annals of the New York Academy of Sciences. 958 (1): 112–116. Bibcode:2002NYASA.958..112L. doi:10.1111/j.1749-6632.2002.tb02953.x. PMID 12021090. S2CID 6804673. Archived from the original on 2006-05-22. Retrieved 2006-05-22.
  17. 1 2 3 4 Pipi, Elena; Marietta Market; Alexandra Tsirogianni (August 15, 2014). "Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus". World Journal of Diabetes. 5 (4): 505–10. doi:10.4239/wjd.v5.i4.505. PMC 4127585. PMID 25126396.
  18. ↑ Khardori, Romesh (September 30, 2016). Griffing, George T. (ed.). "Diabetes Mellitus, Type 1: A Review". eMedicine.com. Retrieved January 20, 2017.
  19. ↑ Latent Autoimmune Diabetes in Adults; David Leslie, Cristina Valerie DiabetesVoice.org; 2003
  20. ↑ Unnikrishnan AG, Singh SK, Sanjeevi CB (December 2004). "Prevalence of GAD65 antibodies in lean subjects with type 2 diabetes". Annals of the New York Academy of Sciences. 1037 (1): 118–21. Bibcode:2004NYASA1037..118U. doi:10.1196/annals.1337.018. PMID 15699503. S2CID 2179462.
  21. 1 2 3 4 5 6 7 8 Carlsson S. (2019). Environmental (Lifestyle) Risk Factors for LADA. Current diabetes reviews, 15(3), 178–187. https://doi.org/10.2174/1573399814666180716150253.
  22. ↑ Hjort, Rebecka; Ahlqvist, Emma; Carlsson, Per-Ola; Grill, Valdemar; Groop, Leif; Martinell, Mats; Rasouli, Bahareh; Rosengren, Anders; Tuomi, Tiinamaija; Åsvold, Bjørn Olav; Carlsson, Sofia (2018-06-01). "Overweight, obesity and the risk of LADA: results from a Swedish case–control study and the Norwegian HUNT Study". Diabetologia. 61 (6): 1333–1343. doi:10.1007/s00125-018-4596-0. ISSN 1432-0428. PMC 6448998. PMID 29589073.
  23. ↑ Hjort, R., Löfvenborg, J. E., Ahlqvist, E., Alfredsson, L., Andersson, T., Grill, V., Groop, L., Sørgjerd, E. P., Tuomi, T., Åsvold, B. O., & Carlsson, S. (2019). Interaction Between Overweight and Genotypes of HLA, TCF7L2, and FTO in Relation to the Risk of Latent Autoimmune Diabetes in Adults and Type 2 Diabetes. The Journal of clinical endocrinology and metabolism, 104(10), 4815–4826. https://doi.org/10.1210/jc.2019-00183.
  24. ↑ Hjort, Rebecka; Alfredsson, Lars; Carlsson, Per-Ola; Groop, Leif; Martinell, Mats; Storm, Petter; Tuomi, Tiinamaija; Carlsson, Sofia (2015-11-01). "Low birthweight is associated with an increased risk of LADA and type 2 diabetes: results from a Swedish case–control study". Diabetologia. 58 (11): 2525–2532. doi:10.1007/s00125-015-3711-8. ISSN 1432-0428. PMID 26208603.
  25. ↑ Löfvenborg, J. E.; Andersson, T.; Carlsson, P.-O.; Dorkhan, M.; Groop, L.; Martinell, M.; Rasouli, B.; Storm, P.; Tuomi, T.; Carlsson, S. (2014). "Coffee consumption and the risk of latent autoimmune diabetes in adults—results from a Swedish case–control study". Diabetic Medicine. 31 (7): 799–805. doi:10.1111/dme.12469. ISSN 1464-5491. PMID 24750356. S2CID 2394699.
