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 *
Claudio Tiberti 1 ,
Carla Giordano 2 ,
Mattia Locatelli 3 ,
Emanuele Bosi 4 ,
Gian Franco Bottazzo 3 ,
Raffaella Buzzetti 1 ,
Domenico Cucinotta 5 ,
Aldo Galluzzo 2 ,
Alberto Falorni 6 and
Francesco Dotta 7
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
Abstract
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.
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
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 10 March 2008. DOI: 10.2337/db07-0874.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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* A complete list of the NIRAD study investigators and commit...

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

10.2337/db07-0874