HLA-DRB1 * 08:03 -Associated Exocrine–Endocrine Immune Linkage: A Pathogenic Mechanism in Ketosis-Prone Type 2 Diabetes

Abstract Context Unprovoked ketosis-prone type 2 diabetes (KPD) is characterized by a male predominance, young age of onset, and abrupt presentation of diabetic ketosis/ketoacidosis without precipitating factors. Although many individuals regain β-cell function after insulin therapy, some progress to insulin dependence, suggesting overlap with type 1 diabetes. We previously reported the involvement of insulin-associated peptide-specific T helper 1 (Th1) responses in KPD pathogenesis. Exocrine pancreatic inflammation has been documented in type 1 diabetes, with evidence suggesting its contribution to disease development; however, its relevance to KPD remains unclear. Objective This cross-sectional study aimed to elucidate mechanisms underlying KPD by investigating the association between endocrine and exocrine immune responses. Methods We recruited 54 participants with KPD, assessed clinical parameters, including human leukocyte antigen (HLA)-DRB1/DQB1 genotypes, carbonic anhydrase II antibody levels, and insulin-associated peptide-specific Th1 responses, and explored their interrelationship. Results HLA-DRB1*08:03 frequency was significantly higher in participants with KPD than in historical healthy controls. Elevated exocrine pancreatic enzyme levels were observed in 29.6% (16/54) of cases. Carbonic anhydrase II antibody levels were increased in HLA-DRB1*08:03-positive participants, especially those with elevated exocrine pancreatic enzyme levels, and positively correlated with insulin-associated peptide-specific Th1 responses. Th1 responses were inversely associated with serum C-peptide levels in all participants, reflecting disease activity, but not in HLA-DRB1*08:03-positive participants. Conclusions HLA-DRB1*08:03 is possibly associated with endocrine and exocrine immune responses in KPD, mediating exocrine–endocrine immune linkage. However, it is unlikely to be directly involved in β-cell impairment via insulin-specific Th1 responses, potentially explaining reversible β-cell dysfunction in early KPD.