The iRhom2-ADAM17 Axis as a Mechanism of Endothelial Insulin Resistance

Endothelial insulin resistance, a hallmark of obesity and type 2 diabetes, plays a key role in the pathogenesis of cardiovascular disease. Our previous work identified ADAM17-mediated shedding of the insulin receptor from the endothelial surface as a novel mechanism contributing to impaired insulin actions in the vasculature. Because ADAM17 is a highly promiscuous sheddase with more than 80 known substrates, understanding its regulation is critical for therapeutic targeting. Part of ADAM17’s regulation includes its maturation and trafficking by the inactive rhomboid (iRhom) proteins, of which iRhom2 is strongly associated with inflammatory signaling. Given that vascular inflammation is commonly coupled with endothelial insulin resistance, herein we hypothesized that iRhom2 promotes ADAM17-dependent cleavage of the insulin receptor. We examined the role of the iRhom2-ADAM17 axis in both telomerase-immortalized human aortic and human umbilical vein endothelial cells. Data are expressed as mean ± standard error of the mean, and differences determined using t-tests or two-way analysis of variance with a post-hoc Bonferonni test, as appropriate. All differences reported herein are significant at P≤0.05. We provide evidence that iRhom2 is present in endothelial cells and, when overexpressed (9.31 ± 0.90-fold increase compared to control, n=12/condition), promotes the insertion of mature ADAM17 into the plasmalemma (1.71 ± 0.11-fold increase compared to control, n=6/condition). We further show that cells overexpressing ADAM17 (2.33 ± 0.22-fold increase compared to control, n=12/condition) have fewer insulin receptors on their membrane (0.82 ± 0.02-fold difference of control, n=6-8/condition), a reduction rescued by incubation with the ADAM17 inhibitor TAPI-0 (0.98 ± 0.03-fold difference of control, n=6-9/condition). No difference was observed when control cells were incubated with TAPI-0 (0.98 ± 0.04-fold difference of control, n=8-9/condition). These findings suggest that iRhom2 may contribute to endothelial insulin resistance by trafficking ADAM17 to the cell membrane and regulating its sheddase activity. Targeting iRhom2-dependent trafficking mechanisms may represent a promising therapeutic strategy to mitigate ADAM17-mediated disruption of endothelial insulin signaling. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.