Islet-specific T-cell responses and proinflammatory monocytes define subtypes of autoantibody-negative ketosis-prone diabetes

Diabetes Care. 2013 Dec;36(12):4098-103. doi: 10.2337/dc12-2328. Epub 2013 Oct 15.


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.

Research design and 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Autoantibodies / immunology*
  • Biomarkers / blood
  • Child
  • DNA / genetics
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology*
  • Diabetic Ketoacidosis / blood
  • Diabetic Ketoacidosis / genetics
  • Diabetic Ketoacidosis / immunology*
  • Female
  • Follow-Up Studies
  • Genotype
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / immunology
  • Humans
  • Immunoblotting
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / pathology
  • Male
  • Middle Aged
  • Monocytes / immunology*
  • Monocytes / pathology
  • Phenotype
  • Real-Time Polymerase Chain Reaction
  • T-Lymphocytes / immunology*
  • Young Adult


  • Autoantibodies
  • Biomarkers
  • HLA-DR Antigens
  • DNA