Clinical and Genetic Characteristics of Non-Insulin-Requiring Glutamic Acid Decarboxylase (GAD) Autoantibody-Positive Diabetes: A Nationwide Survey in Japan

PLoS One. 2016 May 13;11(5):e0155643. doi: 10.1371/journal.pone.0155643. eCollection 2016.

Abstract

Aims: Glutamic acid decarboxylase autoantibodies (GADAb) differentiate slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) from phenotypic type 2 diabetes, but many GADAb-positive patients with diabetes do not progress to insulin-requiring diabetes. To characterize GADAb-positive patients with adult-onset diabetes who do not require insulin therapy for >5 years (NIR-SPIDDM), we conducted a nationwide cross-sectional survey in Japan.

Methods: We collected 82 GADAb-positive patients who did not require insulin therapy for >5 years (NIR-SPIDDM) and compared them with 63 patients with insulin-requiring SPIDDM (IR-SPIDDM). Clinical and biochemical characteristics, HLA-DRB1-DQB1 haplotypes, and predictive markers for progression to insulin therapy were investigated.

Results: Compared with the IR-SPIDDM group, the NIR-SPIDDM patients showed later diabetes onset, higher body mass index, longer duration before diagnosis, and less frequent hyperglycemic symptoms at onset. In addition, C-peptide, LDL-cholesterol, and TG were significantly higher in the NIR-SPIDDM compared to IR-SPIDDM patients. The NIR-SPIDDM group had lower frequency of susceptible HLA-DRB1*04:05-DQB1*04:01 and a higher frequency of resistant HLA-DRB1*15:01-DQB1*06:02 haplotype compared to IR-SPIDDM. A multivariable analysis showed that age at diabetes onset (OR = 0.82), duration before diagnosis of GADAb-positive diabetes (OR = 0.82), higher GADAb level (≥10.0 U/ml) (OR = 20.41), and fasting C-peptide at diagnosis (OR = 0.07) were independent predictive markers for progression to insulin-requiring diabetes. An ROC curve analysis showed that the optimal cut-off points for discriminating two groups was the GADAb level of 13.6 U/ml, age of diabetes onset of 47 years, duration before diagnosis of 5 years, and fasting C-peptide of 0.65 ng/ml.

Conclusions: Clinical, biochemical and genetic characteristics of patients with NIR-SPIDDM are different from those of IR-SPIDDM patients. Age of diabetes onset, duration before GADAb-positivity, GADAb level, and fasting C-peptide at diagnosis must be carefully considered in planning prevention trials for SPIDDM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Aged
  • Autoantibodies / immunology*
  • Biomarkers / metabolism
  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / diagnosis
  • Diabetes Mellitus, Type 1 / epidemiology
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetes Mellitus, Type 2 / diagnosis
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / immunology*
  • Disease Progression
  • Female
  • Gene Frequency / genetics
  • Glutamate Decarboxylase / immunology*
  • HLA-DQ beta-Chains / genetics
  • HLA-DRB1 Chains / genetics
  • Haplotypes / genetics
  • Humans
  • Insulin / therapeutic use*
  • Japan
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • ROC Curve
  • Surveys and Questionnaires*

Substances

  • Autoantibodies
  • Biomarkers
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • HLA-DRB1 Chains
  • Insulin
  • Glutamate Decarboxylase

Grants and funding

This study was supported by a grant-in-aid from the Japan Diabetes Society.