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

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/m(2)). 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.