LADA- Latent Autoimmune Diabetes of the Adult

A proportion of patients ranging from 5-20% with a clinical diagnosis of type 2 diabetes have been found to possess islet autoantibodies, most typically GADA, and patients in this category progress more rapidly to insulin treatment. This is referred to as Latent Autoimmune Diabetes of the Adult (LADA) and occurs in individuals with a clinical phenotype resembling type 2 diabetes. Immunologically LADA is characterized by islet directed autoantibodies and is considered a form of type 1 diabetes. People with LADA do not require insulin for the first 3 to 6 months following diagnosis, but up to 80% will require insulin within the next five years. Some physicians treat LADA electively with insulin before metabolic decompensation has occurred, but the evidence for this is contested and most patients are treated according to standard management guidelines for type 2 diabetes.

Introduction

As early as in the 1970s, Irvine described type 2 diabetes patients who were positive for islet cell antibodies (ICA) who progress faster towards insulin deficiency compared to ICA negative patients with type 2 diabetes [1].

The term latent autoimmune diabetes of the adult (LADA) was introduced in 1995 to define the subgroup of adult diabetes patients who are classified clinically type 2 diabetes subjects but tested positive for GAD or other islet autoantibodies [2]. Five years after diagnosis, 80% of LADA patients progress to insulin dependence[3].

LADA patients who progress to insulin treatment have a phenotype similar to that of type 1 diabetes, and current guidelines classify LADA as a subtype of type 1 diabetes. The main clinical difference is that the requirement for insulin is delayed in LADA patients, who also tend to be older.

A variety of different names have been proposed for variant forms of diabetes which fall between the type 1 and type 2 phenotype, including diabetes mellitus type 1.5, non-insulin requiring autoimmune diabetes (NIRAD), slowly-progressing type 1 diabetes (SPT1D) and others.

Diagnosis

LADA resembles type 2 diabetes at diagnosis clinically, and the diagnosis rests upon detection of antibodies directed against glutamic decarboxylase (GADA), islet cells (ICA), insulinoma-associated antigen (IA2A), or insulin (IAA) or ZnT8 anbibodies LADA. As compared to adult-onset type 1 diabetes, LADA patients achieve good metabolic control with non-insulin antidiabetic medication for at least 3-6 months whereas the diagnosis of type 1 diabetes requires immediate treatment with insulin. LADA differs from type 1 diabetes in this respect and its clinical features oioverlap with those of type 2 diabetes.

Several studies describe a heterogenous clinical picture within the LADA group with a phenotype closer to type 1 diabetes in those LADA with high GADA titres compared to a phenotype closer to type 2 diabetes in LADA patients with low GADA titres.

A study in Australia identified five characteristics that are related to LADA:

  1. manifestation of diabetes below age 50 years;
  2. Acute symptoms at diagnosis;
  3. Body mass index <25kg/m2;
  4. Positive personal history of autoimmune disease;
  5. Positive family history for autoimmune diseases.

If two of these criteria were satisfied, specificity for diagnosis of LADA was 71%; The negative predictive value for LADA was 99% when none of these criteria were met. However, these criteria have not yet been validated with populations outside Australia [4].

Epidemiology

Data from the United Kingdom Prospective Diabetes Study (UKPDS) showed that younger subjects (25-34 years) were more often positive for islet antibodies (prevalence 34%, n=55/ 157) than older subjects (55-65 years) (prevalence 9%, n=160/ 1769). This means that LADA is in relative numbers more frequent at younger age but in absolute numbers is higher at older age [5]. Overall autoimmune diabetes in adults occurs in about 10% of European type 2 diabetes patients, although the prevalence can differ per country [6].

Outside Europe LADA prevalence varies from 0% in Papua New Guinea [8] and Alaska [7], 5.9% in China [8] up to 20% in Indonesia [9]. Following the assumption that in Europe about 90% diabetes patients have type 2 and 10% have type 1 diabetes, further assuming that about 10% of type 2 patients are LADA means that the group of LADA patients is actually bigger than the group of type 1 diabetes patients.

Immunological characteristics

Humoral immunity

By definition, LADA patients are positive for islet directed antibodies, most often often GADA, but they may also have other antibodies such as IA2A, ICA and IAA. Interestingly, ZnT8A were even more prevalent in LADA compared to adult-onset type 1 diabetes [10]

Although some studies report differences of LADA patients versus type 1 diabetes with regard to epitope recognition, autoantibody pattern and frequency [11][12] [13] others find humoral autoimmunity in LADA that is indistinguishable from type 1 diabetes [^7]. Interestingly, low GADA titres relate to certain TCF7L2 gene variants [14] and higher GADA titres are associated with the increased need of insulin treatment [15].

