Acute Blockade by Endothelin-1 of Haemodynamic Insulin Action in Rats.
From: Biochemistry, School of Medicine, University of Tasmania, Private Bag 58, Hobart, 7001, Australia.
Diabetologia
- Publish Date: Feb 2007
- ISSN: 0012-186X
- Volume: 50
- Issue: 2
- Pages: 443-51
- Medium: Print
- Language: English
- Citation (JAMA): Ross R M, Kolka C M, Rattigan S, et al. Acute Blockade by Endothelin-1 of Haemodynamic Insulin Action in Rats.. Diabetologia Feb 2007;50:443-51
Abstract
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.
Mesh Headings (Keywords): Allopurinol, Animals, Blood Glucose, Blood Pressure, Endothelin-1, Glucose Clamp Technique, Insulin, Insulin Antagonists, Male, Rats, Rats, Wistar
Check for Full Text / PubMed Unique Identifier (PMID): 17187249
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