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  • Review Article
  • Published:

Adult-onset autoimmune diabetes: current knowledge and implications for management

Key Points

  • Adult-onset autoimmune diabetes encompasses a wide spectrum of heterogeneous genotypes and phenotypes, ranging from classic adult-onset type 1 diabetes mellitus to latent autoimmune diabetes in adults (LADA)

  • The heterogeneity of LADA arises from its definition as being present in any adult with diabetes who does not require insulin and who is positive for any islet autoantibody, regardless of titre, number or epitope specificity

  • The heterogeneity of LADA manifests in different clinical phenotypes, ranging from prevalent insulin resistance to prevalent insulin deficiency, each of which might be associated with different autoimmune and metabolic markers

  • Although patients with LADA are leaner and have healthier lipid and blood pressure profiles, evidence shows that there is no difference in cardiovascular outcomes between these patients and those with type 2 diabetes mellitus

  • The extensive heterogeneity of adult-onset autoimmune diabetes, and particularly LADA, makes it difficult to determine an a priori algorithm for treatment

  • The successful treatment of adult-onset autoimmune diabetes will require a personalized medicine approach that takes into account the intrinsic characteristics of each patient

Abstract

Adult-onset autoimmune diabetes is a heterogeneous disease that is characterized by a reduced genetic load, a less intensive autoimmune process and a mild metabolic decompensation at onset compared with young-onset type 1 diabetes mellitus (T1DM). The majority of patients with adult-onset autoimmune diabetes do not require insulin treatment for at least 6 months after diagnosis. Such patients are defined as having latent autoimmune diabetes in adults (LADA), which is distinct from classic adult-onset T1DM. The extensive heterogeneity of adult-onset autoimmune diabetes is apparent beyond the distinction between classic adult-onset T1DM and LADA. LADA is characterized by genetic, phenotypic and humoral heterogeneity, encompassing different degrees of insulin resistance and autoimmunity; this heterogeneity is probably a result of different pathological mechanisms, which have implications for treatment. The existence of heterogeneous phenotypes in LADA makes it difficult to establish an a priori treatment algorithm, and therefore, a personalized medicine approach is required. In this Review, we discuss the current understanding and gaps in knowledge regarding the pathophysiology and clinical features of adult-onset autoimmune diabetes and highlight the similarities and differences with classic T1DM and type 2 diabetes mellitus.

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Figure 1: Bimodal distribution of the glutamic acid decarboxylase autoantibody titre in patients with latent autoimmune diabetes in adults.
Figure 2: Potential pathological mechanisms of latent autoimmune diabetes in adults.
Figure 3: Prevalence of chronic diabetes-related complications in latent autoimmune diabetes in adults and type 2 diabetes mellitus.
Figure 4: Interactions between β-cell function, autoimmunity and insulin sensitivity.

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References

  1. Mølbak, A. G., Christau, B., Marner, B., Borch-Johnsen, K. & Nerup, J. Incidence of insulin-dependent diabetes mellitus in age groups over 30 years in Denmark. Diabet. Med. 11, 650–655 (1994).

    Article  PubMed  Google Scholar 

  2. Sabbah, E. et al. Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes. Diabetes Care 23, 1326–1332 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Howson, J. M. et al. Genetic analysis of adult-onset autoimmune diabetes. Diabetes 60, 2645–2653 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Hernandez, 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 Endocr. Disord. 15, 1 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  6. Hawa, M. I. et al. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: action LADA 7. Diabetes Care 36, 908–913 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Maddaloni, E. et al. Latent autoimmune diabetes in adults in the United Arab Emirates: clinical features and factors related to insulin-requirement. PLoS ONE 10, e0131837 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Zimmet, P. Z. et al. 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 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Juneja, R. & Palmer, J. P. Type 1 1/2 diabetes: myth or reality? Autoimmunity 29, 65–83 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. Pozzilli, P. & Di Mario, U. Autoimmune diabetes not requiring insulin at diagnosis (latent autoimmune diabetes of the adult): definition, characterization, and potential prevention. Diabetes Care 24, 1460–1467 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Kobayashi, T. et al. Insulin intervention to preserve beta cells in slowly progressive insulin-dependent (type 1) diabetes mellitus. Ann. NY Acad. Sci. 958, 117–130 (2001).

