Clinical Significance of Insulin Peptide–specific Interferon-γ–related Immune Responses in Ketosis-prone Type 2 Diabetes

Abstract

Abstract Context Unprovoked A−β+ ketosis-prone type 2 diabetes (KPD) is characterized by the sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies (“A−”), and preservation of β-cell function (“β+”) after recovery from DKA. Although this phenotype often appears with acute hyperglycemia and DK/DKA just like acute-onset type 1 diabetes (AT1D), the involvement of anti-islet immune responses remains unknown. Objective We sought to clarify the immunological role of insulin-associated molecules in unprovoked A−β+ KPD. Methods In this cross-sectional study, blood samples from 75 participants (42 with AT1D and 33 with KPD) were evaluated for interferon (IFN)-γ–secreting peripheral blood mononuclear cells (PBMCs) reactive to 4 insulin B-chain amino acid 9-23–related peptides (B:9-23rPep) using an enzyme-linked immunospot (ELISpot) assay. Results Overall, 36.4% (12/33) of KPD participants showed positive IFN-γ ELISpot assay results; the positivity rate in KPD was similar to that in AT1D (38.1%; 16/42) and statistically significantly higher than the previously reported rate in type 2 diabetes (8%; 2/25; P < .0167). Moreover, B:9-23rPep-specific IFN-γ–producing PBMC frequency was negatively correlated with age and ad lib serum C-peptide levels in all KPD participants and positively correlated with glycated hemoglobin A1c level in KPD participants with positive IFN-γ ELISpot results. Conclusion These findings suggest the involvement of B:9-23rPep–specific IFN-γ–related immunoreactivity in the pathophysiology of some unprovoked A−β+ KPD. Moreover, increased immunoreactivity may reflect transiently decreased β-cell function and increased disease activity at the onset of DK/DKA, thereby playing a key role in DK/DKA development in this KPD phenotype.