Diabetology International

, Volume 7, Issue 1, pp 42–52 | Cite as

Predictive value of titer of GAD antibodies for further progression of beta cell dysfunction in slowly progressive insulin-dependent (type 1) diabetes (SPIDDM)

  • Shoichiro Tanaka
  • Minoru Okubo
  • Kaoru Nagasawa
  • Soichi Takizawa
  • Masashi Ichijo
  • Sayaka Ichijo
  • Masahiro Kaneshige
  • Kaoru Aida
  • Hiroki Shimura
  • Yasumichi Mori
  • Tetsuro KobayashiEmail author
Original Article



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.


Slowly 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.


  1. 1.
    Kobayashi T. Subtype of insulin-dependent diabetes mellitus (IDDM) in Japan: slowly progressive IDDM—the clinical characteristics and pathogenesis of the syndrome. Diabetes Res Clin Pract. 1994;24(Suppl):S95–9.CrossRefPubMedGoogle Scholar
  2. 2.
    Kobayashi T, Tamemoto K, Nakanishi K, et al. Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care. 1993;16:780–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Maruyama T, Tanaka S, Shimada A, et al. Insulin intervention in slowly progressive insulin-dependent (type 1) diabetes mellitus. J Clin Endocrinol Metab. 2008;93:2115–21.CrossRefPubMedGoogle Scholar
  4. 4.
    Desai M, Cull CA, Horton VA, et al. GAD autoantibodies and epitope reactivities persist after diagnosis in latent autoimmune diabetes in adults but do not predict disease progression: UKPDS 77. Diabetologia. 2007;50:2052–60.CrossRefPubMedGoogle Scholar
  5. 5.
    Lohmann T, Kellner K, Verlohren HJ, et al. Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Diabetologia. 2001;44:1005–10.CrossRefPubMedGoogle Scholar
  6. 6.
    Buzzetti R, Di Pietro S, Giaccari A, Non Insulin Requiring Autoimmune Diabetes Study Group, et al. High titer of autoantibodies to GAD identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care. 2007;30:932–8.CrossRefPubMedGoogle Scholar
  7. 7.
    The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1997;20:1183–97.Google Scholar
  8. 8.
    Tanaka S, Ohmori M, Awata T, et al. Diagnostic criteria for slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) (2012)—report by the committee on slowly progressive insulin-dependent (type 1) diabetes mellitus of the Japan Diabetes Society. Diabetol Int. 2015;6:1–7.Google Scholar
  9. 9.
    Japan Diabetes Society. Food exchange lists—dietary guidance for persons with diabetes. Tokyo: Bunkodo; 2003.Google Scholar
  10. 10.
    Kobayashi T, Nakanishi K, Murase T, et al. 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. Diabetes. 1996;45:622–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Tanaka S, Endo T, Aida K, et al. Distinct diagnostic criteria of fulminant type 1 diabetes based on serum C-peptide response and HbA1c levels at onset. Diabetes Care. 2004;27:1936–41.CrossRefPubMedGoogle Scholar
  12. 12.
    Schmidli RS, Colman PG, Bonifacio E, et al. High level of concordance between assays for glutamic acid decarboxylase antibodies: the first international glutamic acid decarboxylase antibody workshop. Diabetes. 1994;43:1005–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Masuda M, Powell M, Chen S, et al. Autoantibodies to IA-2 in insulin-dependent diabetes mellitus: measurements with a new immunoprecipitation assay. Clin Chim Acta. 2000;291:53–66.CrossRefPubMedGoogle Scholar
  14. 14.
    Awata T, Kawasaki E, Tanaka S, Japanese Study Group on Type 1 Diabetes Genetics, et al. Association of type 1 diabetes with two Loci on 12q13 and 16p13 and the influence coexisting thyroid autoimmunity in Japanese. J Clin Endocrinol Metab. 2009;94:231–5.CrossRefPubMedGoogle Scholar
  15. 15.