    Article  Google Scholar 

  12. Fourlanos, S. et al. Latent autoimmune diabetes in adults (LADA) should be less latent. Diabetologia 48, 2206–2212 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Brophy, S. et al. Time to insulin initiation cannot be used in defining latent autoimmune diabetes in adults. Diabetes Care 31, 439–441 (2008).

    Article  PubMed  Google Scholar 

  14. American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care 40 (Suppl. 1), S11–S24 (2017).

  15. Alberti, K. G. & Zimmet, P. Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet. Med. 15, 539–553 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Bruno, G. et al. Incidence of type 1 and type 2 diabetes in adults aged 30–49 years: the population-based registry in the province of Turin, Italy. Diabetes Care 28, 2613–2619 (2005).

    Article  PubMed  Google Scholar 

  17. Rawshani, A. et al. The incidence of diabetes among 0–34 year olds in Sweden: new data and better methods. Diabetologia 57, 1375–1381 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Turner, R. 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 350, 1288–1293 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Tuomi, T. et al. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 48, 150–157 (1999).

    Article  CAS  PubMed  Google Scholar 

  20. Takeda, H. et al. Clinical, autoimmune, and genetic characteristics of adult-onset diabetic patients with GAD autoantibodies in Japan (Ehime Study). Diabetes Care 25, 995–1001 (2002).

    Article  PubMed  Google Scholar 

  21. Zinman, B. et al. Phenotypic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe. Diabetes 53, 3193–3200 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Buzzetti, R. et al. High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care 30, 932–938 (2007).

    Article  CAS  PubMed  Google Scholar 

  23. Radtke, M. A., Midthjell, K., Nilsen, T. I. & Grill, V. Heterogeneity of patients with latent autoimmune diabetes in adults: linkage to autoimmunity is apparent only in those with perceived need for insulin treatment: results from the Nord-Trondelag Health (HUNT) study. Diabetes Care 32, 245–250 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Qi, X. et al. Prevalence and correlates of latent autoimmune diabetes in adults in Tianjin, China: a population-based cross-sectional study. Diabetes Care 34, 66–70 (2011).

    Article  PubMed  Google Scholar 

  25. Maioli, M. 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. 163, 541–549 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Zhou, Z. et al. 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 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Tuomi, T. et al. The many faces of diabetes: a disease with increasing heterogeneity. Lancet 383, 1084–1094 (2014).

    Article  PubMed  Google Scholar 

  28. Laugesen, E., Østergaard, J. A. & Leslie, R. D. Latent autoimmune diabetes of the adult: current knowledge and uncertainty. Danish Diabetes Academy Workshop and Workshop Speakers. Diabet. Med. 32, 843–852 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Lampasona, V. et al. 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 (2010).

    Article  CAS  PubMed  Google Scholar 

  30. Yang, Z. et al. Childhood diabetes in China. Enormous variation by place and ethnic group. Diabetes Care 21, 525–529 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Sutanegara, D. & Budhiarta, A. A. The epidemiology and management of diabetes mellitus in Indonesia. Diabetes Res. Clin. Pract. 50, S9–S16 (2000).

    Article  PubMed  Google Scholar 

  32. Mohatt, J., Gilliam, L. K., Bekris, L., Ebbesson, S. & Lernmark, A. Type 1 diabetes-related autoantibodies are rare in Alaska native populations. Int. J. Circumpolar Health 61, 21–31 (2002).

    Article  PubMed  Google Scholar 

  33. Dowse, G. K. et al. Lack of antibodies to glutamic acid decarboxylase in young adults of the high diabetes prevalence Wanigela people of Papua New Guinea. Diabetes Res. Clin. Pract. 24, 195–198 (1994).

    Article  CAS  PubMed  Google Scholar 

  34. Barinas-Mitchell, E. et al. Islet cell autoimmunity in a triethnic adult population of the Third National Health and Nutrition Examination Survey. Diabetes 53, 1293–1302 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Temneanu, O. R., Trandafir, L. M. & Purcarea, M. R. Type 2 diabetes mellitus in children and adolescents: a relatively new clinical problem within pediatric practice. J. Med. Life 3, 235–239 (2016).

    Google Scholar 

  36. Leslie, R. D., Palmer, J., Schloot, N. C. & Lernmark, A. Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment. Diabetologia 59, 13–20 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Nisticò, L. et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum. Mol. Genet. 5, 1075–1080 (1996).