Cellular immune reactivity

The presence of humoral autoreactivity in LADA suggest that autoreactive T cells are also involved in the condition. In a small Chinese study T-cell reactivity to GAD65 was compared between LADA and type 2 diabetes. Low level reactivity for both IFN-gamma and IL-4 was observed, and the number of IFN-gamma producing T-cells was higher in patiens with LADA [16]. Similarly, T cell reactivity in LADA could frequently bedetected when unfractionated PBMCs were tested against immunoblot sections of pancreatic islets [17], and was increased compared to type 2 diabetes patients and was associated with ß-cell function [18] . However, in another study T cell reactivity against GAD65, GAD or IA2 epitopes, insulin, proinsulin or insulin peptide B9-23 did not differ comparing LADA with type 1 or type 2 diabetes [19].

T cells apart, altered natural killer (NK) cell frequency and phenotype in latent autoimmune diabetes in adults (LADA) has been reported prior to insulin deficiency [20]. Furthermore, distinct monocyte gene-expression profiles have been reported in autoimmune diabetes including LADA [21].

Systemic immune status

Studies in people of European and Chinese extraction have been performed to investigate the systemic immune status in patients with LADA. In Europeans, systemic cytokines and adhesion molecules in LADA are indistinguishable from patients with adult type 1 diabetes and lower compared to patients with type 2 diabetes [22][23]. A Chinese study detected some differences in C-reactive protein and adiponectin comparing type 1 diabetes, LADA and type 2 diabetes with the majority of immune mediators similar in type 1 diabetese and LADA [24] .

Genetic characteristics

In comparison to type 1 diabetes, some studies showed that LADA patients have more often HLA diabetes-susceptible haplotypes[^30], and less HLA DQ protective genotypes [25] , another study showed similar HLA data for type 1 diabetes and LADA [26] [27]. Interestingly, the type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by obesity when analysed in a meta-analysis and an individual study [28][29].

Metabolic characteristics

Insulin resistance and metabolic syndrome

As LADA resembles type 2 diabetes clinically, it is not surprising that equivalent insulin resistance was reported in LADA and type 2 diabetic patients [30]. However, other studies suggest that metabolic features in LADA are more similar to type 1 than to type 2 diabetes [31].

ß-cell function

Compared to autoantibody negative type 2 diabetes LADA have lower C-peptide [32]. Furthermore, loss of ß-cell function and the related need for insulin therapy is increasing with the number of islet directed autoantibodies [33].

Treatment recommendations

In the 1970s, Irvine showed in small study, that patients with type 2 diabetes progressed to insulin therapy more rapidly than antibody negative patients when treated with sulfonylureas [^2]. This suggested that sulfonylureas might not be optimal therapy, and the Tokyo study found that treatment of Japanese LADA patients with insulin versus sulfonylureas showed improved endogenous insulin secretory capacity in insulin treated LADA patients [34]. Although this observation has not been replicated, insulin treatment is often offered to LADA patients early in the disease course.

However, data in UKPDS and also from Sweden, did not show a preferential treatment regimen for LADA patients. Early insulin treatment in LADA in Swedish patients lead to better preservation of metabolic control and was safe, however superior preservation of C-peptide could not be significantly demonstrated [35]. Reduction of islet function was similar in UKPDS LADA groups randomised to oral glucose-lowering agents or insulin replacement therapy, contesting the current hypothesis of reduced decline of insulin secretion in LADA by immediate insulin therapy [36].Several small size studies have compared treatment modalities and immune intervention approaches for patients with LADA [37] and require further confirmation as they are small and often non-conclusive.

In practical terms, many diabetologist prefer to offer insulin treatment in LADA patients once they have identified positive autoantibodies [38], however, as antibodies are very often not determined in patients with clinical type 2 diabetes the majority of (undiagnosed) LADA patients are in practise treated with all different types of antihyperglycemic medication.

References

  1. ^ Zimmet PZ. The pathogenesis and prevention of diabetes in adults. Genes, autoimmunity, and demography. Diabetes Care. 1995;1050-64.

  2. ^ Irvine WJ, Gray RS, McCallum CJ. Pancreatic islet-cell antibody as a marker for asymptomatic and latent diabetes and prediabetes. The Lancet. 1976;1097-102.

  3. ^ Zhang Y, Zhou ZG, Yang L, Lin J, Li X, He WM. [Abnormal T cell autoimmunity against GAD65 in LADA patients]. Zhonghua Yi Xue Za Zhi. 2010;1963-5.

  4. ^ Fourlanos S, Perry C, Stein MS, Stankovich J, Harrison LC, Colman PG.A clinical screening tool identifies autoimmune diabetes in adults.Diabetes Care. 2006 May;29(5):970-5.

  5. ^ Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, Nissén M, Ehrnström BO, Forsén B, Snickars B, Lahti K, Forsblom C, Saloranta C, Taskinen MR, Groop LC. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies.

