PCOS is characterized by (1) endothelial dysfunction and (2) resistance to the vasodilating action of insulin. This endothelial dysfunction appears to be associated with both elevated androgen levels and insulin resistance. Given the central vasoprotective role of endothelium, these findings could explain, at least in part, the increased risk for macrovascular disease in women with PCOS.

The effect and time course of free fatty acid (FFA) elevation on insulin-mediated vasodilation (IMV) and the relationship of FFA elevation to changes in insulin-mediated glucose uptake was studied. Two groups of lean insulin-sensitive subjects underwent euglycemic-hyperinsulinemic (40 mU · m -2 · min -1 ) clamp studies with and without superimposed FFA elevation on 2 occasions ~4 weeks apart. Groups differed only by duration of FFA elevation, either short (2-4 h, n = 12) or long (8 h, n = 7). On both occasions, rates of whole-body glucose uptake were measured, and changes in leg blood flow (LBF) and femoral vein nitric oxide nitrite plus nitrate (NOx) flux in response to the clamps were determined. Short FFA infusion did not have any significant effect on the parameters of interest. In contrast, long FFA infusion decreased rates of whole-body glucose uptake from 47.7 ± 2.8 to 32.2 ± 0.6 µmol · kg -1 · min -1 (P < 0.01), insulin-mediated increases in LBF from 66 ± 8 to 37 ± 7% (P < 0.05), and insulin-induced increases in NOx flux from 25 ± 9 to 5 ± 9% (P < 0.05). Importantly, throughout all groups, FFAinduced changes in whole-body glucose uptake correlated significantly with FFA-induced changes in insulin-mediated increases in LBF (r = 0.706, P < 0.001), which indicates coupling of metabolic and vascular effects. In a different protocol, short FFA elevation blunted the LBF response to N G -monomethyl-L-arginine (L-NMMA), which is an inhibitor of NO synthase. LBF in response to L-NMMA decreased by 17.3 ± 2.4 and 9.0 ± 1.4% in the groups without and with FFA elevation, respectively (P < 0.05), which indicates that FFA elevation interferes with shear stress-induced NO production. Thus, impairment of shear stress-induced vasodilation and IMV by FFA elevation occurs with different time courses, and impairment of IMV occurs only if glucose metabolism is concomitantly reduced. These findings suggest that NO production in response to the different stimuli may be mediated via different signaling pathways. FFA-induced reduction in NO production may contribute to the higher incidence of hypertension and macrovascular disease in insulin-resistant patients.

Background-Obesity is a more potent cardiovascular risk factor (CVRF) in men than in women. Because traditional CVRFs cannot fully account for this sex difference, we tested the hypothesis that compared with men, women exhibit more robust endothelial function independent of obesity and that this sex difference is abrogated by diabetes. Methods and Results-We studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of the endothelium-dependent vasodilator methacholine chloride (Mch) and the endothelium-independent vasodilator sodium nitroprusside (SNP) in groups of lean, obese (OB), and type II diabetic (DM) premenopausal women and age-and body mass index-matched men. LBF response to intrafemoral administration of L-NMMA, an inhibitor of nitric oxide synthase, was also assessed in normal men and women. Maximum LBF increments in response to Mch were 347Ϯ57% versus 231Ϯ22% in lean women versus men (PϽ0.05) and 203Ϯ25% versus 111Ϯ17% in OB women versus men (PϽ0.01), respectively. In DM, maximum LBF increments in response to Mch were 104Ϯ24% and 138Ϯ33% in women and men, respectively, (PϭNS). LBF decrements in response to L-NMMA were 34.9Ϯ4.1% and 17.1Ϯ4.2% in women and men, respectively (PϽ0.01). The response to SNP was not different between sexes and groups. Conclusions-Premenopausal nondiabetic women exhibit more robust endothelium-dependent vasodilation owing to higher rates of nitric oxide release than men. Given the protective vascular action of nitric oxide, this difference may partially explain the lower incidence of macrovascular disease in women. In premenopausal women, DM causes impairment of endothelial function beyond that observed with obesity alone and leads to endothelial dysfunction similar to that observed in DM men. These findings may help explain the similar rates of coronary artery disease and mortality in diabetic men and women.