    Article  PubMed  Google Scholar 

  38. Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Grant, S. F. et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 38, 320–323 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Frayling, T. M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Atkinson, M. A. & Eisenbarth, G. S. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet 358, 221–229 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Leslie, R. D. & Delli Castelli, M. Age-dependent influences on the origins of autoimmune diabetes: evidence and implications. Diabetes 53, 3033–3040 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Caillat-Zucman, S. et al. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J. Clin. Invest. 90, 2242–2250 (1992).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Petrone, A. et al. Residual insulin secretion at diagnosis of type 1 diabetes is independently associated with both, age of onset and HLA genotype. Diabetes Metab. Res. Rev. 21, 271–275 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Andersen, M. K. et al. Latent autoimmune diabetes in adults differs genetically from classical type 1 diabetes diagnosed after the age of 35 years. Diabetes Care 33, 2062–2064 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Van der Auwera, B. J. et al. CTLA-4 gene polymorphism confers susceptibility to insulin-dependent diabetes mellitus (IDDM) independently from age and from other genetic or immune disease markers. The Belgian Diabetes Registry. Clin. Exp. Immunol. 110, 98–103 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Cosentino, A., Gambelunghe, G., Tortoioli, C. & Falorni, A. CTLA-4 gene polymorphism contributes to the genetic risk for latent autoimmune diabetes in adults. Ann. NY Acad. Sci. 958, 337–340 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Bennett, S. T. et al. Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. Nat. Genet. 17, 350–352 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Haller, K. et al. Insulin gene VNTR, CTLA-4 + 49A/G and HLA-DQB1 alleles distinguish latent autoimmune diabetes in adults from type 1 diabetes and from type 2 diabetes group. Tissue Antigens 69, 21–27 (2007).

    Article  CAS  Google Scholar 

  50. Gambelunghe, G. Two distinct MICA gene markers discriminate major autoimmune diabetes types. J. Clin. Endocrinol. Metab. 86, 3754–3760 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Sanjeevi, C. B. Genetics of latent autoimmune diabetes in adults. Ann. NY Acad. Sci. 958, 107–111 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Brooks-Worrell, B. M., Juneja, R., Minokadeh, A., Greenbaum, C. J. & Palmer, J. P. Cellular immune responses to human islet proteins in antibody-positive type 2 diabetic patents. Diabetes 48, 983–988 (1999).

    Article  CAS  PubMed  Google Scholar 

  53. Signore, A. et al. Detection of insulitis by pancreatic scintigraphy with 99mTc-labeled IL-2 and MRI in patients with LADA (Action LADA 10). Diabetes Care 38, 652–658 (2015).

    CAS  PubMed  Google Scholar 

  54. Brooks-Worrell, B. M., Reichow, J. L., Goel, A., Ismail, H. & Palmer, J. P. Identification of autoantibody-negative autoimmune type 2 diabetic patients. Diabetes Care 34, 168–173 (2011).

    Article  PubMed  Google Scholar 

  55. Graham, J. et al. Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes. Diabetes 51, 1346–1355 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Kawasaki, E. Type 1 diabetes and autoimmunity. Clin. Pediatr. Endocrinol. 23, 99–105 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Tiberti, C. et al. 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 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Buzzetti, R. et al. 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 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Pham, M. N. et al. Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: action LADA 4. Diabetologia 54, 1630–1638 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Ferrannini, E. The stunned beta cell: a brief history. Cell Metab. 11, 349–352 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Stenström, G., Gottsäter, A., Bakhtadze, E., Berger, B. & Sundkvist, G. Latent autoimmune diabetes in adults: definition, prevalence, beta-cell function, and treatment. Diabetes 54 (Suppl. 2), S68–S72 (2005).

    Article  PubMed  Google Scholar 

  62. Barker, A. et al. Age-dependent decline of β-cell function in type 1 diabetes after diagnosis: a multi-centre longitudinal study. Diabetes Obes. Metab. 16, 262–267 (2014).

