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OBJECTIVE Since patients with type 2 diabetes and positive for type 1 diabetes-specific antibodies have wide variations in BMI, this study evaluated whether the frequency and pattern of islet autoantibody positivity is related to BMI. RESEARCH DESIGN AND METHODS Clinical and biochemical characteristics and islet autoantibodies including GAD and protein tyrosine phosphatases islet antigen-2 (IA-2)IC and IA-2(256-760) were evaluated in 1,850 patients with type 2 diabetes from the Non-Insulin Requiring Autoimmune Diabetes study cohort. BMI was evaluated in all patients, who were then subdivided in three groups according to BMI (<25, ≥25 to <30, and <30 kg/m²). RESULTS Out of 1,850, 120 (6.5%) patients were positive for at least one of the following antibodies: GAD (4.1%), IA-2(256-760) (3.3%), or IA-2IC (1.1%). GAD and IA-2IC antibodies showed decreasing frequencies with increasing BMI (P < 0.0001 and 0.0006, respectively, for trend); in contrast, the frequency of IA-2(256-760) antibodies increased with increasing BMI (P = 0.005 for trend). Patients with type 2 diabetes positive for IA-2(256-760) alone showed a phenotype resembling classical obese type 2 diabetes, with higher BMI, waist circumference, and uric acid (P < 0.005 for all), lower thyroid peroxidase antibodies, and lower progression to insulin requirement than GAD antibody--positive patients (P = 0.04 and P = 0.0005, respectively). CONCLUSIONS The IA-2(256-760) antibody appears to represent an antibody marker that mainly identifies a clinical phenotype very similar to obese type 2 diabetes, suggesting a possible different pathogenetic mechanism. [ABSTRACT FROM AUTHOR]