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


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Ross, RM and Kolka, CM and Rattigan, S and Clark, MG (2007) Acute blockade by endothelin-1 of haemodynamic insulin action in rats. Diabetologia, 50 (2). pp. 443-451. ISSN 0012-186X

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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
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
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
Page Range: pp. 443-451
ISSN: 0012-186X
Identification Number - DOI: 10.1007/s00125-006-0525-8
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Date Deposited: 07 Apr 2008 14:12
Last Modified: 18 Nov 2014 03:33
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