Ishii Michiyo, Hasegawa Goji, Fukui Michiaki, Obayashi Hiroshi, Ohta Mitsuhiro, Ogata Masakazu, Yoshioka Keiji, Kitagawa Yoshihiro, Nakano Koji, Yoshikawa Toshikazu, Nakamura Naoto
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Japan.
Immunol Lett. 2005 Jul 15;99(2):180-5. doi: 10.1016/j.imlet.2005.03.001. Epub 2005 Mar 17.
We investigated the clinical aspects and genetic background of 13 diabetic patients with high-titers (>10,000 U/ml) of anti-glutamic acid decarboxylase antibody (Group A) and compared these 28 middle-aged (35-51 years, Group B) and 13 elderly (66-79 years, Group C) patients with anti-GAD(+) (<1100 U/ml) who were diagnosed initially as having type 2 diabetes. The mean age and mean age at onset of Group A were 70.8 +/- 3.9 years (range, 64-78) and 50.4 +/- 5.4 years (range, 43-61), respectively. In Group A, the prevalence of insulin-deficient patients was significantly lower (30.8%, 4 of 13) than in Group C (96.3%, 27 of 28, P < 0.001). Patients in Group A had a significantly longer interval between the clinical onset of diabetes to initiation insulin therapy (21.8 +/- 2.3 years) compared to patients in both Group B (1.8+/-1.1 years, P < 0.001) and Group C (14.8 +/- 7.1 years, P = 0.049). The frequency of DRB10405-DQB10401/DRB11502-DQB10601 or DRB1501-DQB0602 heterozygous genotypes in Group A (53.8%, 7 of 13) was significantly higher than in both Group B (3.6%, 1 of 28, P < 0.01) and Group C (7.7%, 1 of 13, P < 0.05). Compared with Group B, Group A had an increased frequency of the TNFA-U01 haplotype and the IL-10 -592 C allele (TNFA-U01; 53.8% versus 30.4%, P = 0.05 and IL-10 -592 C; 57.7% versus 33.9 %, P = 0.042). All sera from Group A reacted with GAD(65) protein on Western blots. We conclude that adult-onset diabetic patients with a high-titer of anti-GDAab differ from patients with latent autoimmune diabetes mellitus in adult (LADA) with respect to beta-cell function, cellular autoimmunity and genetic background. Our study also showed that high-titers of antibodies to glutamic acid decarboxylase (anti-GADab) were not predictive of later development of insulin deficiency in adult and/or elderly patients with type 2 diabetes. Furthermore, our results suggest that HLA-DRB11502-DQB10601 or DRB11501-DQB10602/DRB10405-DQB10401 heterozygous genotypes may be associated with high production of anti-GADab that recognizes the linear epitope(s) on the GAD(65) protein.
我们研究了13例抗谷氨酸脱羧酶抗体滴度高（>10,000 U/ml）的糖尿病患者（A组）的临床特征和遗传背景，并将这28例中年（35 - 51岁，B组）和13例老年（66 - 79岁，C组）最初诊断为2型糖尿病的抗GAD（+）（<1100 U/ml）患者与之进行比较。A组的平均年龄和平均发病年龄分别为70.8±3.9岁（范围64 - 78岁）和50.4±5.4岁（范围43 - 61岁）。在A组中，胰岛素缺乏患者的患病率显著低于C组（30.8%，13例中的4例 vs 96.3%，28例中的27例，P<0.001）。与B组（1.8±1.1年，P<0.001）和C组（14.8±7.1年，P = 0.049）的患者相比，A组患者从糖尿病临床发病到开始胰岛素治疗的间隔时间显著更长（21.8±2.3年）。A组中DRB10405 - DQB10401/DRB11502 - DQB10601或DRB1501 - DQB0602杂合基因型的频率（53.8%，13例中的7例）显著高于B组（3.6%，28例中的1例，P<0.01）和C组（7.7%，13例中的1例，P<0.05）。与B组相比，A组中TNFA - U01单倍型和IL - 10 - 592 C等位基因的频率增加（TNFA - U01；53.8%对30.4%，P = 0.05；IL - 10 - 592 C；57.7%对33.9%，P = 0.042）。A组所有血清在蛋白质印迹法中均与GAD（65）蛋白反应。我们得出结论，抗GDAab滴度高的成年发病糖尿病患者在β细胞功能、细胞自身免疫和遗传背景方面与成年隐匿性自身免疫性糖尿病（LADA）患者不同。我们的研究还表明，谷氨酸脱羧酶抗体（抗GADab）高滴度不能预测成年和/或老年2型糖尿病患者以后是否会出现胰岛素缺乏。此外，我们的结果表明，HLA - DRB11502 - DQB10601或DRB11501 - DQB10602/DRB10405 - DQB10401杂合基因型可能与识别GAD（65）蛋白上线性表位的抗GADab的高产生有关。
