Journal of Diabetes & Metabolism

Latent Autoimmune Diabetes in Adult is an autoimmune endocrine disease, in which in spite of positive anti-islet antibodies at the moment of diagnosis, the progression to beta cell insufficiency and destruction is slower than the rate of loss observed in Type 1 Diabetes Mellitus (T1DM) [1]. Due to the positivity of the autoantibodies, these patients have been considered as variants of T1DM, yet several authors suggest that this autoimmune scenario is quiet different and demands its individualization [2]. The initial description was done by Irvine et al. [3], describing a group of T2DM patients, of which 10% had positive anti-ICA antibodies, failure to achieve metabolic control with sulphonylureas, and required insulin therapy sooner than their antibody-negative counterparts. Tuomi et al. [4] and Zimmet et al. [5] proposed the term “LADA” to classify individuals with positive anti-GAD65 who did not require insulin treatment at the beginning of the disease; nevertheless, the American Diabetes Association hasn’t included this type of diabetes in its current classification system [6].

The general consensus is that LADA represent about 10% of the patients who have T2DM phenotype [7]. Brahmkshatriya et al. [8] reported a prevalence of 5% in their population of phenotypic T2DM in India, while Qi et al. [9] published that the incidence of LADA in China increases with age, especially between 50-59 years. In the United States the prevalence has been reported as low as 4.7% [10], while Brazil shows a frequency of 6.2%, with an important increase in diagnosis between 25-35 years of age [11]. In regards to pathophysiology, LADA has been linked to immune dysfunction that is similar genetically and physiologically to T1DM [12-14], with the development of specific LADA T cells [15,16] and reduction of FOXP3 synthesis [17]. Other traits, such as insulin resistance [10] and islet inflammation [18], have been involved in the amplification of the disease and acceleration of insulin requirement.

Fourlanos et al. [19] published a comprehensive criteria for LADA diagnosis: a) Age of diagnosis below 50 years of age; b) Body Mass Index <25 kg/m²; c) presence of acute symptoms of hyperglycemia, such as polydypsia, polyuria and weight loss; d) family history of T1DM and T2DM; and e) personal history of autoimmune diseases. However, the current criteria for diagnosis is (1): a) serological evidence of autoimmunity through the detection of anti-GAD65 autoantibodies; b) age of onset ≥ 25 years of age; and c) conserved β cell function, demonstrated by the fact that they do not require permanent insulin treatment at the moment of debut.

The current challenge for clinicians is to be able to predict according to these shy criterions the probability that a young subject with phenotypic T2DM is actually a LADA patient, and be able to intervene sooner and more aggressively. The purpose of the following case report is to analyze presentation, evidence of autoimmunity and treatment of these peculiar diabetic patients.

Case Presentation

The case concerns a male patient, 26 years of age, who initiates the symptoms 3 years before consulting our institution. He referred polydipsia, polyphagia, polyuria and loss of weight, accompanied by intense headache, tachycardia, and hypertension. In the course of a year, these symptoms intensified and up to current date he refered to have lost 30 kilos in weight. At first, he went to a local medical center where he is diagnosed as T2DM due to a basal glycemia of 282 mg/dL, and started on Sitagliptin 50 mg/Metformin 500 mg (Janumet^®) twice a day; treatment which he abandons 8 months later due to worsening of the symptoms. Then, he was started on synthetic insulin Humalog Mix 70/30^® for the next 6 months, but the symptoms didn´t improve. It´s noteworthy that at no time was he referred to a nutrition specialist for proper nutrition assessment and intervention (Table 1).

Table 1: Factors associated with LADA.

The patient was interviewed and refers to have first and second degree family history of T2DM, hypertension and thyroid pathology (Figure 1). The physical examination revealed him to be eupneic, blood pressure of 140/85 mmHg with 80 beats per second. Currently he is 1.88 mt tall, weighting 107 kg, with a Body Mass Index (BMI) of 30.31 kg/m² and a waist circumference of 107 cm. Primary laboratory workup is shown in Table 2. He has been without any medication for a year, and upon arrival nutritional consult and medication was indicated, Vidagliptin 500 mg/Metformin 1000 mg (GalvusMet^®) twice a day; however, there was no metabolic improvement. Anti-islet antibodies were determined, showing resulting in a positive Anti- GAD65 determination, with 5 UI/mL (normal value <1.0 UI/mL).

Figure 1: First and second degree family history of T2DM, hypertension and thyroid pathology.

Table 2: Primary laboratory workup.