    Nomura N, Ota M, Tsuji K, et al. HLA-DQB1 genotyping by a modified PCR-RFLP method combined with group-specific primers. Tissue Antigens. 1991;38:53–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Ota M, Seki T, Fukushima H, et al. HLA-DRB1 genotyping by modified PCR-RFLP method combined with group-specific primers. Tissue Antigens. 1992;39:187–202.CrossRefPubMedGoogle Scholar
  17. 17.
    Tanaka S, Kobayashi T, Nakanishi K, et al. Association of HLA-DQ genotype in autoantibody-negative and rapid-onset type 1 diabetes. Diabetes Care. 2002;25:2302–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Kobayashi T, Tanaka S, Okubo M, et al. Unique epitopes of glutamic acid decarboxylase autoantibodies in slowly progressive type 1 diabetes. J Clin Endocrinol Metab. 2003;88:4768–75.CrossRefPubMedGoogle Scholar
  19. 19.
    Imanishi T, Akaza T, Kimura A, et al. Allele frequencies and haplotype frequencies for HLA and complement loci in various ethnic groups. In: Tsuji K, Aizawa M, Sasazuki T, editors. HLA 1991. Oxford: Oxford University Press; 1992. p. 1065–220.Google Scholar
  20. 20.
    Rønningen KS, Spurkland A, Tait BD, et al. HLA class II associations in insulin-dependent diabetes mellitus among blacks, Caucasoids, and Japanese. In: Tsuji K, Aizawa M, Sasazuki T, (Eds) HLA 1991. Proceedings of the 11th international histocompatibility workshop and conference, Yokohoma, Japan, 6–13 November 1991. Oxford University Press, Oxford, 1992, p. 713 –22.Google Scholar
  21. 21.
    Yasunaga S, Kimura A, Hamaguchi K, et al. Different contribution of HLA-DR and genes in susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). Tissue Antigens. 1996;47:37–48.CrossRefPubMedGoogle Scholar
  22. 22.
    Suzuki R, Shimada A, Maruyama T, et al. T-cell function in anti-GAD65(+)diabetes with residual beta-cell function. J Autoimmun. 2003;20:83–90.CrossRefPubMedGoogle Scholar
  23. 23.
    Kobayashi T, Nishida Y, Tanaka S, et al. Pathological changes in the pancreas of fulminant type 1 diabetes and slowly progressive insulin-dependent diabetes mellitus (SPIDDM): innate immunity in fulminant type 1 diabetes and SPIDDM. Diabetes Metab Res Rev. 2011;27:965–70.CrossRefPubMedGoogle Scholar
  24. 24.
    Sone H, Ito H, Ohashi Y, et al. Obesity and type 2 diabetes in Japanese patients. Lancet. 2003;361:85.CrossRefPubMedGoogle Scholar
  25. 25.
    Turner R, Stratton I, Horton V, UK Prospective Diabetes Study Group, et al. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet. 1997;350:1288–93.CrossRefPubMedGoogle Scholar
  26. 26.
    Murao S, Kondo S, Ohashi J, et al. Anti-thyroid peroxidase antibody, IA-2 antibody, and fasting C-peptide levels predict beta cell failure in patients with latent autoimmune diabetes in adults (LADA)–a 5-year follow-up of the Ehime study. Diabetes Res Clin Pract. 2008;80:114–21.CrossRefPubMedGoogle Scholar

Copyright information

© The Japan Diabetes Society 2015

Authors and Affiliations

  • Shoichiro Tanaka
    • 1
  • Minoru Okubo
    • 2
    • 3
  • Kaoru Nagasawa
    • 2
    • 3
  • Soichi Takizawa
    • 1
  • Masashi Ichijo
    • 1
  • Sayaka Ichijo
    • 1
  • Masahiro Kaneshige
    • 1
  • Kaoru Aida
    • 1
  • Hiroki Shimura
    • 4
  • Yasumichi Mori
    • 2
    • 3
  • Tetsuro Kobayashi
    • 1
    • 3
    Email author
  1. 1.Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and EngineeringUniversity of YamanashiChuoJapan
  2. 2.Department of Endocrinology and MetabolismToranomon HospitalTokyoJapan
  3. 3.Okinaka Memorial Institute for Medical ResearchTokyoJapan
  4. 4.Department of Laboratory MedicineFukushima Medical UniversityFukushima-shiJapan

Personalised recommendations