Beneficial vascular effects of oral phosphatidylserine supplementation in type 2 diabetes

Endothelial insulin resistance is a characteristic of type 2 diabetes (T2D) that contributes to reduced nitric oxide bioavailability, impaired vasodilation, and arterial stiffening. We recently provided evidence that endothelial insulin resistance in T2D may be attributed to the shedding of insulin receptors by ADAM17. As prior work by others suggested that exogenous phosphatidylserine (PS) can competitively inhibit ADAM17, we hypothesized that oral PS supplementation would improve vascular function in diabetes. First, we corroborated the ability of PS to interact with and inhibit ADAM17 activity using in vitro approaches and experiments in isolated arteries. Next, we tested the vascular effects of PS in diabetic mice (db/db) and subsequently in individuals with T2D through a randomized, double-blind, placebo-controlled clinical trial. In a cell-free system, we found that soluble PS binds to ADAM17 and blunts its activity, an effect also observed in cultured endothelial cells and isolated arteries, underscoring its inhibitory capacity. In diabetic mice, oral administration of PS (200 mg/kg/day for 4 wk) improved insulin-induced dilation in isolated resistance arteries and reduced ex vivo and in vivo indices of arterial stiffness. In individuals with T2D, PS supplementation (900 mg/day for 4 wk, delivering ∼280 mg/day PS) enhanced leg blood flow responses to an oral glucose load and reduced load-dependent aortic pulse wave velocity. Lastly, we observed that PS reduced vascular oxidative stress. This work supports the potential of oral PS as a therapeutic strategy to improve vascular function in T2D and suggests that the beneficial effects of PS may be driven by its vascular insulin-sensitizing and antioxidant actions.NEW & NOTEWORTHY The sheddase activity of a disintegrin and matrix metalloproteinase 17 (ADAM17) is augmented in the setting of type 2 diabetes (T2D), likely contributing to the shedding of the extracellular domain of the insulin receptor on the arterial endothelial surface, leading to endothelial dysfunction. Findings from this work support the notion that exogenous phosphatidylserine can inhibit arterial ADAM17 activity and improve markers of vascular health in diabetic mice and humans with diabetes.