Insulin Receptor Family Autoantibodies in Patients with Type B insulin Resistance

Abstract Objective Type B insulin resistance (TBIR) is a rare autoimmune disorder characterized by insulin resistance (IR) secondary to insulin receptor autoantibodies (InsR-aAb). A paucity of clinical InsR-aAb assays and incomplete mechanistic understanding complicate diagnosis. This study aimed to (1) validate clinical performance of an immune-luminometric InsR-aAb assay in a relatively large cohort; (2) evaluate its diagnostic accuracy and define thresholds for TBIR diagnosis; (3) evaluate autoantibody profiles against InsR, type 1 IGF receptor (IGF-1R), and the insulin receptor-related receptor (IRRR) in TBIR and non-autoimmune IR. Research Design and Methods We conducted a cross-sectional analysis of patients with TBIR and non-autoimmune IR. InsR-aAb, IGF-1R-aAb, and IRRR-aAb titers were measured using receptor-specific immune-luminometric assays. ROC analyses assessed diagnostic performance of the InsR-aAb assay. Multivariate regression models evaluated associations between autoantibody titers and biomarkers of glycemia (HbA1c, glucose, insulin), growth (IGF-1 z-score IGF-1z), and pH regulation (bicarbonate, urine pH). Results In TBIR, higher InsR-aAb titers associated with increased HbA1c, glucose, insulin, and lower IGF-1z (all p0.0001); higher IRRR-aAb titers with lower CO₂ (p=0.04). An optimal InsR-aAb cutoff for distinguishing TBIR from non-autoimmune IR was determined (AUC 0.96, sensitivity 91.3%, specificity 93.9%). In non-autoimmune IR, autoantibody titers were not associated with glycemia biomarkers; IGF-1z increased with mild IR (p=0.005) and decreased with severe IR (p=0.01). Conclusion This study validates an InsR-aAb assay in the largest TBIR cohort to date and identifies a novel association between IRRR-aAb and bicarbonate excretion. While InsR-aAb were detected in other IR disorders, pathogenic effects were specific to TBIR.