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.
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.


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 approximately 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.
Tiberti
Claudio
C
Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy. claudio.tiberti@uniroma1.it
Giordano
Carla
C
Locatelli
Mattia
M
Bosi
Emanuele
E
Bottazzo
Gian Franco
GF
Buzzetti
Raffaella
R
Cucinotta
Domenico
D
Galluzzo
Aldo
A
Falorni
Alberto
A
Dotta
Francesco
F
D000328:Adult; D001323:Autoantibodies / Q000097:blood*; D015551:Autoimmunity; D015415:Biomarkers / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D006306:Health Surveys; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D007558:Italy; D010446:Peptide Fragments / Q000032:analysis / Q000737:chemistry*; D017027:Protein Tyrosine Phosphatases / Q000737:chemistry*
D001323:Autoantibodies; D015415:Biomarkers; D010446:Peptide Fragments; D017027:Protein Tyrosine Phosphatases