Clinical, autoimmune, and genetic characteristics of adult-onset diabetic patients with GAD autoantibodies in Japan (Ehime Study).
OBJECTIVE
To characterize the clinical, autoimmune, and genetic features in Japanese adult-onset diabetic patients with GAD autoantibodies.


METHODS
GAD autoantibodies (GADab) were screened in 4,980 diabetic patients with age of onset >20 years in the hospital-based Ehime Study, and the GADab-positive (GADab(+)) patients were then divided into two groups according to their insulin secretion and compared with nondiabetic subjects. The insulin-deficient state was defined as <0.33 nmol/l serum C-peptide (CPR) at 2 h postprandial or 6 min after a 1-mg glucagon load.


RESULTS
GADab was detected in 188 (3.8%) of the 4,980 diabetic patients tested. Of these patients, 72 (38.3%) were classified as insulin deficient, 97 (51.6%) were classified as non-insulin deficient, and 19 (10.1%) were unclassified. The GADab(+) insulin-deficient patients were characterized by young age at onset of diabetes, low BMI, low maximum BMI, and high levels of HbA(1c). The prevalence of IA-2 autoantibodies and thyrogastric autoantibodies in the GADab(+) insulin-deficient patients were significantly higher than those in the GADab(+) non-insulin-deficient patients (P < 0.05). GADab(+) patients with insulin deficiency had increased frequencies of HLA DRB1*0405-DQB1*0401, *0802-*0302, and *0901-*0303 haplotypes, whereas the frequency of only HLA DRB1*0405-DQB1*0401 was increased in the case of GADab(+) non-insulin-deficient patients. Of note is the fact that the GADab(+) non-insulin-deficient group did not differ from healthy control subjects with respect to type 1 diabetes protective haplotype HLA DRB1*1502-DQB1*0601. A total of 13% of the GADab(+) patients with diabetes had genotypes comprising the DRB1*1501-DQB1*0602 or *1502-*0601 and were characterized by old age at onset of diabetes, high BMI, resistance to the insulin-deficient state, low titer of GADab, and low frequency of other organ-specific autoantibodies.


CONCLUSIONS
We conclude that GADab(+) non-insulin-deficient patients differ from GADab(+) patients with insulin deficiency with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, as well as HLA class II genes.
Takeda
Haruyo
H
Department of Laboratory Medicine, Ehime University School of Medicine, Shigenobu, Ehime, Japan.
Kawasaki
Eiji
E
Shimizu
Ikki
I
Konoue
Etsushi
E
Fujiyama
Masao
M
Murao
Satoshi
S
Tanaka
Kiyonobu
K
Mori
Kennichi
K
Tarumi
Yoshinao
Y
Seto
Isamu
I
Fujii
Yasuhisa
Y
Kato
Kenichi
K
Kondo
Shiori
S
Takada
Yasuharu
Y
Kitsuki
Nobuaki
N
Kaino
Yukikazu
Y
Kida
Kaichi
K
Hashimoto
Naotake
N
Yamane
Yukio
Y
Yamawaki
Takashi
T
Onuma
Hiroshi
H
Nishimiya
Tatsuya
T
Osawa
Haruhiko
H
Saito
Yasushi
Y
Makino
Hideichi
H
D000328:Adult; D017668:Age of Onset; D001323:Autoantibodies / Q000097:blood; D015992:Body Mass Index; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology*; D006442:Glycated Hemoglobin / Q000032:analysis; D006683:HLA-DQ Antigens / Q000235:genetics*; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006239:Haplotypes; D006801:Humans; D007328:Insulin / Q000097:blood / Q000172:deficiency; D007564:Japan; D008297:Male; D008875:Middle Aged; D012016:Reference Values
D001323:Autoantibodies; D002096:C-Peptide; D005968:Glutamate Decarboxylase; D006442:Glycated Hemoglobin; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D007328:Insulin; C069051:HLA-DQB1 antigen; C096322:ICA512 autoantibody