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.


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.


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].


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.


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  1. Gauranga Dhar
    Gauranga Dhar added a suggestion on 22 February 2015 at 01:10PM
    Good information on LADA for practicing diabetologists. Please correct spelling "overlap" at the last line of the first paragraph under "Diagnosis"
  2. no profile image
    Neeraj Sinha added a compliment on 28 November 2014 at 12:12PM
    Good article
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