Once the diagnosis of LADA was confirmed, a new pharmacological protocol was applied, with Sitagliptin 50 mg/Metformin 500 mg (Janumet^®) once a day before breakfast, Metformin 500 mg (Glucofage^®) twice a day on lunch and dinner, and Insulin therapy (starting with Novorapid^® 5 units before each meal, and Levemir^® 10 units at bedtime 10 pm; Table 3). Currently the patient is stable, with both insulin therapy and insulin-sensitizers such as metformin alongside proper nutritional diet, having achieved acceptable metabolic control.

Table 3: Metabolic control using insulin therapy.

Latent Autoimmune Diabetes in Adult is recently established autoimmune endocrine disease, which is commonly described as an overlapping clinical entity between T1DM and T2DM, as proposed by Tuomi et al. [4], Zimmet et al. [5] and Fourlanos et al. [19]. The definitions have dwelled between age of onset, proof of autoimmunity, hyperglycemia symptoms, β cell function and body mass index. In the present report, the patient clearly shows this overlapping conundrum, presenting with symptoms of hyperglycemia starting at 23 years of age, with morbid obesity and strong personal history of T2DM, who didn´t need insulin at first, but progressed in such manner that this medication was required to properly achieve metabolic control. The confirmation of the LADA diagnosis was done via determination of anti-GAD65.

We’re taking the opportunity to analyze the current diagnosis criteria and how, in the midst of a worldwide uprising of this disease, there is a need to modify and adapt these definitions to current evidence. Several pitfalls have been discussed over the last 5 years [20-22], focusing on the validity of the criterions in regards to the pathophysiology of the disease. The age of onset has been in debate since the first reports, given that published cases seem to suggest a wider range and it has been considered that slow β-cell destruction associated with obesity and insulin resistance can be seen in young adults and adolescents and can be classifiable as LADA [23,24]. In fact, we published a previous case of a 23 year old male, who was diagnosed as T2DM, positive for anti-GAD65 and anti-IA2 [24]. However, even though Fourlanos et al. [19] proposed that age of onset should be below 50 years of age the current lower limit is set at 30 years, yet it should not be exclusive.

The weight of the patients is a matter of debate. Fourlanos et al. [19] first reported that a BMI <25 kg/m² was associated with LADA (p=0.0004), but further evidence has surface and challenged this precept. First, there seem to be two groups of LADA in regards to weight, those with low BMI who more resemble T1DM and those with high BMI which share features of T2DM [8,25,26]. Adeleye et al. [27] reported that in a sample of 235 Nigerian patients, mean BMI was 27.05 ± 6.54, with 4% underweight, 30% normal weight, 42% overweight and 24% obese, while, Szepietowska et al. [28] observed a mean BMI of 26.8 ± 9.3 in 19 patients from Poland. Meanwhile, Hwangbo et al. [29] with a sample of 462 patients published a mean BMI of 23.7 ± 3.6 kg/m² and Hosszúfalusi et al. [30] observed a median BMI of 23.5 (22.6–27.1) kg/ m² obtained from a sample of 54 patients.

Obesity and insulin resistance have been considered as part of the mechanisms responsible in the progression of β cell autoimmunity, yet their evaluation is not taken into account in the current definitions. This issue is raised by the fact that LADA patients have residual β cell activity and it seems to be compromised as weight increases [15,31], very similar to what Wilkin proposed in his accelerator hypothesis for T1DM [32]. In full blown autoimmune diabetes, insulin insufficiency comes from T cell mediated destruction of β cells, while in T2DM islet failure occurs when after a period of compensating hyperinsulinemia, when β cell dies from exhaustion. It´s proposed that in those with slow progression autoimmune diabetes (LADA), clinical debut is precipitated by insulin resistance and parallel increasing metabolic demand. However, the presence of Metabolic Syndrome (MS) is questionable, since it has a lower prevalence than T2DM, but it´s not higher than control subjects, rendering this entity as not a characteristic of autoimmune diabetes [33].

The importance of family history of diabetes was confirmed by Carlsson et al. [34], being considered a strong risk factor for LADA, especially as number of afflicted family members rises [35]. This association comes through the clustering of gene risk for both T1DM and T2DM, along with related haplotypes passed from generation through generation. The risk haplotypes have been analyzed in regards to autoantibodies titers, and clinical subsets classified according to the levels of the principal auto-antibody, anti-GAD65. Maioli et al. [36] reported that intermediate and high risk haplotypes for T1DM (HLA-DQB1 and HLA-DRB1) are present in LADA patients and are associated with insulin requirement less than 4 years after the diagnosis (p=0.036), being then considered as a surrogate for β cell dysfunction and diabetes progression (p=0.013). Moreover, from the genes linked with T2DM, polymorphism of FTO (Fat Mass and Obesity-Associated Protein) and tetraspanin-8 are associated with low-GAD titers LADA patients (p=0.004) [37]. Anti-GAD65 is considered the marker of choice [18,38] in the diagnosis of LADA, especially when this type of immunoglobulin seems not to go through epitope spreading, and remain directed against the middle region or C-terminal portion of the glutamic acid decarboxilase enzyme, even after 6 years of diagnosis [39]. Nevertheless, combinations with other types of β cell directed autoantibodies have been reported, such protein tyrosin phosphatase IA-2 (IA-A2) and islet-cell antibodies (ICA) [30], in combination or not with other organ-targeted antibodies, such as anti-Thyroid Peroxidase [36].