  6. ^ Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R, Puente DM, De Leiva A, Yderstraede K, Beck-Neilsen H, Tuomilehto J, Sarti C, Thivolet C, Hadden D, Hunter S, Schernthaner G, Scherbaum WA, Williams R, Brophy S, Pozzilli P, Leslie RD; on behalf of the Action LADA consortium. Adult-Onset Autoimmune Diabetes in Europe Is Prevalent With a Broad Clinical Phenotype: Action LADA 7.Diabetes Care. 2012 Dec 17. [Epub ahead of print]

  7. ^ Mohatt J, Gilliam LK, Bekris L, Ebbesson S, Lernmark A. Type 1 diabetes-related autoantibodies are rare in Alaska native populations.Int J Circumpolar Health. 2002 Feb;61(1):21-31.

  8. ^ Zhou Z, Xiang Y, Ji L, Jia W, Ning G, Huang G, Yang L, Lin J, Liu Z, Hagopian WA, Leslie RD; on behalf of LADA China Study Group.Frequency, Immunogenetics, and Clinical Characteristics of Latent Autoimmune Diabetes in China (LADA China Study): A Nationwide, Multicenter, Clinic-Based Cross-Sectional Study.Diabetes. 2012 Oct 18. [Epub ahead of print]

  9. ^ Sutanegara D, Budhiarta AA (2000) The epidemiology and management of diabetes mellitus in Indonesia. Diabetes Res Clin Pract 50 Suppl S9-S16

  10. ^ Andersen MK, Härkönen T, Forsblom C, Groop PH, Knip M, Tuomi T.Zinc transporter type 8 autoantibodies (ZnT8A): prevalence and phenotypic associations in latent autoimmune diabetes in adults and type 1 diabetes diagnosed >35 years. Autoimmunity. 2013 Jan 10. [Epub ahead of print]

  11. ^ Tiberti C, Giordano C, Locatelli M, et al (2008) Identification of tyrosine phosphatase 2(256-760) construct as a new, sensitive marker for the detection of islet autoimmunity in type 2 diabetic the non-insulin requiring autoimmune diabetes (NIRAD) study 2. Diabetes 1276-1283

  12. ^ Falorni A, Calcinaro F. Autoantibody profile and epitope mapping in latent autoimmune diabetes in adults.

  13. ^ Hosszúfalusi N, Vatay A, Rajczy K, Prohászka Z, Pozsonyi E, Horváth L, Grosz A, Gerõ L, Madácsy L, Romics L, Karádi I, Füst G, Pánczél P (2003) Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes (LADA) compared with adult-onset type 1 diabetes with rapid progression. Diabetes Care 452-457

  14. ^ Zampetti S, Spoletini M, Petrone A, Capizzi M, Arpi ML, Tiberti C, Di Pietro S, Bosi E, Pozzilli P, Giorgino F, Buzzetti R; Nirad Study Group.Association of TCF7L2 gene variants with low GAD autoantibody titre in LADA subjects (NIRAD Study 5).

  15. ^ Radtke MA, Midthjell K, Nilsen TI, Grill V. Heterogeneity of patients with latent autoimmune diabetes in linkage to autoimmunity is apparent only in those with perceived need for insulin results from the Nord-Trøndelag Health (HUNT) study.Diabetes Care. 2009 Feb;32(2):245-50.

  16. ^ Zhang Y, Zhou ZG, Yang L, Lin J, Li X, He WM. [Abnormal T cell autoimmunity against GAD65 in LADA patients].Zhonghua Yi Xue Za Zhi. 2010 Jul 27;90(28):1963-5.

  17. ^ Brooks-Worrell BM, Juneja R, Minokadeh A, Greenbaum CJ, Palmer JP.Cellular immune responses to human islet proteins in antibody-positive type 2 diabetic patients.

  18. ^ Goel A, Chiu H, Felton J, Palmer JP, Brooks-Worrell B.T-cell responses to islet antigens improves detection of autoimmune diabetes and identifies patients with more severe beta-cell lesions in phenotypic type 2 diabetes.Diabetes. 2007 Aug;56(8):2110-5.

  19. ^ Strom A, Menart B, Simon MC, Pham MN, Kolb H, Roden M, Pozzilli P, Leslie RD, Schloot NC.Cellular interferon-γ and interleukin-13 immune reactivity in type 1, type 2 and latent autoimmune diabetes: action LADA 6.Cytokine. 2012 May;58(2):148-51.

  20. ^ Akesson C, Uvebrant K, Oderup C, Lynch K, Harris RA, Lernmark A, Agardh CD, Cilio CM.Altered natural killer (NK) cell frequency and phenotype in latent autoimmune diabetes in adults (LADA) prior to insulin deficiency.Clin Exp Immunol. 2010 Jul 1;161(1):48-56.

