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Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production
Ist Teil von
Diabetes (New York, N.Y.), 2000-07, Vol.49 (7), p.1231-1238
Ort / Verlag
Alexandria, VA: American Diabetes Association
Erscheinungsjahr
2000
Quelle
MEDLINE
Beschreibungen/Notizen
Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production.
H O Steinberg ,
G Paradisi ,
G Hook ,
K Crowder ,
J Cronin and
A D Baron
Department of Medicine, Indiana University School of Medicine, and the Richard L. Roudebush Veterans Affairs Medical Center,
Indianapolis, USA.
Abstract
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 x m(-2) x min(-1)) clamp studies with and without superimposed FFA elevation
on 2 occasions approximately 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 micromol x kg(-1) x 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, FFA-induced 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 NG-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.