Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM)
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Whether the titer of glutamic acid decarboxylase antibodies (GADAs), especially a low titer, is a marker of progression of beta cell dysfunction in patients with slowly progressive insulin-dependent (type 1) diabetes (SPIDDM) is unclear.
Materials and methods
Patients were subdivided as follows: patients with high GADA titers [≥10 U/ml (≥180 WHO U/ml): high GADA] (group 1, n = 37); those with low GADA titers [<10 U/ml (<180 WHO U/ml): low GADA] (group 2, n = 33); those without GADA and with islet cell antibodies (ICA) (group 3, n = 8); those without both GADA and ICA and with insulinoma-associated antigen 2 antibodies (IA-2A) (group 4, n = 6). We also allocated 198 type 2 diabetic patients without any GADA, ICA or IA-2A as group 5. Serum C-peptide responses to annual oral glucose tolerance tests (OGTTs) were followed up for a mean of 107 months from entry.
The proportion of patients progressing to an insulin-dependent state in groups 1, 2, 3 and 4 was significantly higher than in group 5. C-peptide responses in OGTTs of patients in groups 1 and 2 were decreased at a significantly higher rate than in group 5. Multivariate Cox proportional hazard analysis revealed that factors including high GADA, low GADA, onset age <45 years, duration of diabetes <24 months, body mass index (BMI) <22.0 kg/m2, low degree of preserved beta cell function and ICA were independent risk factors for progression to an insulin-dependent state.
SPIDDM patients with low GADA titers have a significantly higher risk of progression to an insulin-dependent state than type 2 diabetic patients, suggesting that the presence of GADA, irrespective of the titer, is a hallmark of beta cell failure. Other risk factors for further progression to an insulin-dependent state in SPIDDM patients were ICA, onset age, duration of diabetes, BMI and residual beta cell function.
KeywordsSlowly progressive insulin-dependent (type 1) diabetes mellitus Glutamic acid decarboxylase antibodies Islet cell antibodies C-peptide
We thank Prof. Kazuhiko Kobayashi (Department of Global Agricultural Sciences, Graduate School of Agricultural and Life Sciences, University of Tokyo) for statistical advice and also thank Ms. Kaori Hosaka, Ms. Chihiro Imai and Ms. Sachiko Osada (Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi) and Ms. Fumie Takano (Department of Endocrinology and Metabolism, Toranomon Hospital) for secretarial work.
Conflict of interest
Tetsuro Kobayashi received honoraria for lectures from Sanofi K.K. and research grants from Sanofi K.K., Tanabe-Mitsubishi K.K., Kowa-Souyaku Co. and Eli Lilly Japan K.K. Shoichiro Tanaka, Minoru Okubo, Kaoru Nagasawa, Shouichi Takizawa, Masashi Ichijo, Sayaka Ichijyo, Masahiro Kaneshige, Kaoru Aida, Hiroki Shimura and Yasumichi Mori declare that they have no conflict of interest.
Human rights statement and informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later revisions. Informed consent or a substitute for it was obtained from all patients for being included in the study.
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