Increased risk for endocrine autoimmunity in Italian type 2 diabetic patients with GAD65 autoantibodies.
OBJECTIVE
Glutamic acid decarboxylase (GAD)65 autoantibodies (GAD65Ab) in type 2 diabetic subjects with secondary failure to sulphonylurea treatment identify the so-called latent autoimmune diabetes of the adult (LADA). The aim of our study was to estimate the risk for endocrine autoimmunity in type 2 diabetic subjects with GAD65Ab.


METHODS
We analysed serum samples from 600 adult subjects with a clinical diagnosis of type 2 diabetes mellitus for the presence and levels of GAD65Ab and antibodies directed against the islet autoantigen IA-2/ICA512 (IA-2/ICA512Ab). All the patients had been treated initially with hypoglycaemic agents and/or diet for at least 1 year. GAD65Ab+ subjects were studied for the presence of thyroid peroxidase autoantibodies (TPOAb), 21 hydroxylase autoantibodies (21OHAb) and frequency of HLA class II haplotypes.


RESULTS
GAD65Ab were found in 67/600 (11%) and IA-2/ICA512Ab in 12/600 (2%) subjects (P < 0.0001). The presence of GAD65Ab, but not that of IA-2/ICA512Ab, was significantly associated with insulin therapy, low BMI (P < 0.0001) and low basal C-peptide (P < 0.01). Islet-cell antibodies (ICA) were detected in 43/67 (64%) GAD65Ab+ and in 10/12 (83%) IA-2/ICA512Ab + subjects. TPOAb occurred more frequently in GAD65Ab+ (16/67, 24%) than in GAD65Ab-subjects (9/174, 5%) (P < 0.0001). 21OHAb were detected only in GAD65Ab+ subjects (3/67, 4.5%) (P = 0.03 vs. GAD65Ab-subjects). None of the 21OHAb+ subjects had metabolic or clinical signs of adrenal dysfunction. HLA-DRB1*03-DQA1*0501-DQB1*0201 (DR3-DQ2) was significantly more frequent in GAD65Ab+ subjects than in healthy controls (OR = 5.42, corrected P < 0.0026). The presence of TPOAb was significantly associated with DR3-DQ2 (P = 0.024).


CONCLUSIONS
Our study demonstrates that the presence of GAD65Ab identifies a subgroup of type 2 diabetic patients with high risk for thyroid and adrenal autoimmunity, and that both GAD65Ab and TPOAb are associated with the presence of HLA-DR3-DQ2, in these patients.
Gambelunghe
G
G
Department of Internal Medicine and Endocrine & Metabolic Sciences, University of Perugia, Perugia, Italy.
Forini
F
F
Laureti
S
S
Murdolo
G
G
Toraldo
G
G
Santeusanio
F
F
Brunetti
P
P
Sanjeevi
C B
CB
Falorni
A
A
D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood*; D001327:Autoimmune Diseases / Q000276:immunology*; D015415:Biomarkers / Q000032:analysis; D016009:Chi-Square Distribution; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D005260:Female; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000032:analysis; D015803:HLA-DR3 Antigen / Q000032:analysis; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D006801:Humans; D007453:Iodide Peroxidase / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology; D007558:Italy; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D018709:Statistics, Nonparametric; D013255:Steroid 21-Hydroxylase / Q000276:immunology
D001323:Autoantibodies; D015415:Biomarkers; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D015803:HLA-DR3 Antigen; D000949:Histocompatibility Antigens Class II; D007453:Iodide Peroxidase; D013255:Steroid 21-Hydroxylase; D005968:Glutamate Decarboxylase