This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glucocorticoids are commonly used to treat numerous medical conditions. Unfortunately, these agents cause numerous side effects including diabetes and hypertension. The underlying mechanisms are unknown. The transcription factoe PPARalpha is expressed at high levels in liver, is induced by glucocortioids, and controls the expression of several genes involved in lipin metabolism. Mice deficient in PPARalpha are protected fro the development of insulin resistance, diabetes and hypertension induced by the glucocorticoid dexamethasone. This project with translate these daatta to humans. Healthy subjects will undergo hyperinsulinemic-euglycemic clamps to measure insulin sensitivity and forearm blood flow testing before and after short-term dexamethasone treatment in the presence and absence of activation of PPARalpha using micronized fenofibrate. We predict that treatment with both dexamethasone adn fenofibrate will result in greater hepatic glucose production and blood pressure thatn treatment with dexamethasone alone. This experiment has the potential to identify the mechanism of steroid-induced insulin resistance in humans.
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