Altered small dense LDL profiles in long-standing controlled type 1 diabetes

Introduction Small dense low-density lipoprotein (sdLDL) is a highly atherogenic LDL subclass associated with cardiovascular disease (CVD). While type 1 diabetes confers increased cardiovascular risk despite adequate glycemic control, the role of sdLDL and its regulators remains unclear. Methods In this cross-sectional observational study, plasma from 69 individuals with long-standing type 1 diabetes and 24 healthy controls was analyzed. sdLDL-cholesterol (sdLDL-C) concentration, sdLDL-C/LDL-cholesterol ratio, LDL size and subclasses were assessed using homogeneous assays, NMR spectroscopy, and gradient gel electrophoresis. Apolipoprotein C3 (ApoC3), hepatic lipase (HL), endothelial lipase (EL), and cholesteryl ester transfer protein (CETP) activity were measured by immunoturbidimetric, ELISA and functional assays. Results Despite adequate glycemic control (mean HbA1c 7.6% [60 mmol/mol]) and near-normal lipid levels, individuals with type 1 diabetes had significantly higher sdLDL-C (0.56 ± 0.28 mmol/L vs 0.43 ± 0.26 mmol/L), increased sdLDL-C/LDL-cholesterol ratio (0.20 ± 0.08 vs 0.12 ± 0.06) and smaller LDL particle size (26.32 ± 1.08 nm vs 26.81 ± 0.68 nm) compared with controls. ApoC3 and HL mass/activity were significantly increased (8.67 ± 3.22 mg/dL vs 6.53 ± 2.42; 46.60 ± 16.12 ng/mL vs 15.45 ± 7.40 ng/mL and 1.03 ± 0.24 U/mL vs 0.89 ± 0.23 U/mL; respectively), CETP activity significantly reduced (808.8 ± 197.0 pmol/mL/h vs 929.7 ± 149.6 pmol/mL/h), and endothelial lipase levels unchanged. sdLDL-C positively correlated with ApoC3 (r = 0.7517) and inversely with CETP activity (r = -0.2682). Conclusion Long-standing type 1 diabetes with adequate glycemic control is associated with an atherogenic sdLDL profile despite near-normal conventional lipid levels. This first multi-method characterization study of sdLDL in type 1 diabetes highlights the contribution of ApoC3, CETP and HL to sdLDL-C enrichment and suggests that direct assessment of sdLDL may improve cardiovascular risk stratification.