High Titer of Autoantibodies to GAD Identifies a Specific Phenotype of Adult-Onset Autoimmune Diabetes

Abstract

OBJECTIVE -The aim of the present study was to define heterogeneity of adult-onset autoimmune diabetes based on characterization of GAD antibodies (GADAs). RESEARCH DESIGN AND METHODS-Patients enrolled in a nationwide survey, the Non Insulin Requiring Autoimmune Diabetes (NIRAD) Study, have been screened for GADAs and IA-2 antibodies (IA-2As) and further characterized for GADA titer, antibodies to thyroid peroxidase (TPO), and HLA DRB1-DQB1 polymorphisms.RESULTS -Of 4,250 consecutive type 2 diabetic patients, 4.5% had either GADAs and/or IA-2As. Patients with autoimmune diabetes showed a clinical phenotype significantly different from that of type 2 diabetes, including higher fasting glucose and A1C, lower BMI and uric acid, lower prevalence of metabolic syndrome and its components, and higher frequency of TPO antibodies. More interestingly, analysis of GADA titers showed a bimodal distribution that identified two subgroups of patients with high (Ͼ32 GADA arbitrary units) and low (Յ32 GADA arbitrary units) GADA titers. Compared with those with low GADA titers, patients with high GADA titers had more prominent traits of insulin deficiency and a profile of more severe autoimmunity resulting in higher A1C, lower BMI, a lower prevalence of metabolic syndrome and its components (P Ͻ 0.02 for all), a higher prevalence of IA-2As, TPO antibodies (P Ͻ 0.003 for both), and DRB1*03-DQB1*0201 (50 vs. 26.8%, P ϭ 0.001), and a decreasing frequency of DQB1*0602 and DRB1*0403 (from type 2 to low and to high GADA titer autoimmune diabetes; P Ͻ 0.001 for trend for both comparisons).CONCLUSIONS -GADA titers identify two subgroups of patients with adult-onset autoimmune diabetes having distinct clinical, autoimmune, and genetic features. Diabetes Care 30:932-938, 2007

Distinct clinical and laboratory characteristics of latent autoimmune diabetes in adults in relation to type 1 and type 2 diabetes mellitus

“…In detail, patients with higher anti-GAD65 titres can be described by a more profound autoimmunity, quite marked dependency on insulin, higher levels of serum A1C, and lower both body mass index (BMI) and metabolic syndrome prevalence and, regarding genetic traits, decreased frequency of HLA-DRB1*0403 and HLA-DQB1*0602 and an increased for HLA-DRB1*03 and HLA-DQB1*0201 characterises the patients with higher anti-GAD65 titres [39] . Furthermore, studies from the same nationwide survey revealed that in LADA, the variant PTPN22 1858T is strongly associated with high titres of anti-GAD65 autoantibodies while the low levels are correlated to the T2D genetic variant of susceptibility, TCF7L2 [40,41] .…”

Tyrosine Phosphatase–Related Islet Antigen 2(256–760) Autoantibodies, the Only Marker of Islet Autoimmunity That Increases by Increasing the Degree of BMI in Obese Subjects With Type 2 Diabetes

“…A total of 1,850 patients, all recruited in central Italy (13) from the NIRAD study cohort of 5,330 consecutive cases of type 2 diabetes (13), was evaluated in the current study.…”

“…In our previous studies (12,13), we demonstrated a great deal of heterogeneity within the type 2 diabetic islet autoantibody-positive population in terms of phenotypic, genetic, immunological, and biochemical characteristics. Specifically, BMI varied widely, ranging from values below normality up to extreme obesity.…”

Exponential increase of glutamic acid decarboxylase (GAD) antibody titer after initiating and stopping insulin in a patient with slowly progressive type 1 diabetes

“…Only a few articles have reported a case with increased GAD antibody titers after diagnosis. It is known that patients with autoimmune thyroid disease (AITD) have a higher prevalence of having GAD antibody and have higher levels of GAD antibody than patients without AITD [11,12]. Irie et al reported a case of a 62-year-old woman with SPIDDM whose GAD antibody titer increased from 1.9 to 126000 U/ mL after emerging Grave's disease [13].…”