ArticleAmerican journal of physiology. Heart and circulatory physiology2024
Neuraminidase-induced externalization of phosphatidylserine activates ADAM17 and impairs insulin signaling in endothelial cells.
Article in American journal of physiology. Heart and circulatory physiology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 4 citations in OpenAlex.
- Beneficial vascular effects of oral phosphatidylserine supplementation in type 2 diabetes.Journal of applied physiology (Bethesda, Md. : 1985) · 2026Trial
- Impact of dietary supplementation of glycocalyx precursors on vascular function in type 2 diabetes.Journal of applied physiology (Bethesda, Md. : 1985) · 2024Trial
- Going with the flow: endothelial dysfunction in type 2 diabetes.Function (Oxford, England) · 2026Article
- Endothelial CD44 cleavage by ADAM17 impairs shear stress mechanotransduction.Function (Oxford, England) · 2026Article
- ADAM17-induced shedding of glypican-1 as a mechanism of impaired endothelial shear stress mechanotransduction.American journal of physiology. Cell physiology · 2026Article
- Analysis and Validation of Mitophagy-Related Genes in Diabetic Foot Ulcers.Journal of inflammation research · 2025Article
- Reduced cofilin activity as a mechanism contributing to endothelial cell stiffening in type 2 diabetes.American journal of physiology. Heart and circulatory physiology · 2025Article
- Integrating molecular and cellular components of endothelial shear stress mechanotransduction.American journal of physiology. Heart and circulatory physiology · 2024Review
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Authors and funding
12 authors at 2 institutions in 1 country.
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Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.