  21. ^ Padmos RC, Schloot NC, Beyan H, Ruwhof C, Staal FJ, de Ridder D, Aanstoot HJ, Lam-Tse WK, de Wit H, de Herder C, Drexhage RC, Menart B, Leslie RD, Drexhage HA; LADA Consortium. Distinct monocyte gene-expression profiles in autoimmune diabetes. Diabetes. 2008 Oct;57(10):2768-73.

  22. ^ Pham MN, Hawa MI, Pfleger C, Roden M, Schernthaner G, Pozzilli P, Buzzetti R, Scherbaum WA, Seissler J, Kolb H, Hunter S, Leslie RD, Schloot NC; Action LADA Study Group. Pro- and anti-inflammatory cytokines in latent autoimmune diabetes in adults, type 1 and type 2 diabetes patients: Action LADA 4.Diabetologia. 2011 Jul;54(7):1630-8.

  23. ^ Pham MN, Hawa MI, Roden M, Schernthaner G, Pozzilli P, Buzzetti R, Scherbaum WA, Seissler J, Hunter S, Leslie RD, Kolb H, Schloot NC; Action LADA Study Group.Increased serum concentrations of adhesion molecules but not of chemokines in patients with Type 2 diabetes compared with patients with Type 1 diabetes and latent autoimmune diabetes in adult age: action LADA 5.Diabet Med. 2012 Apr;29(4):470-8.

  24. ^ Xiang Y, Zhou P, Li X, Huang G, Liu Z, Xu A, Leslie RD, Zhou Z.Heterogeneity of altered cytokine levels across the clinical spectrum of diabetes in China.Diabetes Care. 2011 Jul;34(7):1639-41.

  25. ^ Stenstrom G, Berger B, Borg H, Fernlund P, Dorman JS, Sundkvist G (2002) HLA-DQ genotypes in classic type 1 diabetes and in latent autoimmune diabetes of the adult. Am J Epidemiol 787-796

  26. ^ Hosszufalusi N, Vatay A, Rajczy K, et al (2003) Similar genetic features and different islet cell autoantibody pattern of latent autoimmune diabetes in adults (LADA) compared with adult-onset type 1 diabetes with rapid progression. Diabetes Care 452-457

  27. ^ Desai M, Zeggini E, Horton VA, et al (2007) An association analysis of the HLA gene region in latent autoimmune diabetes in adults. Diabetologia 68-73

  28. ^ Lukacs K, Hosszufalusi N, Dinya E, Bakacs M, Madacsy L, Panczel P.The type 2 diabetes-associated variant in TCF7L2 is associated with latent autoimmune diabetes in adult Europeans and the gene effect is modified by a meta-analysis and an individual study. Diabetologia. 2012 Mar;55(3):689-93.

  29. ^ Cervin C, Lyssenko V, Bakhtadze E, Lindholm E, Nilsson P, Tuomi T, Cilio CM, Groop L. Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes.Diabetes. 2008 May;57(5):1433-7

  30. ^ 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.

  31. ^ Hawa MI, Thivolet C, Mauricio D, Alemanno I, Cipponeri E, Collier D, Hunter S, Buzzetti R, de Leiva A, Pozzilli P, Leslie RD; Action LADA Group.Metabolic syndrome and autoimmune diabetes: action LADA 3.Diabetes Care. 2009 Jan;32(1):160-4.

  32. ^ Gottsäter A, Landin-Olsson M, Fernlund P, Lernmark A, Sundkvist G.Islet cell antibodies are associated with beta-cell failure also in obese adult onset diabetic patients.Acta Diabetol. 1994 Dec;31(4):226-31.

  33. ^ Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R.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 Nov 1;350(9087):1288-93.

  34. ^ Maruyama T, Shimada A, Kanatsuka A, et al (2003) Multicenter prevention trial of slowly progressive type 1 diabetes with small dose of insulin (the Tokyo study): preliminary report. Ann N Y Acad Sci 362-369

  35. ^ 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. 2011 Feb;164(2):239-45.

  36. ^ Desai M, Clark A.Autoimmune diabetes in adults: lessons from the UKPDS.Diabet Med. 2008 Aug;25 Suppl 2:30-4.

  37. ^ Brophy S, Davies H, Mannan S, Brunt H, Williams R.Interventions for latent autoimmune diabetes (LADA) in adults.Cochrane Database Syst Rev. 2011 Sep 7;(9):CD006165.

  38. ^ Brophy S, Yderstraede K, Mauricio D, Hunter S, Hawa M, Pozzilli P, Schernthaner G, Schloot N, Buzzetti R, Davies H, Leslie D, Williams R; Action LADA Group.Time to insulin initiation cannot be used in defining latent autoimmune diabetes in adults.Diabetes Care. 2008 Mar;31(3):439-41.

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    Neeraj Sinha added a compliment on 28 November 2014 at 12:12PM
    Good article

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