Islet-Specific T-Cell Responses and Proinflammatory Monocytes Define Subtypes of Autoantibody-Negative Ketosis-Prone Diabetes

OBJECTIVEKetosis-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-- (lean, early onset, lacking -cell functional reserve) and A-+ (obese, late onset, with substantial -cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A-+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant (provoked, with progressive -cell function loss over time) or no precipitant (unprovoked, with sustained -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 METHODSIslet-specific T-cell responses and the percentage of proinflammatory (CD14+CD16+) blood monocytes were measured in A-- (n = 7), provoked A-+ (n = 15), and unprovoked A-+ (n = 13) KPD patients. Genotyping was performed for type 1 diabetes-associated HLA class II alleles.RESULTSProvoked A-+ and A-- 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-+ KPD patients. A significant relationship between type 1 diabetes HLA class II protective alleles and negative T-cell responses was observed.CONCLUSIONSProvoked A-+ KPD and A-- KPD are associated with a high frequency of cellular islet autoimmunity and proinflammatory monocyte populations. In contrast, unprovoked A-+ KPD lacks both humoral and cellular islet autoimmunity.