title: Clinical and Genetic Characteristics of Non-Insulin-Requiring Glutamic Acid Decarboxylase (GAD) Autoantibody-Positive Diabetes: A Nationwide Survey in Japan.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Yasui
authors.affiliation: Department of Endocrinology and Metabolism, Nagasaki University Hospital, Nagasaki, Japan.|Department of Diabetes and Endocrinology, Shin-Koga Hospital, Kurume, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kawasaki
authors.affiliation: Third Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Diabetes, Endocrinology and Metabolism, International University of Health and Welfare Hospital, Tochigi, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Awata
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ikegami
authors.affiliation: Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Imagawa
authors.affiliation: Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Uchigata
authors.affiliation: Department of Laboratory Medicine, Ehime University School of Medicine, Ehime, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Osawa
authors.affiliation: Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kajio
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Kawabata
authors.affiliation: Department of Internal Medicine, Saiseikai Central Hospital, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.affiliation: Department of Diabetes and Metabolism, Iwate Medical University, Iwate, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Metabolic Disorder, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Division of Health Sciences, Department of Community Health Sciences, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Department of Internal Medicine (I), Osaka Medical College, Takatsuki, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hanafusa
authors.affiliation: Okinaka Memorial Institute for Medical Research, Tokyo, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D017668:Age of Onset; D000368:Aged; D001323:Autoantibodies / Q000276:immunology*; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology*; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005968:Glutamate Decarboxylase / Q000276:immunology*; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000627:therapeutic use*; D007564:Japan; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012372:ROC Curve; D011795:Surveys and Questionnaires
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D007328:Insulin; D005968:Glutamate Decarboxylase