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Identification of tyrosine posphatase 2_(256–760) construct as a new, sensitive marker for the detection of islet autoimmunity in type 2 diabetic patients (NIRAD Study 2)

¹Department of Clinical Sciences, University of Rome "La Sapienza", Rome, Italy
²Department of Endocrinology, University of Palermo, Italy
³Scientific Institute, Bambino Gesù Hospital, Rome, Italy
⁴General Medicine, Diabetes & Endocrinology, San Raffaele Scientific Institute and Vita Salute University, Milan, Italy
⁵Department of Internal Medicine, University of Messina, Messina, Italy
⁶Department of Internal Medicine, University of Perugia, Perugia, Italy
⁷Department of Internal Medicine, Endocrine and Metabolic Sciences and Biochemistry, University of Siena, Siena, Italy

Objective: The presence of autoantibodies to islet antigens GAD and/or IA-2 in type 2 diabetic patients identifies those subjects (LADA) at high risk to develop insulin dependency. Aim of this study was to dissect humoral anti-IA-2 immune response in Caucasian LADA patients, identifying the most sensitive construct to evaluate IA-2 immunoreactivity and comparing LADA IA-2 epitope specificities to those found in type 1 diabetes

Research Design and Methods: Patients: 177 LADA and 978 type 2 diabetic patients with different disease duration, collected in a nationwide italian survey (NIRAD Study) aimed at assessing prevalence and characteristics of autoimmune diabetes in type 2 diabetic patients; 106 newly-diagnosed type 1 diabetic patients (53 children, 53 adults) Method: analysis by radioimmunoassay of humoral immunoreactivity to 7 IA-2 constructs [IA-2_{PTP(687–979),}IA-2_(761–964),IA-2_(256–760),IA-2_{JM(601–630)},IA-2_{IC(605–979),}IA-2_{BDC(256–556:630–979),}IA-2_FL(1–979)]

Results: IA-2_(256–760) fragment was identified as the marker with the highest sensitivity for detection of humoral IA-2 immunoreactivity in LADA, identifying IA-2 autoantibodies in almost 30% of GADA positive LADA and in 3.4% of GADA negative type 2 diabetic patients. LADA IA-2_(256–760)A positivity was associated to an increased frequency of autoimmune diabetes HLA susceptible genotypes and to a higher risk for developing thyroid autoimmunity compared to autoantibody negative type 2 diabetic patients. At disease diagnosis, adult-onset type 1 diabetic and LADA patients showed a lower IA-2 C-terminal immunoreactivity compared to childhood-onset type 1 diabetic patients

Conclusions: IA-2 immunoreactivity in LADA patients was so far underestimated and IA-2_(256–760) autoantibody detection may represent a novel diagnostic tool for the identification of islet autoimmunity in these patients.

Key Words: IA-2 autoantibodies • epitopes • LADA • type 1 diabetes • type 2 diabetes

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