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Principal Investigator: Luis A Martinez-Lemus
Organization: UNIVERSITY OF MISSOURI-COLUMBIA
Fiscal Year: 2024
Award: $667,915
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Vascular insulin resistance is a hallmark of type 2 diabetes (T2D) and dampening of insulin-induced
vasodilation is its primary consequence. Notably, in T2D, reduced insulin-stimulated vasodilation and blood
flow to tissues such as skeletal muscle significantly limits glucose uptake and contributes to impaired glucose
control. A detailed understanding of the precipitating factors and mechanisms underlying the defects in
vasodilator actions of insulin is critical for the development of therapeutic strategies aimed at improving
glycemic control and protecting against cardiovascular disease. Based on our prior work and most recent and
exciting preliminary data, we propose the novel hypothesis that ADAM17-mediated shedding of the insulin
receptor alpha (IRα) from endothelial cells impairs insulin-stimulated vasodilation in T2D. We further propose
that the increased activity of endothelial ADAM17 is attributed to protein kinase-C (PKC) activation and
subsequent externalization of phosphatidylserine (PS) to the outer leaflet of the cell membrane, which serves
to guide ADAM17 to its targeted substrates. As exogenous PS is a competitive inhibitor of ADAM17 sheddase
activity, we will also determine the efficacy of oral administration of PS for restoring vascular insulin sensitivity
in T2D patients. We will test our innovative hypotheses with gain- and loss-of-function genetic-manipulation
experiments in human cultured endothelial cells, in isolated resistance arteries harvested from patients
undergoing abdominal surgery, and in patients with T2D. Experimental results will determine the role of PS
externalization-ADAM17 activation-IRα shedding as a mechanism impairing the vasodilatory actions of insulin
in T2D. Specifically, in Aim 1, we will determine the mechanism by which PKC causes the externalization of
PS and whether PS externalization is needed for PKC-dependent activation of ADAM17 in endothelial cells.
Next, in Aim 2, we will determine the role of ADAM17 activity in IRα shedding and subsequent impairment of
insulin-stimulated vasodilation in T2D. Finally, in Aim 3, we will perform a randomized double-blind clinical trial
to determine the therapeutic efficacy of oral administration of the competitive inhibitor of ADAM17 sheddase
activity, PS, on insulin-stimulated leg blood flow in patients with T2D. Our team is poised to move
cardiovascular and diabetes research forward with a project that will exert a sustained, powerful impact across
a number of levels of inquiry that are novel conceptually, mechanistically, methodologically, and
therapeutically. Indeed, this proposal represents a paradigm shift from our current mechanistic understanding
of vascular insulin resistance. Targeting ADAM17 activation holds extraordinary promise for correcting
vascular insulin resistance and ultimately preventing/treating T2D-associated metabolic and cardiovascular
diseases.
Terms: <Abdomen><Adult-Onset Diabetes Mellitus><American><Animal Model><Animal Models and Related Studies><Arteries><Biopsy><Blood Vessels><Blood flow><Body Tissues><Calcium Phospholipid-Dependent Protein Kinase><Calcium-Activated Phospholipid-Dependent Kinase><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell membrane><Cell surface><Clinical Trials><Cytoplasmic Membrane><Data><Defect><Diabetes Mellitus><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Down-Regulation><Endogenous Nitrate Vasodilator><Endothelial Cells><Endothelium><Endothelium-Derived Nitric Oxide><Enzyme Gene><Enzymes><Euglycemic Clamping><Exhibits><Glucose Clamp><Goals><Harvest><Healthcare><Heart Vascular><Human><Humulin R><Hyperinsulinemia><Hyperinsulinism><Impairment><Insulin><Insulin Receptor><Insulin Receptor Protein-Tyrosine Kinase><Insulin Resistance><Insulin Signaling Pathway><Insulin-Dependent Tyrosine Protein Kinase><Integral Membrane Protein><Intervention><Intervention Strategies><Intrinsic Membrane Protein><Ketosis-Resistant Diabetes Mellitus><Leg><MMPs><Matrix Metalloproteinases><Maturity-Onset Diabetes Mellitus><Mediating><Metabolic Diseases><Metabolic Disorder><Methodology><Modern Man><Mononitrogen Monoxide><NIDDM><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Operative Procedures><Operative Surgical Procedures><Oral Administration><Oral Drug Administration><Pathogenesis><Patients><Phosphatidylserines><Phospholipid-Sensitive Calcium-Dependent Protein Kinase><Plasma Membrane><Precipitating Factors><Prevalence><Production><Protein Kinase C><Publishing><Randomized><Receptor Protein><Regular Insulin><Research><Resistance><Role><Serine Phosphoglycerides><Skeletal Muscle><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Surface><Surgical><Surgical Interventions><Surgical Procedure><T2 DM><T2D><T2DM><Testing><Therapeutic><Thesaurismosis><Tissues><Transmembrane Protein><Transmembrane Protein Gene><Treatment Efficacy><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vascular Endothelium><Vasodilatation><Vasodilating Agent><Vasodilation><Vasodilator Agents><Vasodilator Drugs><Vasodilators><Vasorelaxation><Voluntary Muscle><Work><adult onset diabetes><blood glucose regulation><cardiovascular disorder><circulatory system><determine efficacy><diabetes><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><endothelial cell derived relaxing factor><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><experiments><extracellular><gain of function><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><glucose control><glucose homeostasis><glucose regulation><glucose uptake><glycemic control><health care><improved><inhibitor><innovate><innovation><innovative><insulin resistant><insulin sensitivity><insulin signaling><insulin tolerance><intervention efficacy><interventional strategy><intraoral drug delivery><ketosis resistant diabetes><loss of function><maturity onset diabetes><metabolism disorder><model of animal><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><non-diabetic><nondiabetic><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><overexpress><overexpression><plasmalemma><preservation><prevent><preventing><randomisation><randomization><randomly assigned><receptor><resistant><response><social role><surgery><therapeutic agent development><therapeutic development><therapeutic efficacy><therapy efficacy><type 2 DM><type II DM><type two diabetes><vascular><vascular bed>