Latent Autoimmune Diabetes in Adults: Autoimmune Diabetes in Adults with Slowly Progressive β-cell Failure

Corresponding author: Byung Wan Lee Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Korea E-mail: [email protected] 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 Editorial