    Article  CAS  PubMed  Google Scholar 

  63. Joanes, D. N. & Gill, C. A. Comparing measures of sample skewness and kurtosis. Statistician 47, 183–189 (1998).

    Google Scholar 

  64. Petrone, A. et al. The protein tyrosine phosphatase nonreceptor 22 (PTPN22) is associated with high GAD antibody titer in latent autoimmune diabetes in adults: non Insulin Requiring Autoimmune Diabetes (NIRAD) Study 3. Diabetes Care 31, 534–538 (2008).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  66. Pettersen, E., Skorpen, F., Kvaløy, K., Midthjell, K. & Grill, V. Genetic heterogeneity in latent autoimmune diabetes is linked to various degrees of autoimmune activity: results from the Nord-Trøndelag Health Study. Diabetes 59, 302–310 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Zampetti, S. et al. 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 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Bottazzo, G. F. et al. IA-2 antibody prevalence and risk assessment of early insulin requirementin subjects presenting with type 2diabetes (UKPDS 71). Diabetologia 48, 703–708 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Genovese, S. et al. Clinical phenotype and β-cell autoimmunity in Italian patients with adult-onset diabetes. Eur. J. Endocrinol. 154, 441–447 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Desai, M. et al. 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 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Zampetti, S. 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. 171, 697–704 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Itariu, B. K. & Stulnig, T. M. Autoimmune aspects of type 2 diabetes mellitus — a mini-review. Gerontology 60, 189–196 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Zhang, B., Lan, M. S. & Notkins, A. L. Autoantibodies to IA-2 in IDDM: location of major antigenic determinants. Diabetes 46, 40–43 (1997).

    Article  PubMed  Google Scholar 

  74. Brooks-Worrell, B., Narla, R. & Palmer, J. P. Islet autoimmunity in phenotypic type 2 diabetes patients. Diabetes Obes. Metab. 3, 137–140 (2013).

    Article  CAS  Google Scholar 

  75. Palmer, J. P., Hampe, C. S., Chiu, H., Goel, A. & Brooks-Worrell, B. M. Is latent autoimmune diabetes in adults distinct from type 1 diabetes or just type 1 diabetes at an older age? Diabetes 54, S62–S67 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Acevedo-Calado, M. et al. Identification of unique antigenic determinants in the amino terminus of IA-2 (ICA512) in childhood and adult autoimmune diabetes: new biomarker development. Diabetes Care 40, 561–568 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Andersen, M. K. et al. Type 2 diabetes susceptibility gene variants predispose to adult-onset autoimmune diabetes. Diabetologia 57, 1859–1868 (2014).

    Article  CAS  PubMed  Google Scholar 

  78. Carlsson, A., Sundkvist, G., Groop, L. & Tuomi, T. Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes (LADA). J. Clin. Endocrinol. Metab. 85, 76–80 (2000).

    CAS  PubMed  Google Scholar 

  79. Maruyama, T. Multicenter prevention trial of slowly progressive type 1 diabetes with small dose of insulin (the Tokyo study): preliminary report. Ann. NY Acad. Sci. 1005, 362–369 (2003).

    Article  CAS  PubMed  Google Scholar 

  80. Fourlanos, S. et al. A clinical screening tool identifies autoimmune diabetes in adults. Diabetes Care 29, 970–975 (2006).

    Article  PubMed  Google Scholar 

  81. Gregg, E. W. et al. Changes in diabetes-related complications in the United States1990–2010. N. Engl. J. Med. 370, 1514–1523 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Lind, M. et al. Glycemic control and excess mortality in type 1 diabetes. N. Engl. J. Med. 371, 1972–1982 (2014).

    Article  CAS  PubMed  Google Scholar 

  83. Secrest, A. M., Becker, D. J., Kelsey, S. F., Laporte, R. E. & Orchard, T. J. Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes 59, 3216–3222 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Myhill, P. et al. Chronic complications and mortality in community-based patients with latent autoimmune diabetes in adults: the Fremantle Diabetes Study. Diabet. Med. 25, 1245–1250 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Isomaa, B. et al. Chronic complications in patients with slowly progressing autoimmune type 1 diabetes (LADA). Diabetes Care 22, 1347–1353 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Lu, J. et al. Associations between clinical characteristics and chronic complications in latent autoimmune diabetes in adults and type 2 diabetes. Diabetes. Metab. Res. Rev. 31, 411–420 (2015).

    Article  PubMed  Google Scholar 

  87. Wang, C. et al. Evaluating peripheral nerve function in asymptomatic patients with type 2 diabetes or latent autoimmune diabetes of adults (LADA): results from nerve conduction studies. J. Diabetes Complications 29, 265–269 (2015).

    Article  PubMed  Google Scholar 

  88. Hawa, M. I. et al. LADA and CARDS: a prospective study of clinical outcome in established adult-onset autoimmune diabetes. Diabetes Care 37, 1643–1649 (2014).

