IA-2 Extracellular Antibody in Ketosis Prone Diabetes

Presentation Number: MON 580
Date of Presentation: April 3rd, 2017

Surya Narayan Mulukutla*1, Maria Acevedo-Calado2, Massimo Pietropaolo1 and Ashok Balasubramanyam3
1Baylor College of Medicine, Houston, TX, 2Baylor College of Medicine, 3Baylor Coll of Med, Houston, TX


Introduction: Autoimmunity against the neuroendocrine autoantigen tyrosine phosphatase IA-2 is common in type 1 diabetes (T1D). However, conventional assays target its intracellular domain. We have developed a new assay that targets the full-length IA-2 protein (IA-2var) as well as its extracellular domain (IA-2ec) and have found that IA-2var responses are associated with high risk of progression to insulin-requiring diabetes among first-degree relatives of T1D patients. Also, 28% of newly diagnosed T1D patients demonstrate positivity for IA-2ec and a small subset lack responses to conventional assays that target only the intracellular portion of IA-2. Similar studies in patients with “typical” type 2 diabetes (T2D) demonstrate a ~5% positive rate. We have characterized the novel syndromes of Ketosis-Prone Diabetes (KPD) in which more than 70% of patients present with diabetic ketoacidosis despite absence of beta-cell autoimmunity. The objective of this study was to assess IA-2var and IA-2ec autoantibody responses of patients with antibody-negative KPD compared to those in autoimmune T1D and “typical” T2D patients.

Hypothesis: Antibody-negative KPD patients will demonstrate antibody higher rate of positivity to IA2ec than “typical” T2D (5%) but less than T1D (28%).

Methods: We analyzed stored sera of 293 subjects with autoantibody-negative KPD (i.e., all patients negative for GAD65Ab and IA-2 using the WHO islet cell autoantibody standard) for IA-2var and IA-2ec autoantibody responses.

Results: Of the 293 samples, 3 patients were positive for the IA-2var autoantibody. Of these 3, 100% remain on insulin. One patient was diagnosed at age 7, and the others at 24 and 44 years of age. 10 patients were positive for IA-2ec autoantibody (3.41%).

Discussion: Presence of IA-2var autoantibody is highly specific as a marker of need of long-term insulin requirement. In one case, it was the only marker of autoimmunity still present in a patient with diabetes for more than 40 years. Also, of the 293 patients, only 3.41% were positive for IA2ec autoantibody. This difference in frequency for these novel autoantibodies between T1D, “typical” T2D and ketosis prone diabetes patients who are antibody negative for GAD-65 and IA-2 further underscores the unique pathophysiology of KPD.

Conclusion: IA-2var autoantibodies are highly predictive of need for long-term insulin use. Ketosis prone diabetes patients have much lower frequencies of IA2-ec autoantibodies compared to both T1D and "typical" T2D patients.

Disclosures: none


Nothing to Disclose: SNM, MA, MP, AB