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Acute blockade by endothelin-1 of haemodynamic insulin action in rats


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Ross, RM ORCID: 0000-0001-8361-2712, Kolka, CM, Rattigan, S and Clark, MG 2007 , 'Acute blockade by endothelin-1 of haemodynamic insulin action in rats' , Diabetologia, vol. 50, no. 2 , pp. 443-451 , doi: 10.1007/s00125-006-0525-8.

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\(Aims/hypothesis\) Plasma levels of endothelin-1 are frequently elevated in patients with hypertension, obesity and type 2 diabetes. We hypothesise that this vasoconstrictor may prevent full perfusion of muscle, thereby limiting delivery of insulin and glucose and contributing to insulin resistance.
\(Materials\) \(and\) \(methods\) The acute effects of endothelin-1 on insulin-mediated haemodynamic and metabolic effects were examined in rats in vivo. Endothelin-1 (50 pmol min\(^{−1}\) kg\(^{−1}\) for 2.5 h) was infused alone, or 30 min prior to a hyperinsulinaemic-euglycaemic insulin clamp (10 mU min\(^{−1}\) kg\(^{−1}\) for 2 h). Insulin clamps (10 or 15 mU min\(^{−1}\) kg\(^{−1}\)) were performed after 30 min of saline infusion.
\(Results\) Endothelin-1 infusion alone increased plasma endothelin-1 11-fold (p<0.05) and blood pressure by 20% (p<0.05). Endothelin-1 alone had no effect on femoral blood flow, capillary recruitment or glucose uptake, but endothelin-1 with 10 mU min\(^{−1}\) kg\(^{−1}\) insulin caused a decrease in insulin clearance from 0.35±0.6 to 0.19± 0.02 ml/min (p=0.02), resulting in significantly higher plasma insulin levels (10 mU min\(^{−1}\) kg\(^{−1}\) insulin: 2,120± 190 pmol/l; endothelin-1+10 mU min\(^{−1}\) kg\(^{−1}\) insulin: 4,740± 910 pmol/l), equivalent to 15 mU min\(^{−1}\) kg\(^{−1}\) insulin alone (4,920±190 pmol/l). The stimulatory effects of equivalent doses of insulin on femoral blood flow, capillary recruitment and glucose uptake were blocked by endothelin-1.
\(Conclusions/interpretation\) Endothelin-1 blocks insulin’s haemodynamic effects, particularly capillary recruitment, and is associated with decreased muscle glucose uptake and glucose infusion rate. These findings suggest that elevated endothelin-1 levels may contribute to insulin resistance of muscle by increasing vascular resistance and limiting insulin and glucose delivery.

Item Type: Article
Authors/Creators:Ross, RM and Kolka, CM and Rattigan, S and Clark, MG
Keywords: Capillary recruitment . 2-Deoxyglucose uptake . Endothelin-1-mediated hypertension . Femoral blood flow . 1-Methylxanthine metabolism . Muscle insulin action
Journal or Publication Title: Diabetologia
Publisher: Springer
ISSN: 0012-186X
DOI / ID Number: 10.1007/s00125-006-0525-8
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