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. Claudio Tiberti1,
  2. Carla Giordano2,
  3. Mattia Locatelli3,
  4. Emanuele Bosi4,
  5. Gian Franco Bottazzo3,
  6. Raffaella Buzzetti1,
  7. Domenico Cucinotta5,
  8. Aldo Galluzzo2,
  9. Alberto Falorni6 and
  10. Francesco Dotta7
  1. 1Department of Clinical Sciences, University of Rome “La Sapienza,” Rome, Italy
  2. 2Department of Endocrinology, University of Palermo, Palermo, Italy
  3. 3Scientific Institute, Bambino Gesù Hospital, Rome, Italy
  4. 4General Medicine, Diabetes, and Endocrinology, San Raffaele Scientific Institute and Vita Salute University, Milan, Italy
  5. 5Department of Internal Medicine, University of Messina, Messina, Italy
  6. 6Department of Internal Medicine, University of Perugia, Perugia, Italy
  7. 7Department of Internal Medicine, Endocrine and Metabolic Sciences, and Biochemistry, University of Siena, Siena, Italy
  1. 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-2PTP (687–979), IA-2(761–964), IA-2(256–760), IA-2JM (601–630), IA-2IC (605–979), IA-2BDC (256–556:630–979), and IA-2FL (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.

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.

  • *

    * A complete list of the NIRAD study investigators and committees can be found in an online appendix at http://dx.doi.org/10.2337/db07-0874.

    • Accepted January 23, 2008.
    • Received June 28, 2007.
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  1. Published online before print March 10, 2008, doi: 10.2337/db07-0874 Diabetes May 2008 vol. 57 no. 5 1276-1283
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