The titers of anti-GAD65 have been taken into consideration to predict insulin dependence and total β cell progressive failure. Hosszúfalusi et al. [30] reported anti-GAD65 titers in newly diagnosed LADA patients as 2.4 UI/mL (0.7 – 29.8 UI/mL), which was lower compared to those observed in those with newly diagnosed adult onset T1DM (12.5 UI/mL; 0.8 – 50.1 UI/mL) and newly diagnosed childhood T1DM (3.1 UI/mL; 0.9-8.1 UI/mL). In the latest multicentered, nationwide study focusing on LADA frequency and characteristics conducted by Zhou et al. [40], 4,480 subjects were thoroughly analyzed and 287 were reclassified as LADA taking into account anti-GAD65 titres, personal history of disease, ketosis status and HLA haplotyping. These LADA patients were then categorized as High Titer LADA (anti-GAD65 ≥180 units) and Low Titer LADA (<180 units). The first group was characterized by bring normal weight (22.3 ± 3.2 kg/m²), HbA1c of 10.17 ± 2.60%, 45.9% had low levels of fasting C-peptide (0.32 ng/mL [0.01–1.57]), 21% had personal history of diabetes, 50% had hyperlipidemia, 21.1% had hypertension, 19.7% had overweight/ obesity, and 39.5% had MS. The latter was predominantly male, normalhigh body weight (24.5 ± 3.7 kg/m²), HbA1c 9.19 ± 2.47%, 21.6% had low levels of C-peptide (0.51 [0.11–3.34]), 24.2% had personal history of diabetes, 66.8% had hyperlipidemia, 38.9% had hypertension, 41.7% were overweight/obese, and 70.1% had MS. Clearly, our patient is a perfect fit for the Low Titer LADA group, exhibiting all the characteristics.

Once diagnosed, LADA treatment is not as simple as supplementing insulin like in T1DM patients. In fact, several have published that achievement of metabolic goals is considered more difficult than in any of the other two major types of diabetes, and its characterized by poor glycemic control and loss of weight [41,42]. By default, insulin is the therapy of choice due to the evidence of autoreactivity, yet insulin dependency is not observed at first, and most of the patients begin their treatment with sulfonylureas, metformin, or a combination of both. It would be ideal to initiate insulin supplementation as early as possible to protect β cell integrity and proper glycemic control. This protection is due to lesser metabolic demand on a cell that is under immune attack, and is highly susceptible to this kind of cell death during an inflammatory environment, as such observed during β−cell stunning and RER stress [22].

Sulfonylureas act as insulin secretagoges, which would only act in a deleterious manner in LADA patients, accelerating cell death by exhaustion (crinophagy) [43] and amplifies the exposure of criptic antigens and epitope spreading [22]. Metformin is considered beneficial to those LADA patients who have MS diagnosis and confirmed insulin resistance [44,45]. Thiazolidinediones have been proposed as another therapeutic choice due to their anti-inflammatory properties [46], and slight improvement on C-peptide levels as observed by Zhou et al. [47]. Incretin mimetics are another ideal choice in the treatment of LADA given their effects on insulin secretion and β cell mass restoration in T2DM patients [48], yet no official studies have been published on their effect.

In conclusion, LADA is an autoimmune disease with an overall prevalence between 8-12%, characterized by patients who can be classified as phenotypic T2DM who progress to insulin dependency in less than 6 years, acquiring the fundamental feature of T1DM. Even though the main criteria for diagnosis are age, autoreactivity and conserved β cell function, weight and physical inactivity are raising markers for the disease as surrogates for insulin resistance [49]. This clinical case shows how a very phenotypic T2DM showed early signs of poor glycemic control which were masked by his insubordinate behavior. Autoantibody titer evaluation should be considered in young adults presenting with clinical symptoms of T2DM who do not respond well to first and second lines of therapy. Insulin should be initiated as soon as possible to try and preserve as much β cell mass as possible.

This work was supported by research grant Nº CC-0437-10-21-09-10 from the Technological, Humanistic, and Scientific Development Council (CONDES), University of Zulia, and research grant Nº FZ-0058-2007 from Fundacite-Zulia.