EFFECT OF HIV-1 PROTEASE INHIBITORS ON ENDOTHELIAL FUNCTION AND GLUCOSE

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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. The overall objective of this proposal is to demonstrate that HIV-1 protease inhibitors (PI) will adversely affect cardiovascular risk factors due their effects on endothelial function and glucose and lipid metabolism.This exploratory analysis will be done in healthy volunteers so that it is free from the confounding effects of other antiretroviral drugs and from HIV infection itself. The introduction of PI drugs into routine clinical practice has resulted in unprecedented reductions in HIV-related mortality and opportunistic infections, but has been associated with marked abnormalities in glucose and lipid metabolism and alterations in body fat distribution. We will study 10 non obese, non hypertensive, non diabetic, HIV-negative subjects. All will be healthy, between the ages of 20 and 50 years, not pregnant, and not ingesting any drugs. Subjects will be studied on 2 occasions, once before and again at the end of 28-30 days of administration of the PI indinavir. Insulin secretion and whole- body glucose uptake will measured by the hyperglycemic clamp technique. Endothelium dependent and independent blood flow will be evaluated by invasive femoral arterial measurements. The following variables will compare between the baseline and 28-30 day evaluations: Fasting plasma glucose, insulin, c-peptide, whole-body glucose disposal rate, steady-state insulin secretion during hyperglycemia, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, free fatty acids, and changes in LBF in response to the graded drug infusion. Correlations between measures of glucose and lipid metabolism and measures of endothelial function will also be performed.