Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production

Helmut Steinberg, Giancarlo Paradisi, Ginger Hook, Kristin Crowder, Jessica Cronin, Alain D. Baron

Research output: Contribution to journalArticle

277 Citations (Scopus)

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-hyper-insulinemic (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, 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 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.

Original languageEnglish (US)
Pages (from-to)1231-1238
Number of pages8
JournalDiabetes
Volume49
Issue number7
DOIs
StatePublished - Jan 1 2000

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Nonesterified Fatty Acids
Vasodilation
Nitric Oxide
Insulin
Leg
Glucose
omega-N-Methylarginine
Femoral Vein
Nitrites
Nitric Oxide Synthase
Nitrates
Blood Vessels
Arginine
Hypertension

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. / Steinberg, Helmut; Paradisi, Giancarlo; Hook, Ginger; Crowder, Kristin; Cronin, Jessica; Baron, Alain D.

In: Diabetes, Vol. 49, No. 7, 01.01.2000, p. 1231-1238.

Research output: Contribution to journalArticle

Steinberg, Helmut ; Paradisi, Giancarlo ; Hook, Ginger ; Crowder, Kristin ; Cronin, Jessica ; Baron, Alain D. / Free fatty acid elevation impairs insulin-mediated vasodilation and nitric oxide production. In: Diabetes. 2000 ; Vol. 49, No. 7. pp. 1231-1238.
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