    Article  CAS  PubMed  Google Scholar 

  89. Arikan, E., Sabuncu, T., Ozer, E. M. & Hatemi, H. The clinical characteristics of latent autoimmune diabetes in adults and its relation with chronic complications in metabolically poor controlled Turkish patients with Type 2 diabetes mellitus. J. Diabetes Complications 19, 254–258 (2005).

    Article  PubMed  Google Scholar 

  90. Balme, M., McAllister, I., Davis, W. A. & Davis, T. M. E. Retinopathy in latent autoimmune diabetes of adults: the Fremantle Diabetes Study. Diabet. Med. 19, 602–605 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Harris, M. I., Klein, R., Welborn, T. A. & Knuiman, M. W. Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 15, 815–819 (1992).

    Article  CAS  PubMed  Google Scholar 

  92. Porta, M. et al. Estimating the delay between onset and diagnosis of type 2 diabetesfrom the time course of retinopathy prevalence. Diabetes Care 37, 1668–1674 (2014).

    Article  PubMed  Google Scholar 

  93. Martinell, M. et al. Prevalence and risk factors for diabetic retinopathy at diagnosis (DRAD) in patients recently diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA). J. Diabetes Complications 30, 1456–1461 (2016).

    Article  PubMed  Google Scholar 

  94. Roh, M.-O., Jung, C.-H., Kim, B.-Y., Mok, J.-O. & Kim, C.-H. The prevalence and characteristics of latent autoimmune diabetes in adults (LADA) and its relation with chronic complications in a clinical department of a university hospital in Korea. Acta Diabetol. 50, 129–134 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Baum, P. et al. Diabetic neuropathy in patients with latent autoimmune diabetes of the adult (LADA) compared with patients with type 1 and type 2 diabetes. J. Neurol. 250, 682–687 (2003).

    Article  PubMed  Google Scholar 

  96. Olsson, L. et al. Mortality in adult-onset autoimmune diabetes is associated with poor glycemic control: results from the HUNT Study. Diabetes Care 36, 3971–3978 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Brophy, S., Davies, H., Mannan, S., Brunt, H. & Williams, R. Interventions for latent autoimmune diabetes (LADA) in adults. Cochrane Database Syst. Rev. 9, CD006165 (2011).

    Google Scholar 

  98. Kobayashi, T., Nakanishi, K., Murase, T. & Kosaka, K. Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Diabetes 45, 622–626 (1996).

    Article  CAS  PubMed  Google Scholar 

  99. Maruyama, T. et al. Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus. J. Clin. Endocrinol. Metab. 93, 2115–2121 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Thunander, M., Thorgeirsson, H., Törn, C., Petersson, C. & Landin-Olsson, M. β-Cell function and metabolic control in latent autoimmune diabetes in adults with early insulin versus conventional treatment: a 3-year follow-up. Eur. J. Endocrinol. 164, 239–245 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Zhu, L., Liu, Y., Huang, M., Wei, H. & Liu, Z. Study on improvement of islet beta cell function in patients with latent autoimmune diabetes mellitus in adults by integrative Chinese and Western medicine [Chinese]. Zhongguo Zhong Xi Yi Jie He Za Zhi 24, 581–584 (2004).

    CAS  PubMed  Google Scholar 

  102. Davis, T. M. E. et al. Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70). Diabetologia 48, 695–702 (2005).

    Article  CAS  PubMed  Google Scholar 

  103. American Diabetes Association. 7. Approaches to glycemic treatment. Diabetes Care 38, S41–S48 (2015).

  104. Cernea, S., Buzzetti, R. & Pozzilli, P. β-Cell protection and therapy for latent autoimmune diabetes in adults. Diabetes Care 32, S246–S252 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Pozzilli, P., Maddaloni, E. & Buzzetti, R. Combination immunotherapies for type 1 diabetes mellitus. Nat. Rev. Endocrinol. 11, 289–297 (2015).

    Article  CAS  PubMed  Google Scholar 

  106. Rosário, P. W. S. et al. Latent autoimmune diabetes in adults (LADA): usefulness ofanti-GAD antibody titers and benefit of early insulinization. Arq. Bras. Endocrinol. Metabol. 51, 52–58 (2007).

