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Role of ADAM17 in mediating vascular insulin resistance in type 2 diabetes

Grant number: 18/18854-0
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): February 01, 2019
Effective date (End): October 31, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Maria Urbana Pinto Brandão Rondon
Grantee:Larissa Ferreira dos Santos
Supervisor abroad: Luis Aruro Martinez-Lemus
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
Local de pesquisa : University of Missouri, Columbia (UM), United States  
Associated to the scholarship:17/24605-0 - Influence of microRNAs in angiogenic and antiangiogenic factors in the pathway of vascular endothelial growth factor in patients with Coronary Artery Disease, BP.DR

Abstract

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.

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