Patients with T2D remain at high risk of cardiovascular (CV) events despite adequate glycemic and LDL-C control. Changes in HDL particle composition and function may explain part of this increased CV risk. The aim of this study was to determine the proteomic composition of isolated HDL particles in T2D patients, and establish which factors contribute to these abnormalities. Patients (n=213) with and without T2D were included in the study and underwent an OGTT, liver MRS, and routine blood chemistries. Advanced lipid testing and lipoprotein subfractions were measured by ion mobility. ApoA-I containing particles (i.e., HDL) were isolated and a novel targeted proteomic approach using multiple reaction monitoring (MRM) by liquid chromatography and tandem mass spectrometry (LC-MS/MS) was undertaken to measure HDL-bound proteins. Patients with (n=146) vs. without (n=67) T2D were older (56±9 vs. 47±12) , more obese (34.2±4.7 vs. 32.6±5.3 kg/m2) , but had no significant differences in other important clinical characteristics, such as gender or race. Patients with T2D had lower HDL-C (38±9 vs. 43±13 mg/dl, p<0.001) , but no difference in the number of HDL particles. A panel of 28 HDL-bound proteins were targeted and quantified by MRM LC-MS/MS. After correction for multiple comparisons (false discovery rate set at 5%) and adjustment for obesity and NAFLD, 4 proteins were found to be decreased in T2D patients (ApoA-I, ApoC-I, ApoM, and PON3; all p<0.0015) . The pCAD index (well-validated score for coronary artery disease and CV mortality based on HDL-bound proteins) was increased in patients with T2D, irrespectively of obesity or NAFLD (93±15 vs. 61±38, p<0.0001) .
In conclusion, patients with T2D showed significant differences in the apolipoproteomic composition of HDL particles, and this translated into increased CV risk based on pCAD index. Different HDL composition and function may explain the residual CV risk of patients with T2D optimally treated for hyperglycemia and LDL-C.
F.Bril: None. R.Pearce: Employee; Quest Diagnostics. T.S.Collier: Employee; Quest Diagnostics, Stock/Shareholder; Quest Diagnostics. S.Kalavalapalli: None. M.J.Mcphaul: Employee; Quest Diagnostics. K.Cusi: Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Fractyl Health, Inc., Genentech, Inc., Hanmi Pharm. Co., Ltd., Intercept Pharmaceuticals, Inc., Novo Nordisk.
American Diabetes Association (1-08-CR-08) ; The Obesity Society (Early-Career Research Grant) Veterans Affairs (1 I01 CX000167-01) . UF CTSI (UL1TR001427)