Free fatty acid elevation impairs insulin-mediated vasodilation and nitricoxide production

The effect and time course of free fatty acid (FFA) elevation on insulin-me diated 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) . m in(-1)) clamp studies with and without superimposed FFA elevation on 2 occa sions similar to 4 weeks apart. Groups differed only by duration of FFA ele vation, either short (2-4 h, n = 12) or long (8 h, n = 7). On both occasion s, rates of whole-body glucose uptake were measured, and changes in leg blo od 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 FF A infusion decreased rates of whole-body glucose uptake from 47.7 +/- 2.8 t o 32.2 +/- 0.6 mu mol . kg(-1) . min(-1) (P < 0.01), insulin-mediated incre ases in LBF from 66 +/- 8 to 37 +/- 7% (P < 0.05), and insulin-induced incr eases in NOx flux from 25 +/- 9 to 5 +/- 9% (P < 0.05). Importantly, throug hout all groups, FFA-induced changes in whole-body glucose uptake correlate d significantly with FFA-induced changes in insulin-mediated increases in L BF (r = 0.706, P < 0.001), which indicates coupling of metabolic and vascul ar effects. In a different protocol, short FFA elevation blunted the LBF re sponse to N-G-monomethyl-L-arginine (L-NMMA), which is an inhibitor of NO s ynthase. 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), w hich indicates that FFA elevation interferes with shear stress-induced NO p roduction. Thus, impairment of shear stress-induced vasodilation and IMV by FFA elevation occurs with different time courses, and impairment of IMV oc curs only if glucose metabolism is concomitantly reduced. These finding sug gest that NO production in response to the different stimuli may be mediate d via different signaling pathways. FFA-induced reduction in NO production may contribute to the higher incidence of hypertension and macrovascular di sease in insulin-resistant patients.