Journal of the Endocrine Society · 2026
HLA-DRB1*08:03-associated exocrine-endocrine immune linkage: a pathogenic mechanism in ketosis-prone type 2 diabetes.
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Suzuki Seiya, Oikawa Yoichi, Satomura Atsushi, Haisa Akifumi, Nakanishi Shumpei, Fujisawa Masashi, Morita Hideo, Katsuki Takeshi, Shimada Akira
Аннотация
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 (CA2) 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. CA2 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.
CONCLUSION: 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.
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 (CA2) 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. CA2 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.
CONCLUSION: 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.