Medicine:Latent autoimmune diabetes in adults

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Latent autoimmune diabetes in adults
Other namesLADA, late-onset autoimmune diabetes of adulthood,[1] adult-onset autoimmune diabetes
Blue circle for diabetes.svg
Universal blue circle symbol for diabetes[2]
Pronunciation
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] and is sometimes referred to as type 1.5 diabetes.[5] 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][6] Since many people develop the disease later in life, it is often misdiagnosed as type 2 diabetes.[7]

LADA appears to share genetic risk factors with both T1D and T2D but is genetically distinct from both.[8][9][10][11][4] Within the LADA patient group, a genetic and phenotypic heterogeneity has been observed with varying degrees of insulin resistance and autoimmunity.[6][12] 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,[13] 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.[14]

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.[15] Compared to juvenile type 1 diabetes, the symptoms develop comparatively slowly, over a period of at least six months.[16]

Diagnosis

A fasting blood sugar level of ≥ 7.0 mmol / L (126 mg/dL) is used in the general diagnosis of diabetes.[17] 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.[3][4][6]

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.[18]

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.[16][19]

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.[19]

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.[19][20] 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[19][21][22] 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 have some form of diabetes[17] and it is estimated that LADA accounts for about 3-12% of all adult diabetes cases.[23] 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.[4][23] As with both T1D and T2D, the risk of LADA depends on both genetic and environmental factors.[23][17] 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.[23] 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.[23]

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.[23][24][25] Physical activity also affects the risk of LADA, with less physical activity increasing the risk.[23] A Swedish study showed that low birth weight, in addition to increasing the risk of T2D, increases the risk of LADA.[26]

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.[23] However, results from two studies based on the same population seem to indicate that coffee consumption increases the risk of LADA.[27][28] Other foods that have been shown to increase the risk of LADA are sweetened beverages and processed red meat[29][30][31] while consumption of fatty fish has been shown to have a protective effect.[32]

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.[17] 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.[3][6] 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).[33]

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.[34] 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.[35]

A Cochrane systematic review from 2011 showed that treatment with Sulphonylurea did not improve control of glucose levels more than insulin at 3 nor 12 months of treatment.[36] This same review actually found evidence that treatment with Sulphonylurea could lead to earlier insulin dependence, with 30% of cases requiring insulin at 2 years.[36] When studies measured fasting C-peptide, no intervention influenced its concentration, but insulin maintained concentration better compared to Sulphonylurea.[36] The authors also examined a study utilizing Glutamic Acid Decarboxylase formulated with aluminium hydroxide (GAD65), which showed improvements in C-peptide levels that were maintained for 5 years.[36] Vitamin D with insulin also demonstrated steady fasting C-peptide levels in the vitamin group, with the same levels declining in the insulin-only group at a 12-month follow-up. One study examining the effects of Chinese remedies on fasting C-peptide on a 3-month follow-up did not show a difference compared to insulin alone.[36] Still, it is important to highlight that the studies available to be included in this review presented considerable flaws in quality and design.[36]

History

Although type 1 diabetes has been identified as an autoimmune disease since the 1970s,[37] 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.[38] This followed the concept that GAD autoantibodies were a feature of type 1 diabetes and not type 2 diabetes.[39]

