We read with great interest the recent article by Takeda et al. (1) reporting that GAD autoantibody (GADab)-positive non-insulin-deficient patients differ from GADab-positive insulin-deficient patients with respect to clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, and HLA class II genes.

The prevalence of GADab in Takeda’s study was lower than that in our study (3.8 vs. 6.8%; P = 0.0009 by χ2 analysis), even in patients who were initially diagnosed as having type 2 diabetes (2). The authors should present the number of patients with insulin-deficient and non-insulin-deficient diabetes and the prevalence of GADab in both groups of patients. We speculate that the lower prevalence of GADab might have been due to a higher number of non-insulin-deficient patients in their study than in our study because the prevalence of GADab is reported to be higher in insulin-deficient patients than in non-insulin-deficient patients (3). The authors defined insulin-deficient patients as those patients with typical type 1 diabetes and slowly progressive type 1 diabetes. The authors stated that there are distinct differences between typical type 1 diabetes (rapid progression to insulin dependency) and slowly progressive type 1 diabetes (slowly progressive deterioration of β-cell function through the non-insulin-dependent state and ultimately to insulin dependency). Therefore, the authors should have further divided these phenotypes into two subgroups in order to investigate the differences in clinical characteristics, humoral autoimmunity to other organ-specific autoantibodies, and HLA class II genes.

The results of this study are in accordance with those of our study in that both studies demonstrate that HLA-DRB1 alleles contributed to the prognosis of Japanese patients with diabetes who are positive for GADab (4). The prevalence of HLA-DRB1*0405, which is one of the susceptible alleles to typical type 1 diabetes, was significantly lower, and the prevalence of HLA-DRB1*1502, which is one of the protective alleles to typical type 1 diabetes, was significantly higher in non-insulin-deficient diabetic patients positive for GADab than in typical type 1 diabetic patients positive for GADab.

Furthermore, we demonstrated a significantly greater proliferative response of peripheral blood mononuclear cells to GAD in type 2 diabetes positive for GADab (5), especially in those with alleles susceptible to typical type 1 diabetes; the responses were useful markers for the later development of insulin deficiency in type 2 diabetes positive for GADab. Interestingly, low GADab levels declined to negative levels during a few years in our study (5). Low levels of GADab in non-insulin-deficient diabetic patients may decline to negative levels, which demonstrates the possibility of pseudopositive GADab. Higher levels of GADab (6), seropositivity for GADab with humoral autoimmunity to other organ-specific autoantibodies, HLA class II genes, or cellular response to GAD may be useful for predicting the clinical course of diabetic patients positive for GADab.

Finally, Kobayashi et al. (7) reported that small doses of subcutaneous insulin in islet cell antibody-positive patients with type 2 diabetes resulted in improved serum C-peptide response. Non-insulin-deficient diabetic patients with GADab without insulin therapy in Takeda’s study may prefer to be treated with insulin to reserve residual β-cell function.

1
Takeda H, Kawasaki E, Shimizu I, Konoue E, Fujiyama M, Murao S, Tanaka K, Mori K, Tarumi Y, Seto I, Fujii Y, Kato K, Kondo S, Takada Y, Kitsuki N, Kaino Y, Kida K, Hashimoto N, Yamane Y, Yamawaki T, Onuma H, Nishimiya T, Osawa H, Saito Y, Makino H: Clinical, autoimmune, and genetic characteristics of adult-onset diabetic patients with GAD autoantibodies in Japan (Ehime Study).
Diabetes Care
 
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2002
2
Fukui M, Nakano K, Maruya E, Saji H, Ohta K, Ohta M, Obayashi H, Mori H, Kajiyama S, Wada S, Shigeta H, Kitagawa Y, Nakamura N, Kondo M: Diagnostic significance of antibodies to glutamic acid decarboxylase in Japanese diabetic patients with secondary oral hypoglycemic agents failure.
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1997
3
Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR: Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease.
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1993
4
Fukui M, Nakano K, Nakamura N, Maruya E, Saji H, Obayashi H, Ohta K, Ohta M, Mori H, Kajiyama S, Wada S, Kida Y, Kosaka K, Deguchi M, Shigeta H, Kitagawa Y, Kondo M: HLA-DRB1 alleles contribute to determining the prognosis of Japanese diabetes mellitus positive for antibodies to glutamate decarboxylase.
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1998
5
Fukui M, Nakamura N, Nakano K, Kajiyama S, Matsuo S, Obayashi H, Ohta M, Shigeta M, Shigeta H, Kitagawa Y, Kondo M: HLA-associated cellular response to GAD in type 2 diabetes with antibodies to GAD.
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2000
6
Kasuga A, Maruyama T, Nakamoto S, Ozawa Y, Suzuki Y, Saruta T: High-titer autoantibodies against glutamic acid decarboxylase plus autoantibodies against insulin and IA-2 predicts insulin requirement in adult diabetic patients.
J Autoimmun
 
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1999
7
Kobayashi T, Nakanishi K, Murase T, Kosaka K: Small doses of subcutaneous insulin as a strategy for preventing slowly progressive β-cell failure in islet cell antibody-positive patients with clinical features of NIDDM.
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1996

Address correspondence to Michiaki Fukui, MD, Department of Endocrinology and Hematology, Osaka General Hospital of West Japan Railway Company, 1-2-22 Matsuzaki-cho, Abeno-ku, Osaka 545-0053, Japan. E-mail: [email protected].

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2002