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document
Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans . Endogenous endothelin action is augmented in human obesity and type 2 diabetes and contributes to endothelial dysfunction and impairs insulin-mediated vasodilation in humans . We hypothesized that insulin resistance-associated hyperinsulinemia could preferentially drive endothelin-mediated vasoconstriction . We applied hyperinsulinemic-euglycemic clamps with higher insulin dosing in obese subjects than lean subjects ( 30 vs. 10 mU.m ( -2 ) .min ( -1 ) , respectively ) , with the goal of matching insulin 's nitric oxide ( NO ) -mediated vascular effects . We predicted that , under these circumstances , insulin-stimulated endothelin-1 ( ET-1 ) action ( assessed with the type A endothelin receptor antagonist BQ-123 ) would be augmented in proportion to hyperinsulinemia . NO bioactivity was assessed using the nitric oxide synthase inhibitor N ( G ) -monomethyl-l-arginine . Insulin-mediated vasodilation and insulin-stimulated NO bioavailability were well matched across groups by this approach . As expected , steady-state insulin levels were approximately threefold higher in obese than lean subjects ( 109.2 +/- 10.2 pmol/l vs. 518.4 +/- 84.0 , P = 0.03 ) . Despite this , the augmentation of insulin-mediated vasodilation by BQ-123 was not different between groups . ET-1 flux across the leg was not augmented by insulin alone but was increased with the addition of BQ-123 to insulin ( P = 0.01 BQ-123 effect , P = not significant comparing groups ) . Endothelin antagonism augmented insulin-stimulated NO bioavailability and NOx flux , but not differently between groups and not proportional to hyperinsulinemia . These findings do not support the hypothesis that insulin resistance-associated hyperinsulinemia preferentially drives endothelin-mediated vasoconstriction .
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Intervention_Pharmacological
hyperinsulinemic-euglycemic clamps
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Intervention_Pharmacological
insulin
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Intervention_Pharmacological
Insulin-mediated
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Outcome_Physical
endothelin-mediated vasoconstriction
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Outcome_Physical
NO bioactivity
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Outcome_Physical
Insulin-mediated vasodilation
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Outcome_Physical
insulin-stimulated NO bioavailability
37750
Outcome_Physical
steady-state insulin levels
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Outcome_Physical
insulin-mediated vasodilation
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Outcome_Physical
ET-1 flux
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Outcome_Physical
insulin-stimulated NO bioavailability
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Outcome_Physical
NOx flux
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Outcome_Physical
endothelin-mediated vasoconstriction
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Participant_Condition
obese subjects
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Participant_Condition
lean subjects
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Participant_Sample-size
30
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Participant_Sample-size
10