Diabetes Metab J > Volume 36(2); 2012 > Article
Seok and Lee: Latent Autoimmune Diabetes in Adults: Autoimmune Diabetes in Adults with Slowly Progressive β-cell Failure
Type 1 diabetes (T1D) is caused by interactions of genetic predisposition, immunologic triggers, and environmental events leading to autoimmune-mediated pancreatic β-cell destruction and insulin deficiency, although some subjects show lack of autoantibodies to pancreatic islets. Regarding the time lag of complete β-cell mass loss in T1D, simple or unique patterns may not be identified, with some individuals progressing for more than several years. Contrary to T1D, type 2 diabetes (T2D), irrelevant of autoimmune-mediated β-cell destruction, is a heterogeneous disorder characterized by insidious onset and insulin resistance with relative insulin secretory dysfunction. Clinically, some diabetic patients exhibit autoimmune antibodies without insulin requirement. This biphasic type of diabetes is a special form of diabetes that is clinically similar to the early stage of T2D and pathophysiologically defined as a disorder of the autoimmune-mediated progressive β-cell dysfunction. To clarify different features from T1D and T2D, Zimmet [1] introduced the eponym "latent autoimmune diabetes of adults" (LADA) to describe this subgroup of adult phenotypic T2D patients positive for autoantibodies. Based on the natural history of LADA, in which secretory β-cell dysfunction is prominently aggravated depending on the presence of antibodies seen in T1D, Stenstrom et al. [2] suggested LADA is not always a latent disease. Therefore, autoimmune diabetes in adults with slowly progressive β-cell failure might be a more adequate concept. The Immunology of Diabetes Society (IDS) has proposed criteria to standardize the definition of LADA: 1) ≥35 years of age, 2) positive for at least 1 of the 4 antibodies commonly seen in T1D patients; islet cell autoantibodies (ICA), anti-glutamic acid decarboxylase (anti-GAD), Insulinoma-associated protein-2 antibodies (IA-2A), and insulin autoantibodies (IAA), and 3) not requiring insulin therapy within the first 6 months after diagnosis [3].
Regarding the genetic and immunologic characteristics in LADA, subjects with LADA show a type of difference from patients with T1D. First, compared with T1D, susceptibility genes are much less prevalent, but protective genes are more prevalent in LADA [4]. HLA alleles associated with T1D susceptibility are HLA DR3, DR4, and DQB1*0201 and 0302, while the alleles associated with T1D protection are DR2 and DQB1*0301 and 0602 [5,6]. These differences may partially explain the relatively late onset of LADA. Second, there are several differences in autoantibodies between T1D and LADA. Compared with T1D, anti-GAD and ICA are much more common than IAA, IA-2A, and zinc transporter 8 (ZnT8) antibodies in subjects with LADA [7,8]. GAD is a neuronal enzyme involved in the synthesis of the neurotransmitter gamma-aminobutyric acid. Anti-GAD is seen not only in a variety of autoimmune neurologic disorders including stiff-man syndrome, autoimmune cerebellitis, brain stem encephalitis etc., but also in autoimmune T1D. In clinical practice, anti-GAD is not only an important serological marker of predisposition to T1D but also the major pancreatic islet antibody for diagnosing T1D [9]. Of the anti-GAD subclasses, the IgG4 subclass is more frequent in LADA than in T1D [10]. T1D and LADA also show different epitope specificity for anti-GAD. The middle or COOH-terminal portion of GAD was recognized by more than 90% of sera from T1D compared with only 65% of LADA patients. In contrast, 20% of LADA patients' sera bound to the NH2-terminal portion of GAD, compared with 5% of T1D patients [11].
There are many controversial issues regarding prevalence of LADA. In previous epidemiological studies, LADA accounted for 2% to 12% of all cases of diabetes [1,8,12]. Some studies suggested that LADA accounts for approximately 10% of the patients initially diagnosed as T2D [13,14]. Despite several studies on the prevalence in the Korean population [15-17], controversy still remains on the accurate prevalence. Most studies tested for anti-GAD only when the patients were suspected to have T1D. Recently, Hwangbo et al. [18] reported a 4.3% prevalence of LADA in newly-diagnosed Korean T2D subjects regardless of their clinical characteristic at the time of presentation. Though Hwangbo et al. [18] indicated that 4.3% prevalence of anti-GAD positivity was similar to that in Japan, they did not thoroughly review the well-designed trials studying the prevalence of LADA in Korea, where a recent-onset T2D Korean National Diabetes Program cohort showed a 4.4% prevalence by the positivity of circulating autoantibodies to pancreatic islet cell antigens (GAD, IA-2, and ZnT8) [19], as well as 5.1% to 5.3% prevalence in a single center trial [20,21]. Another limitation of the study conducted by Hwangbo et al. [18] is that the authors only evaluated for the anti-GAD, and not other autoantibodies such as ICA, IA-2A, and IAA. Based on the data, the prevalence of LADA in Korea may be around 5% in T2D. However, the ambiguity in diagnosis criteria in previous studies such as age (more than 30 or 35 years), antibodies (ICAs and anti-GAD, IA-2A, and IAA in IDS criteria, or anti-GAD, IA-2A, anti-ZnT8 in European NIRAD LADA group criteria), and period of insulin independence after diagnosis did not come to a conclusive answer regarding prevalence and incidence.
