The prevalence of type 2 diabetes (T2D) is increasing by alarming proportions in the US and worldwide. Over the last two decades, the number of new cases of diabetes has almost tripled in the US and current projections estimate that one in three Americans will have diabetes by 2050. The effects of vascular insulin resistance are particularly important at the level of resistance arteries, where a diminished insulin-induced vasodilation limits blood perfusion and delivery of circulating insulin and glucose to tissues. However, the specific mechanisms by which endothelial insulin signaling is impaired in T2D remain largely unknown. Hyperglycemia is a hallmark component of T2D and cumulative research shows that exposure to high glucose levels induces protein kinase-C (PKC) activation in endothelial cells. In turn, PKC is considered a primary activator of a disintegrin and matrix metalloproteinase-17 (ADAM17, enzyme that cleaves the ectodomain of various transmembrane proteins and releases the soluble ectodomains from the cell surface) in multiple cell types including endothelial cells. This scenario is also consistent with the idea that the activation of PKC and ADAM17 are implicated in microvascular insulin resistance, since previous data showed that high glucose induces ADAM17-mediated shedding of insulin receptor ±-subunit (IR±) via PKC activation, which in turn reduces the capacity of insulin to stimulate endothelial cells. However, the capacity of ADAM17 to shed IR± from the surface of endothelial cells and its functional outcomes are not known and will be determined in human endothelial cells and isolated resistance arteries. Thus, the specific aim of this proposal is to determine the role of hyperglycemia in the expression and activity of ADAM17, and the shedding of IR± in microvascular endothelium. We hypothesize that in cultured endothelial cells and in isolated arteries from the omentum vasculature of obese non-T2D patients undergoing bariatric surgery, high glucose activates PKC, which in turn upregulates ADAM17 expression and activity with the subsequent shedding of IR±. We further hypothesize that inhibition of PKC and/or ADAM17 in endothelial cells cultured in high glucose, or in isolated arteries from obese T2D patients undergoing bariatric surgery will reduce ADAM17-dependent shedding of IR± and restore insulin signaling. Our approach is to test our working hypotheses in gain- and loss-of-function experiments using physiological, pharmacological and genetic strategies to manipulate the expression and activity of PKC and ADAM17. Thus, targeting ADAM17 activity holds extraordinary promise for correcting microvascular insulin resistance and ultimately preventing/treating T2D-associated metabolic and cardiovascular diseases.
News published in Agência FAPESP Newsletter about the scholarship:
RAMIREZ-PEREZ, I, FRANCISCO; CABRAL-AMADOR, FRANCISCO J.; WHALEY-CONNELL, ADAM T.; AROOR, ANNAYYA R.; MORALES-QUINONES, MARIANA; WOODFORD, MAKENZIE L.; GHIARONE, THAYSA; FERREIRA-SANTOS, LARISSA; JURRISSEN, THOMAS J.; MANRIQUE-ACEVEDO, CAMILA M.; et al. ystamine reduces vascular stiffness in Western diet-fed female mic. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 322, n. 2, p. H167-H180, FEB 2022. (18/18854-0)
Please report errors in scientific publications list using