ArticleAmerican journal of physiology. Heart and circulatory physiology2022
ADAM17 cleaves the insulin receptor ectodomain on endothelial cells and causes vascular insulin resistance.
Article in American journal of physiology. Heart and circulatory physiology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 18 citations in OpenAlex.
- Beneficial vascular effects of oral phosphatidylserine supplementation in type 2 diabetes.Journal of applied physiology (Bethesda, Md. : 1985) · 2026Trial
- 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
- EctoShed: a novel gene delivery platform for functional analysis of adipocyte-shed proteoforms.BMC research notes · 2026Article
- ADAM17-induced shedding of glypican-1 as a mechanism of impaired endothelial shear stress mechanotransduction.American journal of physiology. Cell physiology · 2026Article
- Obesity-induced pyroptotic adipocyte death leads to TREM2-dependent macrophage dysfunction and adipose tissue inflammation.iScience · 2026Article
- Novel insights into the central protective role of ACE2 in diabetic cardiomyopathy: from underlying signaling pathways to therapeutic perspectives.Molecular and cellular biochemistry · 2025Review
- Allosteric targeted drug delivery for enhanced blood-brain barrier penetration via mimicking transmembrane domain interactions.Nature communications · 2025Article
- Article
- Integrating molecular and cellular components of endothelial shear stress mechanotransduction.American journal of physiology. Heart and circulatory physiology · 2024Review
- Chronic intermittent hypoxia facilitates the development of angiotensin II-induced abdominal aortic aneurysm in male mice.Journal of applied physiology (Bethesda, Md. : 1985) · 2024Article
- Neuraminidase-induced externalization of phosphatidylserine activates ADAM17 and impairs insulin signaling in endothelial cells.American journal of physiology. Heart and circulatory physiology · 2024Article
- Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment.Current neuropharmacology · 2024Review
- Diabetic Endothelial Cell Glycogen Synthase Kinase 3β Activation Induces VCAM1 Ectodomain Shedding.International journal of molecular sciences · 2023Article
- New insights into mechanisms of endothelial insulin resistance in type 2 diabetes.American journal of physiology. Heart and circulatory physiology · 2022Review
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Inflammation and vascular insulin resistance are hallmarks of type 2 diabetes (T2D). However, several potential mechanisms causing abnormal endothelial insulin signaling in T2D need further investigation. Evidence indicates that the activity of ADAM17 (a disintegrin and metalloproteinase-17) and the presence of insulin receptor (IR) in plasma are increased in subjects with T2D. Accordingly, we hypothesized that in T2D, increased ADAM17 activity sheds the IR ectodomain from endothelial cells and impairs insulin-induced vasodilation. We used small visceral arteries isolated from a cross-sectional study of subjects with and without T2D undergoing bariatric surgery, human cultured endothelial cells, and recombinant proteins to test our hypothesis. Here, we demonstrate that arteries from subjects with T2D had increased ADAM17 expression, reduced presence of tissue inhibitor of metalloproteinase-3 (TIMP3), decreased extracellular IRα, and impaired insulin-induced vasodilation versus those from subjects without T2D. In vitro, active ADAM17 cleaved the ectodomain of the IRβ subunit. Endothelial cells with ADAM17 overexpression or exposed to the protein kinase-C activator, PMA, had increased ADAM17 activity, decreased IRα presence on the cell surface, and increased IR shedding. Moreover, pharmacological inhibition of ADAM17 with TAPI-0 rescued PMA-induced IR shedding and insulin-signaling impairments in endothelial cells and insulin-stimulated vasodilation in human arteries. In aggregate, our findings suggest that ADAM17-mediated shedding of IR from the endothelial surface impairs insulin-mediated vasodilation. Thus, we propose that inhibition of ADAM17 sheddase activity should be considered a strategy to restore vascular insulin sensitivity in T2D.
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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.