References

  1. ↑ Williams, Wilkins & Munden 2006, p. 20.
  2. ↑ "Diabetes Blue Circle Symbol". International Diabetes Federation. 17 March 2006. http://www.diabetesbluecircle.org. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Carlsson, Sofia (2019). "Etiology and Pathogenesis of Latent Autoimmune Diabetes in Adults (LADA) Compared to Type 2 Diabetes" (in en). Frontiers in Physiology 10: 320. doi:10.3389/fphys.2019.00320. ISSN 1664-042X. PMID 30971952. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 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" (in en). Trends in Endocrinology & Metabolism 29 (9): 638–650. doi:10.1016/j.tem.2018.07.001. ISSN 1043-2760. PMID 30041834. http://www.sciencedirect.com/science/article/pii/S1043276018301292. 
  5. ↑ "Latent autoimmune diabetes in adults (LADA): What is it?". Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/type-1-diabetes/expert-answers/lada-diabetes/faq-20057880#:~:text=Many%20researchers%20believe%20LADA%20%2C%20sometimes,are%20usually%20over%20age%2030.. 
  6. ↑ 6.0 6.1 6.2 6.3 Buzzetti, Raffaella; Zampetti, Simona; Maddaloni, Ernesto (November 2017). "Adult-onset autoimmune diabetes: current knowledge and implications for management" (in en). Nature Reviews Endocrinology 13 (11): 674–686. doi:10.1038/nrendo.2017.99. ISSN 1759-5037. PMID 28885622. https://www.nature.com/articles/nrendo.2017.99. 
  7. ↑ "Latent autoimmune diabetes in adults (LADA): What is it?" (in en). https://www.mayoclinic.org/diseases-conditions/type-1-diabetes/expert-answers/lada-diabetes/faq-20057880. 
  8. ↑ 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" (in en). Diabetes Care 33 (9): 2062–2064. doi:10.2337/dc09-2188. ISSN 0149-5992. PMID 20805278. 
  9. ↑ Andersen, Mette K.; Sterner, Maria; Forsén, Tom; Käräjämäki, Annemari; Rolandsson, Olov; Forsblom, Carol; Groop, Per-Henrik; Lahti, Kaj et al. (2014-09-01). "Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes" (in en). Diabetologia 57 (9): 1859–1868. doi:10.1007/s00125-014-3287-8. ISSN 1432-0428. PMID 24906951. 
  10. ↑ 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" (in en). Diabetes 57 (5): 1433–1437. doi:10.2337/db07-0299. ISSN 0012-1797. PMID 18310307. https://diabetes.diabetesjournals.org/content/57/5/1433. 
  11. ↑ Cousminer, Diana L.; Ahlqvist, Emma; Mishra, Rajashree; Andersen, Mette K.; Chesi, Alessandra; Hawa, Mohammad I.; Davis, Asa; Hodge, Kenyaita M. et al. (2018-11-01). "First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes" (in en). Diabetes Care 41 (11): 2396–2403. doi:10.2337/dc18-1032. ISSN 0149-5992. PMID 30254083. 
  12. ↑ 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" (in en). Diabetes 59 (1): 302–310. doi:10.2337/db09-0923. ISSN 0012-1797. PMID 19833889. 
  13. ↑ 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. 
  14. ↑ 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. http://care.diabetesjournals.org/content/30/suppl_1/S42.full. 
  15. ↑ Flynn, Choi & Wooster 2013, p. 286.
  16. ↑ 16.0 16.1 Eisenbarth 2010, p. 316.
  17. ↑ 17.0 17.1 17.2 17.3 World Health Organization. (2016). Global Report on Diabetes. Geneva: World Health Organization.
  18. ↑ Landin-Olsson, Mona (April 2002). "Latent autoimmune diabetes in adults". Annals of the New York Academy of Sciences 958 (1): 112–116. doi:10.1111/j.1749-6632.2002.tb02953.x. PMID 12021090. Bibcode: 2002NYASA.958..112L. http://www.annalsnyas.org/cgi/content/full/958/1/112. Retrieved 2006-05-22. 
  19. ↑ 19.0 19.1 19.2 19.3 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. PMID 25126396. 
  20. ↑ Khardori, Romesh (September 30, 2016). "Diabetes Mellitus, Type 1: A Review". in Griffing, George T.. eMedicine.com. http://www.emedicine.com/EMERG/topic133.htm. Retrieved January 20, 2017. 
  21. ↑ Latent Autoimmune Diabetes in Adults; David Leslie, Cristina Valerie DiabetesVoice.org; 2003
  22. ↑ "Prevalence of GAD65 antibodies in lean subjects with type 2 diabetes". Annals of the New York Academy of Sciences 1037 (1): 118–21. December 2004. doi:10.1196/annals.1337.018. PMID 15699503. Bibcode: 2004NYASA1037..118U. 
  23. ↑ 23.0 23.1 23.2 23.3 23.4 23.5 23.6 23.7 Carlsson, Sofia (2019). "Environmental (Lifestyle) Risk Factors for LADA". Current Diabetes Reviews 15 (3): 178–187. doi:10.2174/1573399814666180716150253. PMID 30009710. https://doi.org/10.2174/1573399814666180716150253. 