Regarding the β-cell secretory dysfunction in LADA, several studies have reported the presence of a single autoantibody and/or lower anti-GAD titer is associated with older age, a slower rate of disease progression, and lower risk of insulin dependency. In contrast, the presence of multiple autoantibodies and/or higher anti-GAD titer is associated with younger age, a faster rate of disease progression, and higher risk of insulin dependency [10,22]. Similar to the above-mentioned results, Hwangbo et al. [18] reported that high anti-GAD titer showed significantly lower C-peptide level and was more likely to require insulin treatment. A well-designed 12-year prospective study [23] showed diabetic subjects with multiple islet antibodies (ICA, anti-GAD, IA-2A) are more prone to deteriorate in insulin secretory resulting in β-cell failure within 5 years, whereas patients with only anti-GAD or only ICA mostly develop β-cell failure after 5 years. Though Hwangbo et al. [18] were unable to observe the natural course of the β-cells, a prospective 36-month multicenter study in Korean diabetic subjects showed 7.7% subjects with LADA were dependent on insulin within 3 years, but true insulin dependency evidenced by multiple antibody positivity was not high and did not increase in Korean subjects [19]. Considering the characteristics of Korean patients with T2D, whose secretory β-cell dysfunction is a major contributing factor to the development and aggravation of hyperglycemia [24,25], a large scale nationwide prospective study is warranted to verify the meaning of autoantibody positivity to pancreatic islets and the natural course of β-cell secretory dysfunction in LADA.
Another controversy on subjects with LADA may be the relevance of metabolic syndrome. As described previously, T2D, irrelevant of autoimmune-mediated β-cell destruction, has a heterogeneous pathophysiology characterized by insulin resistance with relative insulin secretory dysfunction, but LADA is an autoimmune diabetes in adults with slowly progressive β-cell failure. Regarding islet autoantibodies in metabolic features, LADA patients with multiple autoantibodies and/or a high titer of anti-GAD showed a higher risk of β-cell dysfunction and presence of other autoimmune disorders, but a lower prevalence of metabolic syndrome in Western populations [22]. Hwangbo et al. [18] could not find differences in the metabolic syndrome and its components including HOMA-IR between subjects with anti-GAD positive and subjects with anti-GAD negative, and suggested LADA in the Korean population might be different from LADA in the Caucasian population. However, Lee et al. [20] showed that low C-peptide level and absence of metabolic syndrome were variables independently associated with the diagnosis of LADA.
Due to the ambiguous pathophysiology and clinical characteristics of LADA, no specific guideline for treatment of LADA has been established. The primary defect in autoimmune diabetes is loss of insulin secretion. Insulin secretory capacity in LADA has been recognized as between T1D and T2D [23]. LADA patients have a faster decline in C-peptide levels compared with patients with T2D [23,26], whereas a slower rate of decline compared with adult T1D [27]. Several Japanese studies demonstrated insulin treatment showed better preservation of β-cell function compared with sulfonylurea in ICA-positive and anti-GAD-positive phenotypic T2D subjects [28]. Anti-inflammatory therapy that slows progression of β-cell destruction could be another option. Thiazoledinediones also might be of value in the treatment of LADA, because of the anti-inflammatory effect, as well as improving insulin sensitivity. LADA patients treated with rosiglitazone were reported to have greater β-cell preservation compared with a group of LADA subjects treated with insulin alone during a 3-year follow-up [29]. Recently, antigen-specific immunomodulation has been reported as potential treatment choice, such as GAD vaccine [30].
LADA is not a rare disease, and many subjects are still underdiagnosed. Without awareness, a correct diagnosis of LADA is not easy. Earlier correct diagnosis of LADA could help clinicians and patients to manage ongoing β-cell dysfunction. A large scale nationwide study to examine the natural course and clinical characteristics of subjects with LADA in Korean subjects is essential to preserve β-cell function in subjects with LADA.

NOTES

No potential conflict of interest relevant to this article was reported.

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