Open AccessHyperinsulinemia augments endothelin‐1 protein expression and impairs vasodilation of human skeletal muscle arterioles
Author(s) -
Mahmoud Abeer M.,
Szczurek Mary R.,
Blackburn Brian K.,
Mey Jacob T.,
Chen Zhenlong,
Robinson Austin T.,
Bian JingTan,
Unterman Terry G.,
Minshall Richard D.,
Brown Michael D.,
Kirwan John P.,
Phillips Shane A.,
Haus Jacob M.
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12895
Subject(s) - hyperinsulinemia , medicine , endocrinology , enos , skeletal muscle , insulin resistance , insulin , basal (medicine) , vasodilation , nitric oxide synthase , nitric oxide
Hyperinsulinemia is a hallmark of insulin resistance‐associated metabolic disorders. Under physiological conditions, insulin maintains a balance between nitric oxide ( NO ) and, the potent vasoconstrictor, endothelin‐1 ( ET ‐1). We tested the hypothesis that acute hyperinsulinemia will preferentially augment ET ‐1 protein expression, disrupt the equilibrium between ET ‐1 expression and endothelial NO synthase ( eNOS ) activation, and subsequently impair flow‐induced dilation ( FID ) in human skeletal muscle arterioles. Skeletal muscle biopsies were performed on 18 lean, healthy controls ( LHC s) and 9 older, obese, type 2 diabetics (T2 DM ) before and during (120 min) a 40 mU/m 2 /min hyperinsulinemic‐euglycemic (5 mmol/L) clamp. Skeletal muscle protein was analyzed for ET ‐1, eNOS , phosphorylated eNOS (p‐ eNOS ), and ET ‐1 receptor type A ( ETAR ) and B ( ETBR ) expression. In a subset of T2 DM ( n = 6) and LHC s ( n = 5), FID of isolated skeletal muscle arterioles was measured. Experimental hyperinsulinemia impaired FID (% of dilation at ∆60 pressure gradient) in LHC s (basal: 74.2 ± 2.0; insulin: 57.2 ± 3.3, P = 0.003) and T2 DM (basal: 62.1 ± 3.6; insulin: 48.9 ± 3.6, P = 0.01). Hyperinsulinemia increased ET ‐1 protein expression in LHC s (0.63 ± 0.04) and T2 DM (0.86 ± 0.06) compared to basal conditions ( LHC s: 0.44 ± 0.05, P = 0.007; T2 DM : 0.69 ± 0.06, P = 0.02). Insulin decreased p‐ eNOS (serine 1177) only in T2 DM (basal: 0.28 ± 0.07; insulin: 0.17 ± 0.04, P = 0.03). In LHC s, hyperinsulinemia disturbed the balance between ETAR and ETBR receptors known to mediate vasoconstrictor and vasodilator actions of ET ‐1, respectively. Moreover, hyperinsulinemia markedly impaired plasma NO concentration in both LHC s and T2 DM . These data suggest that hyperinsulinemia disturbs the vasomotor balance in human skeletal muscle favoring vasoconstrictive pathways, eventually impairing arteriolar vasodilation.