  26. ↑ Rasouli, B.; Ahlqvist, E.; Alfredsson, L.; Andersson, T.; Carlsson, P. -O.; Groop, L.; Löfvenborg, J. E.; Martinell, M.; Rosengren, A.; Tuomi, T.; Wolk, A. (2018-09-01). "Coffee consumption, genetic susceptibility and risk of latent autoimmune diabetes in adults: A population-based case-control study". Diabetes & Metabolism. 44 (4): 354–360. doi:10.1016/j.diabet.2018.05.002. hdl:10138/305740. ISSN 1262-3636. PMID 29861145.
  27. ↑ Löfvenborg, Josefin E.; Ahlqvist, Emma; Alfredsson, Lars; Andersson, Tomas; Dorkhan, Mozhgan; Groop, Leif; Tuomi, Tiinamaija; Wolk, Alicja; Carlsson, Sofia (2020-02-01). "Genotypes of HLA, TCF7L2, and FTO as potential modifiers of the association between sweetened beverage consumption and risk of LADA and type 2 diabetes". European Journal of Nutrition. 59 (1): 127–135. doi:10.1007/s00394-019-01893-x. ISSN 1436-6215. PMC 7000500. PMID 30656477.
  28. ↑ Löfvenborg, Josefin E.; Ahlqvist, Emma; Alfredsson, Lars; Andersson, Tomas; Groop, Leif; Tuomi, Tiinamaija; Wolk, Alicja; Carlsson, Sofia (2020-05-22). "Consumption of red meat, genetic susceptibility, and risk of LADA and type 2 diabetes". European Journal of Nutrition. 60 (2): 769–779. doi:10.1007/s00394-020-02285-2. ISSN 1436-6215. PMC 7900036. PMID 32444887.
  29. ↑ Löfvenborg, Josefin E.; Andersson, Tomas; Carlsson, Per-Ola; Dorkhan, Mozhgan; Groop, Leif; Martinell, Mats; Tuomi, Tiinamaija; Wolk, Alicja; Carlsson, Sofia (2016-12-01). "Sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes". European Journal of Endocrinology. 175 (6): 605–614. doi:10.1530/EJE-16-0376. ISSN 0804-4643. PMID 27926472.
  30. ↑ Löfvenborg, J. E.; Andersson, T.; Carlsson, P.-O.; Dorkhan, M.; Groop, L.; Martinell, M.; Tuomi, T.; Wolk, A.; Carlsson, S. (October 2014). "Fatty fish consumption and risk of latent autoimmune diabetes in adults". Nutrition & Diabetes. 4 (10): e139. doi:10.1038/nutd.2014.36. ISSN 2044-4052. PMC 4216999. PMID 25329601.
  31. ↑ Eisenbarth, George. "Prediction of Type I Diabetes". University of Colorado, Denver. Retrieved March 23, 2016.
  32. ↑ Castro, M. Regina. "Latent autoimmune diabetes". Mayo Clinic. Retrieved May 26, 2014.
  33. ↑ Nguyen, Than; Tara L. Muzyk (October 15, 2009). "LADA: A Little Known Type of Diabetes". Pharmacy Times. Retrieved May 26, 2014.
  34. ↑ Bottazzo, GF; Florin-Christensen, A; Doniach, D (Nov 30, 1974). "Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies". Lancet. 2 (7892): 1279–83. doi:10.1016/s0140-6736(74)90140-8. PMID 4139522.
  35. ↑ Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR (February 1993). "Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease". Diabetes. 42 (2): 359–62. doi:10.2337/diab.42.2.359. PMID 8425674.
  36. ↑ Hagopian, W A; Karlsen, A E; Gottsäter, A; Landin-olsson, M; Grubin, C E; Sundkvist, G; Petersen, J S; Boel, E; Dyrberg, T; Lernmark, A (January 1993). "Quantitative assay using recombinant human islet glutamic acid decarboxylase (GAD65) shows that 64K autoantibody positivity at onset predicts diabetes type Hagopian, W A; Karlsen, A E; Gottsäter, A; Landin-olsson, M; Grubin, C E; Sundkvist, G; Petersen, J S; Boel, E; Dyrberg, T; Lernmark, A". The Journal of Clinical Investigation. 91 (1): 368–74. doi:10.1172/JCI116195. PMC 330036. PMID 8423232.

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