Type 2 diabetes (T2D) is characterized by endothelial insulin resistance, a factor contributing to overall vascular dysfunction, including reduced nitric oxide bioavailability, impaired vasodilation, and arterial stiffening. We recently provided evidence supporting the hypothesis that endothelial insulin resistance in T2D may be partly attributed to the shedding of insulin receptors by a disintegrin and metalloproteinase-17 (ADAM17). As prior work by others using cell culture models suggested that exogenous phosphatidylserine (PS) can competitively inhibit ADAM17, we hypothesized that oral PS supplementation would improve overall vascular function in diabetes. First, we corroborated the ability of PS to inhibit ADAM17 activity using in vitro approaches and experiments in isolated arteries. Next, we tested the vascular effects of PS in diabetic mice and subsequently in individuals with T2D through a randomized, double-blinded, placebo-controlled clinical trial. All data were tested for normality before performing statistical analyses, including Student's t tests or two-way ANOVA repeated measures, followed by Bonferroni post hoc testing when appropriate. Data are expressed as means±SEM, and P≤0.05 was considered significant for all analyses. In a cell-free-based assay, endothelial cells (HUVECs), and isolated mesenteric resistance arteries from male mice, water-soluble PS blunted ADAM17 activity, underscoring its capability as an inhibitor. In db/db male mice, oral administration of PS (200 mg/kg/day for 4 weeks) enhanced insulin-induced dilation in isolated resistance arteries (n=8-9/group; 79.4±8.83 vs. 43.4±13.6 %) and reduced in vivo and ex vivo arterial stiffness indices, including pulse wave velocity (PWV; n=9-10/group; 2.24±0.04 vs. 2.57±0.11 m/s), aortic endothelial cell stiffness measured by atomic force microscopy (n=8-9/group; 6.63±0.52 vs. 8.19±0.55 kPa), and the incremental modulus of elasticity in aortas (n=7-9/group; 8.37±0.29 vs. 10.30±0.66 dyn/cm2), femoral arteries (n=9-10/group; 3.83±0.47 vs. 7.83±0.94 dyn/cm2), and mesenteric arteries (n=9-10/group; 10.74±0.78 vs. 15.02±1.32 dyn/cm2), all assessed using pressure myography. Similarly, in individuals with T2D (Placebo: n=18, M/F=11/7; PS: n=16, M/F=10/6), PS supplementation (900 mg/day for 4 weeks) enhanced leg blood flow responses to an oral glucose load (n=16/group; 3.10±0.67 vs. 1.00±0.73 AUC fold difference) and reduced carotid-femoral PWV (n=15-18/group; 8.14±0.35 vs. 8.63±0.44 m/s). Taken together, this work supports the potential of oral PS as a therapeutic approach to improve vascular function in T2D, and suggests that the beneficial effects of PS may be driven in part by its vascular insulin-sensitizing effects. L.A.M.-L. and J.P. are supported by the National Institutes of Health grant: R01HL151384. FIR-P is supported by the American Heart Association 25DIVSUP1463861. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Ramirez-Perez et al. (2026) studied this question.