  24. ↑ Hjort, Rebecka; Ahlqvist, Emma; Carlsson, Per-Ola; Grill, Valdemar; Groop, Leif; Martinell, Mats; Rasouli, Bahareh; Rosengren, Anders et al. (2018-06-01). "Overweight, obesity and the risk of LADA: results from a Swedish case–control study and the Norwegian HUNT Study" (in en). Diabetologia 61 (6): 1333–1343. doi:10.1007/s00125-018-4596-0. ISSN 1432-0428. PMID 29589073. 
  25. ↑ Hjort, Rebecka; Löfvenborg, Josefin E.; Ahlqvist, Emma; Alfredsson, Lars; Andersson, Tomas; Grill, Valdemar; Groop, Leif; Sørgjerd, Elin P. et al. (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 & Metabolism 104 (10): 4815–4826. doi:10.1210/jc.2019-00183. PMID 31125083. 
  26. ↑ 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" (in en). Diabetologia 58 (11): 2525–2532. doi:10.1007/s00125-015-3711-8. ISSN 1432-0428. PMID 26208603. 
  27. ↑ Löfvenborg, J. E.; Andersson, T.; Carlsson, P.-O.; Dorkhan, M.; Groop, L.; Martinell, M.; Rasouli, B.; Storm, P. et al. (2014). "Coffee consumption and the risk of latent autoimmune diabetes in adults—results from a Swedish case–control study" (in en). Diabetic Medicine 31 (7): 799–805. doi:10.1111/dme.12469. ISSN 1464-5491. PMID 24750356. 
  28. ↑ Rasouli, B.; Ahlqvist, E.; Alfredsson, L.; Andersson, T.; Carlsson, P. -O.; Groop, L.; Löfvenborg, J. E.; Martinell, M. et al. (2018-09-01). "Coffee consumption, genetic susceptibility and risk of latent autoimmune diabetes in adults: A population-based case-control study" (in en). Diabetes & Metabolism 44 (4): 354–360. doi:10.1016/j.diabet.2018.05.002. ISSN 1262-3636. PMID 29861145. http://www.sciencedirect.com/science/article/pii/S1262363618300879. 
  29. ↑ Löfvenborg, Josefin E.; Ahlqvist, Emma; Alfredsson, Lars; Andersson, Tomas; Dorkhan, Mozhgan; Groop, Leif; Tuomi, Tiinamaija; Wolk, Alicja et al. (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" (in en). European Journal of Nutrition 59 (1): 127–135. doi:10.1007/s00394-019-01893-x. ISSN 1436-6215. PMID 30656477. 
  30. ↑ 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" (in en). European Journal of Nutrition 60 (2): 769–779. doi:10.1007/s00394-020-02285-2. ISSN 1436-6215. PMID 32444887. 
  31. ↑ Löfvenborg, Josefin E.; Andersson, Tomas; Carlsson, Per-Ola; Dorkhan, Mozhgan; Groop, Leif; Martinell, Mats; Tuomi, Tiinamaija; Wolk, Alicja et al. (2016-12-01). "Sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes" (in en-US). European Journal of Endocrinology 175 (6): 605–614. doi:10.1530/EJE-16-0376. ISSN 0804-4643. PMID 27926472. https://eje.bioscientifica.com/view/journals/eje/175/6/605.xml. 
  32. ↑ Löfvenborg, J. E.; Andersson, T.; Carlsson, P.-O.; Dorkhan, M.; Groop, L.; Martinell, M.; Tuomi, T.; Wolk, A. et al. (October 2014). "Fatty fish consumption and risk of latent autoimmune diabetes in adults" (in en). Nutrition & Diabetes 4 (10): e139. doi:10.1038/nutd.2014.36. ISSN 2044-4052. PMID 25329601. 
  33. ↑ Eisenbarth, George. "Prediction of Type I Diabetes". University of Colorado, Denver. http://som.ucdenver.edu/bdc/Book-Type1Diabetes/HTML/CH11/CH11.html. Retrieved March 23, 2016. 
  34. ↑ Castro, M. Regina. "Latent autoimmune diabetes". Mayo Clinic. http://www.mayoclinic.org/diseases-conditions/type-1-diabetes/expert-answers/lada-diabetes/FAQ-20057880. Retrieved May 26, 2014. 
  35. ↑ Nguyen, Than; Tara L. Muzyk (October 15, 2009). "LADA: A Little Known Type of Diabetes". Pharmacy Times. October 2009 75 (10). http://www.pharmacytimes.com/publications/issue/2009/october2009/FeatureFocusLADA-1009. Retrieved May 26, 2014. 
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 Brophy, Sinead; Davies, Helen; Mannan, Sopna; Brunt, Huw; Williams, Rhys (2011-09-07). "Interventions for latent autoimmune diabetes (LADA) in adults". Cochrane Database of Systematic Reviews 2011 (9): CD006165. doi:10.1002/14651858.cd006165.pub3. ISSN 1465-1858. PMID 21901702. PMC 6486159. https://doi.org/10.1002/14651858.CD006165.pub3. 
  37. ↑ 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. 
  38. ↑ "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. February 1993. doi:10.2337/diab.42.2.359. PMID 8425674. 
  39. ↑ Hagopian, W A; Karlsen, A E; Gottsäter, A; Landin-olsson, M; Grubin, C E; Sundkvist, G; Petersen, J S; Boel, E et al. (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. PMID 8423232. 

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