The functionality of high-density lipoproteins is impaired in people with diabetes who require minor amputations

Objective: High-density lipoprotein (HDL) functionality is emerging as a novel predictor of disease outcomes. The role of HDL functionality in patients with diabetes-related amputations is unexplored. We aimed to assess changes in HDL functionality in people with diabetes who had minor amputations and to determine the relationship between HDL functionality and wound closure (WC). Approach: Thirty patients with diabetes mellitus (DM) and 11 without (non-DM) undergoing minor amputations were recruited. Blood was collected at baseline (DM, n = 30; non-DM, n = 11), 1 month (DM, n = 22; non-DM, n = 5), and 6 months (DM, n = 14; non-DM, n = 3) postamputation and from 20 healthy gender- and age-matched control participants. HDL was isolated from plasma and functionality markers of macrophage cholesterol efflux, and anti-inflammatory and proangiogenic capacities in endothelial cells were assessed. The study adhered to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Results: HDL-cholesterol (HDL-c) levels positively correlated with WC (r = 0.44, p < 0.05). Cholesterol efflux capacity of DM HDL was reduced 1-month postamputation (−44% vs. non-DM HDL, d = −1.5, p < 0.05). Following inflammatory stimulation, DM HDL-treated cells had elevated levels of C-X3-C motif chemokine ligand 1 (+92%, d = 0.9), C-C motif chemokine ligand 2 (+49%, d = 0.8), vascular cell adhesion molecule 1 (+67%, d = 0.9), and intracellular adhesion molecule 1 (+58%, d = 0.9) (vs. non-DM HDL, p < 0.05). The capacity of endothelial cells to form tubules reduced linearly with time following DM HDL treatment (p < 0.05), concomitant with reduced vascular endothelial growth factor A (−47% vs. non-DM HDL, d = −1.2, p < 0.05). Endothelial cells treated with HDL from participants with delayed WC (<50%, 1-month postamputation) exhibited increased v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) expression (+52%, d = 1.2, p < 0.05). The impairment of HDL functionality in DM was concomitant with reduced apolipoprotein AI (−34%, d = 1.2) and paraoxonase 1 (−32%, d = −1.3, vs. non-DM, p < 0.05) protein in HDL 1-month postamputation. Innovation: An HDL panel, including HDL-c and HDL functionality and composition, could be used in early screening to identify patients who may benefit from early therapeutic intervention, guiding wound care management. Conclusion: Impaired HDL functionality, mediated through changes in HDL composition, may contribute to delayed wound healing.