ADAM17 Cleaves the Insulin Receptor Ectodomain on Endothelial Cells and Induces Vascular Insulin Resistance

Abstract

Despite efforts to reduce the incidence of type 2 diabetes (T2D) and its cardiovascular consequences, T2D‐associated cardiovascular mortality continues to rise in the US and worldwide. The presence of a pro‐inflammatory state and microvascular insulin resistance are hallmarks of T2D that contribute to cardiovascular disease. The former is associated with increased activity of ADAM17, an enzyme that cleaves the ectodomain of multiple transmembrane proteins, while the latter is characterized by decreased insulin‐induced vasodilatory responses. However, the specific mechanisms, including the potential role(s) of ADAM17, underlying vascular insulin resistance in T2D, remain unknown. We hypothesize that in T2D, increased expression and activation of ADAM17 sheds the insulin receptor ectodomain (IRα) from endothelial cells and thus impairs insulin‐induced vasodilation. We tested this hypothesis using isolated small visceral arteries from T2D and non‐T2D subjects undergoing bariatric surgery and cultured human endothelial cells. Results indicate that arteries from subjects with T2D exhibit increased ADAM17 expression, reduced presence of TIMP3 (the endogenous inhibitor of ADAM17), decreased extracellular IRα, and impaired insulin‐induced vasodilation in comparison with arteries from non‐T2D subjects (P<0.05). In vitro, ADAM17 cleaved insulin receptor recombinant proteins at a specific extracellular site of the IRβ subunit (p<0.05). Exposure of endothelial cells to the PKC activator, PMA, increased the shedding activity of ADAM17 (P<0.05) and decreased the presence of IRα on cell surfaces occupied by ADAM17, as observed using super‐resolution microscopy. Moreover, pharmacological inhibition of ADAM17 with TAPI‐0 rescued PMA‐induced impairments in insulin signaling in endothelial cells and insulin‐stimulated vasodilation in human small visceral arteries (P<0.05). Collectively, these findings suggest that ADAM17‐mediated shedding of IR ectodomains from the endothelial surface impairs insulin‐mediated vasodilation. Therefore, inhibition of ADAM17 sheddase activity should be considered a potential new therapeutic strategy to restore vascular insulin sensitivity in T2D.Support or Funding InformationResearch support: National Institutes of Health grants: R01 HL137769 (JP), R01 HL088105 (LM‐L).