title: Islet-specific T-cell responses and proinflammatory monocytes define subtypes of autoantibody-negative ketosis-prone diabetes.
abstract: OBJECTIVE
  Ketosis-prone diabetes (KPD) is characterized by diabetic ketoacidosis (DKA) in patients lacking typical features of type 1 diabetes. A validated classification scheme for KPD includes two autoantibody-negative ("A-") phenotypic forms: "A-β-" (lean, early onset, lacking β-cell functional reserve) and "A-β+" (obese, late onset, with substantial β-cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A-β+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant ("provoked," with progressive β-cell function loss over time) or no precipitant ("unprovoked," with sustained β-cell functional reserve). These three A- KPD subtypes are characterized by absence of humoral islet autoimmune markers, but a role for cellular islet autoimmunity is unknown.
  
  
  METHODS
  Islet-specific T-cell responses and the percentage of proinflammatory (CD14+CD16+) blood monocytes were measured in A-β- (n = 7), provoked A-β+ (n = 15), and unprovoked A-β+ (n = 13) KPD patients. Genotyping was performed for type 1 diabetes-associated HLA class II alleles.
  
  
  RESULTS
  Provoked A-β+ and A-β- KPD patients manifested stronger islet-specific T-cell responses (P < 0.03) and higher percentages of proinflammatory CD14+CD16+ monocytes (P < 0.01) than unprovoked A-β+ KPD patients. A significant relationship between type 1 diabetes HLA class II protective alleles and negative T-cell responses was observed.
  
  
  CONCLUSIONS
  Provoked A-β+ KPD and A-β- KPD are associated with a high frequency of cellular islet autoimmunity and proinflammatory monocyte populations. In contrast, unprovoked A-β+ KPD lacks both humoral and cellular islet autoimmunity.
authors.affiliation: Corresponding authors: Barbara M. Brooks-Worrell, bbrooks@u.washington.edu.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Brooks-Worrell
authors.forename: Dinakar
authors.initials: D
authors.lastname: Iyer
authors.forename: Ivonne
authors.initials: I
authors.lastname: Coraza
authors.forename: Christiane S
authors.initials: CS
authors.lastname: Hampe
authors.forename: Ramaswami
authors.initials: R
authors.lastname: Nalini
authors.forename: Kerem
authors.initials: K
authors.lastname: Ozer
authors.forename: Radhika
authors.initials: R
authors.lastname: Narla
authors.forename: Jerry P
authors.initials: JP
authors.lastname: Palmer
authors.forename: Ashok
authors.initials: A
authors.lastname: Balasubramanyam
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D002648:Child; D004247:DNA / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D016883:Diabetic Ketoacidosis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D015151:Immunoblotting; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D006684:HLA-DR Antigens; D004247:DNA