Abstract 15804: Hyperinsulinemia Disrupts Vascular Homeostasis, Enhances Oxidative Stress and Impairs Flow Induced Dilation of Human Skeletal Muscle Arterioles
Insulin resistance promotes vascular endothelial dysfunction (VED) and subsequent development of cardiovascular disease. At physiological levels, insulin maintains balance between vasodilators, mainly nitric oxide (NO), and endothelin-1 (ET-1), a potent vasoconstrictor. We hypothesized that hyperinsulinemia (HI) associated with insulin resistance contributes to VED via augmenting ET-1, disrupting ET-1/endothelial NO synthase (eNOS) balance and subsequently impairing flow induced dilation (FID) in human skeletal muscle (SkM) arterioles. To further help explain the link between HI and VED, we examined expression of extracellular superoxide dismutase (SOD3) . Muscle biopsies were performed on 18 lean healthy controls (LHC: Age 30.7±1.9 y, BMI 22.3±0.6 kg/m2, M: 6.6±0.4 mg/kg/min) and 8 obese, type 2 diabetics (OB: Age 59.6±0.3, BMI 35±2.2 kg/m2, M: 2.4±0.3 mg/kg/min) before and after a 40 mU/m2/min hyperinsulinemic clamp. SkM protein was probed for ET-1, eNOS and SOD3. In a subset of OB (n=6) and LHC (n=5), the internal diameter of isolated arterioles was measured before and during intraluminal flow with an increasing pressure gradient. FID (% of dilation at [[Unable to Display Character: ∆]]60 pressure gradient) was impaired with HI in LHC (basal: 74.2±2.0; insulin: 57.2±3.3, p=0.003) and OB (basal: 62.1±3.6; insulin: 48.5±5.6, p=0.04). ET-1 expression was increased during HI in LHC (0.63±0.04) and OB (0.86±0.05) compared to basal conditions (LHC: 0.44±0.05, p=0.01; OB: 0.69±0.05, p=0.01). eNOS showed a marked increase in muscle of LHC under HI (basal: 0.66±0.06; insulin: 0.91±0.11, p=0.008) however, no changes were observed in OB. Consequently, the ET-1/eNOS ratio was increased in OB subjects though preserved in LHC. Furthermore, HI reduced SOD3 levels in both LHC (basal: 1.27±0.26; insulin: 0.69±0.06, p=0.03) and OB (basal: 0.64±0.09, insulin: 0.49±0.04, p=0.08) suggesting increased oxidative stress. This was supported by data from human primary microvascular cell cultures, showing that superoxide (O2• [[Unable to Display Character: ‒]]) was increased 3 folds in response to insulin (10 nmol/L). In conclusion, HI may induce VED via (1) disturbing the ET-1/eNOS balance favoring vasoconstriction during obesity when the NOS pathway is compromised and (2) inducing oxidative stress.
Author Disclosures: A.M. Mahmoud: None. M.R. Szczurek: None. A.T. Robinson: None. J.T. Mey: None. B.K. Blackburn: None. J. Bian: None. M.D. Brown: None. P.A. Shane: None. J.M. Haus: None.
- © 2014 by American Heart Association, Inc.