This K23 application is aimed at promoting career development through a structured, mentored program. This award will allow the development of expertise in the area of cardiovascular pharmacogenomics and functional genomics by characterizing variability in the cardiometabolic responses of beta-blockers among individuals with diabetes. Despite numerous advances made in the treatment of cardiovascular disease (CVD), morbidity and mortality remain unacceptably high, particularly among people with diabetes. The optimization of drug therapy is critical in patients with CVD and type 2 diabetes, as these patients 1) experience a particularly aggressive disease process, 2) are often resistant to traditional CVD pharmacotherapies, and 3) bear a disproportionate burden of CVD. The factors contributing to poor outcomes experienced by diabetic individuals remain largely unknown. Some commonly prescribed CV medications, such as beta-blockers, have adverse metabolic profiles, the mechanisms of which are not completely understood, that may dampen their ability to prevent adverse outcomes in some patients. It is important to identify which patients may experience this attenuation of drug benefit, and pharmacogenomics provides the opportunity to characterize the genetic contribution to inter-patient variability in drug responses. The mitochpndrial uncoupling proteins (UCPs) have been suggested to play a role in CVD, diabetes, and obesity through their effects on oxidative stress, insulin sensitivity, and energy expenditure. The genes that encode the UCPs are of high priority as candidate genes in explaining the discrepancy in outcomes experienced by diabetic patients compared to non-diabetic patients and may contribute to beta-blockers'mechanism of benefit or to their adverse effects on lipid metabolism. The studies proposed herein represent a prospective pharmacogenetic study with extensive phenotyping in diabetic patients designed to provide insight into the mechanism and validation of our previous association with UCP polymorphisms and adverse beta-blocker outcomes. In doing this mechanistically-driven validation study, we are laying the framework for translating our findings into clinical practice. Specifically, this project aims to: 1) compare cardiac function in response to beta-blocker treatment using sensitive imaging techniques by UCP2-3 genotypes, 2) determine whether 24-hour free fatty acid (FFA) kinetics in response to beta-blocker therapy differ among individuals with diabetes by UCP2-3 genotypes, and 3) evaluate the functional consequences of UCP2-3 polymorphisms which may contribute to differences in response to CV medications. This study has important public health implications in that CVD is the leading cause of death in diabetes. By better understanding why some patients with diabetes respond more favorably to CV therapies than others, we may be able to more appropriately treat individual patients, thereby improving outcomes.
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