5123 Remission of Antibodies Blocking the Insulin Receptor Reduces Atherogenicity of LDL Particles but Increases HDL Particle Atherogenicity

Abstract Disclosure: M. Hwang: None. R. Shamburek: None. M. Lightbourne: None. M. Sampson: None. A. Remaley: None. B. Abel: None. R.J. Brown: None. Background: Type B insulin resistance syndrome (TBIR) is a rare autoimmune disorder defined by the presence of autoantibodies against the insulin receptor, usually in the context of systemic autoimmune diseases such as lupus. In TBIR, insulin signaling is disrupted at the receptor-level, resulting in failure of insulin to both suppress hepatic glucose production and to stimulate de novo lipogenesis. This leads to a phenotype of extreme insulin resistance (IR) and hyperglycemia without dyslipidemia. IR and hyperglycemia resolve when remission of the autoantibody is induced by immunosuppression. Given the known association between IR and cardiovascular disease (CVD), we sought to compare biomarkers of CVD risk using lipoprotein particles measured by Nuclear Magnetic Resonance (NMR) in patients with TBIR during their active disease state vs remission. Methods: Patients with TBIR (N=14) had fasting labs including NMR lipoprotein profiles (analyzed using LP4 deconvolution algorithm) during active disease (positive antibodies to the insulin receptor and severe IR) and remission (defined by discontinuation of insulin or amelioration of hyperglycemia). Particle size (nm) and concentration of subclasses by size were measured for low-density lipoprotein (LDL) particles (nmol/L) and high-density lipoprotein (HDL) particles (umol/L). Results: Upon remission from TBIR, there were large decreases in hemoglobin A1c (from 10.9±3.0% to 6.1±1.1%, p<0.001) and insulin (from 1000.0 (715.9, 1000.0) mcU/mL to 16.8 (8.1, 39.2) mcU/mL, normal 2.6-24.9 mcU/mL, p<0.001), and increases in BMI (from 21.8±3.5 to 28.6±7.4 kg/m2, p<0.01), C3 (from 76±27 to 114±20 mg/dL, normal 82-185 mg/dL, p<0.01), and C4 (from 16±8 to 25±9 mg/dL, normal 15-53 mg/dL, p<0.01). After remission of TBIR, LDL profiles became less atherogenic: small LDL particle concentration decreased (from 523.4±170.2 to 362.8±119.7, normal 63.8-1719.6, p<0.01) and LDL particle size increased (from 20.6±0.5 to 21.2±0.3, normal 19.9 -21.6, p<0.01). By contrast, HDL profiles became more atherogenic after remission of TBIR: small HDL particle concentration increased (from 4.6±2.6 to 8.2±4.3, normal 6.6-19.3, p<0.01); the largest HDL particle concentration decreased (from 1.5±0.8 to 0.7±0.7, normal 0-1.2, p<0.01), and HDL particle size decreased (from 10.3±0.4 to 9.6±0.5, normal 8.4-9.9, p<0.001). Conclusions: Active TBIR is a pro-inflammatory state characterized by excess consumption of C3 and C4. Inflammation may contribute to an unfavorable LDL particle profile that improves after remission. However, lack of insulin signaling through the insulin receptor during active TBIR likely leads to an anti-atherogenic HDL profile that returns to normal levels when insulin signaling is restored after remission. Future studies will further investigate the role of insulin resistance and inflammation in CVD risk. Presentation: 6/3/2024