title: Autoantibodies to insulin, insulinoma-associated antigen-2, and zinc transporter 8 improve the prediction of early insulin requirement in adult-onset autoimmune diabetes.
abstract: OBJECTIVE
  The aim of this study was to identify the predictive marker for early insulin requirement in adult-onset autoimmune diabetes in the Japanese populations.
  
  
  METHODS
  We analyzed insulin autoantibodies (IAA), insulinoma-associated antigen-2 (IA-2) autoantibodies (IA-2icA), and zinc transporter 8 (ZnT8) autoantibodies (ZnT8A) by radioimmunoassay in 47 Japanese patients with adult-onset autoimmune diabetes who were identified by native GAD autoantibody (nGADA) screening of approximately 3000 non-insulin-requiring diabetes patients and 302 nGADA-negative type 2 diabetes patients. Furthermore, GAD65 autoantibody-specific epitopes were also analyzed using GAD65/GAD67 chimeric constructs.
  
  
  RESULTS
  The prevalence of IAA, IA-2icA, and ZnT8A in nGADA-positive patients was 26, 15, and 19%, respectively, which was significantly higher than that in nGADA-negative type 2 diabetes (2, 2, and 2%; P < 0.0001). Among nGADA-positive patients, 38% had one or more of IAA, IA-2icA, or ZnT8A, and 15% had two or more of these autoantibodies, compared with none of the nGADA-negative patients (P < 0.0001). Thirty-six percent of nGADA-positive patients subsequently required insulin therapy; and high nGADA titer (log-rank P = 0.003), middle epitope recognition of GAD65A (P = 0.002), and the presence of one or more of IAA, IA-2icA, or ZnT8A (P = 0.002) at diagnosis marked the risk for early requirement of insulin therapy. Multivariate logistic regression analysis showed the multiple islet autoantibodies to be independently associated with the risk for insulin requirement (odds ratio = 13.77; 95% confidence interval, 2.77-68.45; P = 0.001).
  
  
  CONCLUSIONS
  These results indicate that the determination of IAA, IA-2icA, and ZnT8A improves the prediction of a future insulin insufficiency in adult-onset autoimmune diabetes, which appears to be superior to GADA titer and GAD65A-specific epitopes.
authors.affiliation: Department of Metabolism/Diabetes and Clinical Nutrition, Nagasaki University Hospital, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan. eijikawa@nagasaki-u.ac.jp
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawasaki
authors.forename: Kan
authors.initials: K
authors.lastname: Nakamura
authors.forename: Genpei
authors.initials: G
authors.lastname: Kuriya
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Satoh
authors.forename: Hironaga
authors.initials: H
authors.lastname: Kuwahara
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Norio
authors.initials: N
authors.lastname: Abiru
authors.forename: Hironori
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Katsumi
authors.initials: K
authors.lastname: Eguchi
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000097:blood*; D027682:Cation Transport Proteins / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000276:immunology* / Q000627:therapeutic use*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D000075703:Zinc Transporter 8
chemical_list: D001323:Autoantibodies; D027682:Cation Transport Proteins; C096322:ICA512 autoantibody; D007328:Insulin; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D005968:Glutamate Decarboxylase