The long-term objective of this grant has been to define the role played by resistance to insulin-mediated glucose disposal (and the abnormalities related to this fundamental defect) in the genesis of coronary heart disease (CHD). The studies outlined in this proposal will attempt to show that the metabolic abnormalities associated with insulin resistance (Syndrome X) have adverse effects on endothelial vasodilator reactivity and the interaction between monocytes and the endothelium that represent early stages in the process of atherogenesis. Studies will be performed in normal subjects and patients with either impaired glucose tolerance or hypertension, further sub-divided into insulin sensitive and insulin resistant subjects. A variety of experimental variables will be measured at baseline in order to define multiple facets of their glucose, insulin, and lipoprotein metabolism. In addition, we plan to characterize alterations in endothelial function by quantifying nitric oxide and cyclic GMP concentrations, and brachial artery vasodilatory responses to endothelium-dependent and endothelium-independent stimuli. Furthermore, the investigators will perform ex vivo and in vitro studies of determinants of endothelial-monocyte interactions. Following these baseline comparisons, all subjects will begin a 10-week period in which two diets will be consumed, in a randomly assigned, cross-over design. The diets will be similar, with the exception that in one diet carbohydrate will be substituted for saturated fat (CHO), whereas in the other diet primarily mono- and poly-unsaturated fat will be substituted for saturated fat (MF/PF). Based upon previous results, it is known that the abnormalities in glucose, insulin, and lipoprotein metabolism present in insulin resistant subjects will be accentuated by the CHO diet and attenuated by the MF/PF diet, with relatively little change seen in the insulin sensitive subjects. At the end of each dietary period, all baseline tests will be repeated. The results of the measurements following dietary manipulation will provide an even more sensitive means to further evaluate the effect of differences in insulin resistance, and its associated metabolic abnormalities, on brachial artery vasodilator responses and factors regulating endothelial-monocyte interaction, as modified by variations in glucose tolerance status and blood pressure. As such, this study will provide considerable new knowledge relevant to the link between Syndrome X and atherogenesis.
| Stuhlinger, Markus C; Abbasi, Fahim; Chu, James W et al. (2002) Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 287:1420-6 |
