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

OBJECTIVEdKetosis-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 (“A2”) phenotypic forms: “A2b2 ” (lean, early onset, lack-ing b-cell functional reserve) and “A2b+ ” (obese, late onset, with substantial b-cell functional reserve after the index episode of DKA). Recent longitudinal analysis of a large KPD cohort revealed that the A2b+ phenotype includes two distinct subtypes distinguished by the index DKA episode having a defined precipitant (“provoked,”with progressive b-cell function loss over time) or no precipitant (“unprovoked, ” with sustained b-cell functional reserve). These three A2 KPD subtypes are characterized by absence of humoral islet autoimmune markers, but a role for cellular islet autoimmunity is unknown. RESEARCHDESIGNANDMETHODSdIslet-specific T-cell responses and the percent-age of proinflammatory (CD14+CD16+) blood monocytes were measured in A2b2 (n = 7), provoked A2b+ (n = 15), and unprovoked A2b+ (n = 13) KPD patients. Genotyping was performed for type 1 diabetes–associated HLA class II alleles. RESULTSdProvoked A2b+ and A2b2KPD patientsmanifested stronger islet-specific T-cel