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Identification of Tyrosine Phosphatase 2_(256–760) Construct as a New, Sensitive Marker for the Detection of Islet Autoimmunity in Type 2 Diabetic Patients

The Non–Insulin Requiring Autoimmune Diabetes (NIRAD) Study 2^*

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

Corresponding author: Claudio Tiberti, Department of Clinical Sciences, Policlinico Umberto I, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy. E-mail: claudio.tiberti{at}uniroma1.it

Abbreviations: DASP, Diabetes Antibody Standardization Program; GADA, GAD autoantibody; IA-2, tyrosine phosphatase 2; IA-2A, IA-2 autoantibody; LADA, latent autoimmune diabetes in adults; NIRAD, Non–Insulin Requiring Autoimmune Diabetes; TPO-A, thyroid peroxidase autoantibody

OBJECTIVE—The presence of autoantibodies to islet antigens GAD and/or tyrosine phosphatase 2 (IA-2) in type 2 diabetic patients (latent autoimmune diabetes in adults [LADA]) identifies subjects at high risk to develop insulin dependency. The 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—We analyzed 177 LADA and 978 type 2 diabetic patients with different disease duration, collected in a nationwide Italian survey, the Non–Insulin Requiring Autoimmune Diabetes (NIRAD) study aimed at assessing prevalence and characteristics of autoimmune diabetes in type 2 diabetic patients and 106 newly diagnosed type 1 diabetic patients (53 children, 53 adults). By radioimmunoassay, we analyzed humoral immunoreactivity to seven 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)}, and 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 patients, identifying IA-2 autoantibodies in 30% of GAD antibody (GADA)-positive LADA patients and in 3.4% of GADA-negative type 2 diabetic patients. LADA IA-2_(256–760)A positivity was associated with an increased frequency of autoimmune diabetes HLA-susceptible genotypes and with a higher risk for developing thyroid autoimmunity compared with autoantibody-negative type 2 diabetic patients. At disease diagnosis, adult-onset type 1 diabetic and LADA patients showed a lower IA-2 COOH-terminal immunoreactivity compared with childhood-onset type 1 diabetic patients.

CONCLUSIONS—IA-2 immunoreactivity in LADA patients has thus far been underestimated, and IA-2_(256–760) autoantibody detection may represent a novel diagnostic tool for the identification of islet autoimmunity in these patients.

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