    Article  PubMed  Google Scholar 

  107. Steffes, M. W., Sibley, S., Jackson, M. & Thomas, W. Beta-cell function and thedevelopment of diabetes-related complications in the diabetes control and complicationstrial. Diabetes Care 26, 832–836 (2003).

    Article  PubMed  Google Scholar 

  108. Agardh, C.-D. et al. Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes. J. Diabetes Compl. 19, 238–246 (2005).

    Article  Google Scholar 

  109. Pozzilli, P. & Guglielmi, C. Immunomodulation for the prevention of SPIDDM and LADA. Ann. NY Acad. Sci. 1079, 90–98 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Agardh, C. D., Lynch, K. F., Palmér, M., Link, K. & Lernmark, A. GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes. Diabetologia 52, 1363–1368 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Pettus, J., Hirsch, I. & Edelman, S. GLP-1 agonists in type 1 diabetes. Clin. Immunol. 149, 317–323 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Farilla, L. et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 144, 5149–5158 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Jones, A. G. et al. Markers of β-cell failure predict poor glycemic response to GLP-1 receptor agonist therapy in type 2 diabetes. Diabetes Care 39, 250–257 (2016).

    CAS  PubMed  Google Scholar 

  114. Johansen, O. E. et al. C-Peptide levels in latent autoimmune diabetes in adults treated with linagliptin versus glimepiride: exploratory results from a 2-year double-blind, randomized, controlled study. Diabetes Care 37, e11–e12 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Zhao, Y. et al. Dipeptidyl peptidase 4 inhibitor sitagliptin maintains β-cell function in patients with recent-onset latent autoimmune diabetes in adults: one year prospective study. J. Clin. Endocrinol. Metab. 99, E876–E880 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. Buzzetti, R., Pozzilli, P., Frederich, R., Iqbal, N. & Hirshberg, B. Saxagliptin improves glycaemic control and C-peptide secretion in latent autoimmune diabetes in adults (LADA). Diabetes Metab. Res. Rev. 32, 289–296 (2016).

    Article  CAS  PubMed  Google Scholar 

  117. Carlsson, S., Midthjell, K., Grill, V. & Nord-Trøndelag study. Smoking is associated with an increased risk of type 2 diabetes but a decreased risk of autoimmune diabetes in adults: an 11-year follow-up of incidence of diabetes in the Nord-Trøndelag study. Diabetologia 47, 1953–1956 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Rasouli, B. et al. Smoking is associated with reduced risk of autoimmune diabetes in adults contrasting with increased risk in overweight men with type 2 diabetes: a 22-year follow-up of the HUNT study. Diabetes Care 36, 604–610 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Rasouli, B. Smoking and the Risk of LADA: results from a Swedish population-based case-control study. Diabetes Care 39, 794–800 (2016).

    Article  CAS  PubMed  Google Scholar 

  120. Rasouli, B. Alcohol and the risk for latent autoimmune diabetes in adults: results based on Swedish ESTRID study. Eur. J. Endocrinol. 171, 535–543 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Zhou, Z. et al. Rosiglitazone combined with insulin preserves islet beta cell function in adult-onset latent autoimmune diabetes (LADA). Diabetes Metab. Res. Rev. 21, 203–208 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Argoud, G. M., Schade, D. S. & Eaton, R. P. Insulin suppresses its own secretion in vivo. Diabetes 36, 959–962 (1987).

    Article  CAS  PubMed  Google Scholar 

  123. Maddaloni, E. & Pozzilli, P. SMART diabetes: the way to go (Safe and Multifactorial Approach to reduce the Risk for Therapy in diabetes). Endocrine 46, 3–5 (2014).

    Article  CAS  PubMed  Google Scholar 

  124. Biesenbach, G., Auinger, M., Clodi, M., Prischl, F. & Kramar, R. Prevalence of LADA and frequency of GAD antibodies in diabetic patients with end-stage renal disease and dialysis treatment in Austria. Nephrol. Dial. Transplant. 20, 559–565 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The Non Insulin Requiring Autoimmune Diabetes Study was sponsored by 'Fondazione Diabete e Ricerca' of the Italian Society of Diabetology.

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Correspondence to Raffaella Buzzetti.

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Buzzetti, R., Zampetti, S. & Maddaloni, E. Adult-onset autoimmune diabetes: current knowledge and implications for management. Nat Rev Endocrinol 13, 674–686 (2017). https://doi.org/10.1038/nrendo.2017.99

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