ADAM17 Cleaves the Insulin Receptor α‐Subunit on Endothelial Cells and Induces Vascular Insulin Resistance in Type 2 Diabetes

Abstract

Microvascular insulin resistance is a hallmark of type 2 diabetes (T2D) and an underlying event in the pathophysiology of endothelial dysfunction and cardiovascular disease. However, the molecular mechanisms by which T2D causes vascular insulin resistance remain largely unknown. Hyperglycemia and the proinflammatory state associated with T2D are characterized, in part, by an increased activity of ADAM17, an enzyme that cleaves the ectodomain of various transmembrane proteins. Here, we hypothesized that increased expression and activation of ADAM17 sheds the insulin receptor α‐subunit (IRα) from endothelial cells causing vascular insulin resistance in T2D. We tested this hypothesis in isolated resistance arteries from T2D and non‐T2D subjects undergoing bariatric surgery and in cultured human umbilical vein endothelial cells (HUVECs). Resistance arteries from T2D subjects exhibited increased ADAM17 expression, reduced presence of endothelial IRα as well as the endogenous ADAM17 inhibitor, TIMP3, and impaired insulin‐induced vasodilation, relative to arteries from non‐T2D subjects (P<0.05). Exposure of HUVECs to high glucose (30mM, 24h) increased the expression and activity of ADAM17 (P<0.05), led to increased shedding of IRα detected in the cell culture media supernatant (P<0.05) and decreased IRα on cell surfaces as observed using super‐resolution microscopy. Moreover, pharmacological inhibition of ADAM17 led to reduced shedding of IRα and improved insulin signaling in cells exposed to high glucose or the ADAM17 activator, PMA (P<0.05). Collectively, these findings suggest that T2D, and in particular hyperglycemia, leads to ADAM17 shedding of IRα from the endothelial surface and reduced insulin‐dependent vasodilation, all of which supports ADAM17 activity as a new therapeutic target to ameliorate vascular insulin resistance in T2D.Support or Funding InformationResearch support: National Institutes of Health grants: R01 HL137769 (JP), R01 HL088105 (LM‐L).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.