NextGen Precision Health, University of Missouri, Columbia, Missouri, United States.
Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri, United States.
Am J Physiol Heart Circ Physiol. 2024 Jan 1;326(1):H270-H277. doi: 10.1152/ajpheart.00638.2023. Epub 2023 Nov 24.
Endothelial insulin resistance represents a causal factor in the pathogenesis of type 2 diabetes (T2D) and vascular disease, thus the need to identify molecular mechanisms underlying defects in endothelial insulin signaling. We previously have shown that a disintegrin and metalloproteinase-17 (ADAM17) is increased while insulin receptor α-subunit (IRα) is decreased in the vasculature of patients with T2D, leading to impaired insulin-induced vasodilation. We have also demonstrated that ADAM17 sheddase activity targets IRα; however, the mechanisms driving endothelial ADAM17 activity in T2D are largely unknown. Herein, we report that externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane causes ADAM17-mediated shedding of IRα and blunting of insulin signaling in endothelial cells. Furthermore, we demonstrate that endothelial PS externalization is mediated by the phospholipid scramblase anoctamin-6 (ANO6) and that this process can be stimulated by neuraminidase, a soluble enzyme that cleaves sialic acid residues. Of note, we demonstrate that men and women with T2D display increased levels of neuraminidase activity in plasma, relative to age-matched healthy individuals, and this occurs in conjunction with increased ADAM17 activity and impaired leg blood flow responses to endogenous insulin. Collectively, this work reveals the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D. This work provides the first evidence that neuraminidase, an enzyme increased in the circulation of men and women with type 2 diabetes (T2D), promotes anoctamin-6 (ANO6)-dependent externalization of phosphatidylserine in endothelial cells, which in turn leads to activation of a disintegrin and metalloproteinase-17 (ADAM17) and consequent shedding of the insulin receptor-α from the cell surface. Hence, this work supports that consideration should be given to the neuraminidase-ANO6-ADAM17 axis as a novel potential target for restoring endothelial insulin sensitivity in T2D.
内皮细胞胰岛素抵抗是 2 型糖尿病（T2D）和血管疾病发病机制中的一个因果因素，因此需要确定内皮细胞胰岛素信号转导缺陷的分子机制。我们之前已经表明，在 T2D 患者的血管中，解整合素和金属蛋白酶 17（ADAM17）增加，而胰岛素受体α亚基（IRα）减少，导致胰岛素诱导的血管舒张受损。我们还证明了 ADAM17 脱落酶活性靶向 IRα；然而，T2D 中内皮细胞 ADAM17 活性的驱动机制在很大程度上尚不清楚。在此，我们报告称，质膜外叶的磷脂酰丝氨酸（PS）外化导致 ADAM17 介导的 IRα 脱落和胰岛素信号转导钝化在血管内皮细胞中。此外，我们证明内皮细胞 PS 外化是由磷脂 scramblase anoctamin-6（ANO6）介导的，并且这个过程可以被神经氨酸酶刺激，神经氨酸酶是一种能切割唾液酸残基的可溶性酶。值得注意的是，我们证明 T2D 男性和女性的血浆中神经氨酸酶活性水平高于年龄匹配的健康个体，并且这种情况与 ADAM17 活性增加和内源性胰岛素引起的腿部血流反应受损同时发生。总的来说，这项工作揭示了神经氨酸酶-ANO6-ADAM17 轴作为恢复 T2D 内皮细胞胰岛素敏感性的一个新的潜在靶点。这项工作首次提供了证据，证明神经氨酸酶，一种在 2 型糖尿病（T2D）男性和女性循环中增加的酶，促进了内皮细胞中磷脂酰丝氨酸的 anoctamin-6（ANO6）依赖性外化，进而导致了 a 分裂素和金属蛋白酶 17（ADAM17）的激活，从而导致胰岛素受体-α从细胞表面脱落。因此，这项工作支持将神经氨酸酶-ANO6-ADAM17 轴作为恢复 T2D 内皮细胞胰岛素敏感性的一个新的潜在靶点。
