Regulation of Glucose Uptake by Endothelin-1 in Human Skeletal Muscle in Vivo and in Vitro

• Published in: The journal of clinical endocrinology and metabolism Vol. 95; no. 5; pp. 2359 - 2366
• Main Authors: Shemyakin, Alexey, Salehzadeh, Firoozeh, Böhm, Felix, Al-Khalili, Lubna, Gonon, Adrian, Wagner, Henrik, Efendic, Suad, Krook, Anna, Pernow, John
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.05.2010; Copyright by The Endocrine Society
• Subjects: Biological and medical sciences; Biological Transport; Blood Glucose - analysis; Body Mass Index; Brachial Artery; C-Reactive Protein - metabolism; Endocrinopathies; Endothelin-1 - administration & dosage; Endothelin-1 - pharmacology; Endothelin-1 - physiology; Feeding. Feeding behavior; Forearm - blood supply; Fundamental and applied biological sciences. Psychology; Glucose - metabolism; Glycated Hemoglobin A - analysis; Humans; Hypertension - metabolism; Infusions, Intra-Arterial; Insulin - administration & dosage; Insulin - blood; Insulin - pharmacology; Insulin Resistance - physiology; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Muscle, Skeletal - metabolism; Oligopeptides - administration & dosage; Oligopeptides - pharmacology; Peptides, Cyclic - administration & dosage; Peptides, Cyclic - pharmacology; Piperidines - administration & dosage; Piperidines - pharmacology; Regional Blood Flow; Triglycerides - blood; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology; Human; Obesity; Nutrition; Nutrition disorder; Metabolic diseases; Endothelin 1; Glucose; Striated muscle; In vitro; Uptake; In vivo; Regulation(control); Endocrinology; Nutritional status
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2009-1506

Context: Expression of the vasoconstrictor and proinflammatory peptide endothelin (ET)-1 is increased in insulin-resistant (IR) subjects. Objective: The aim of this study was to investigate whether ET-1 regulates skeletal muscle glucose uptake in IR subjects in vivo and in cultured human skeletal muscle cells. Design and Participants: Eleven subjects participated in three protocols using brachial artery infusion of: A) BQ123 (10 nmol/min) and BQ788 (10 nmol/min) (ETA and ETB receptor antagonist, respectively), followed by coinfusion with insulin (0.05 mU/kg/min); B) insulin alone; and C) insulin followed by coinfusion with ET-1 (20 pmol/min). Main Outcome Measures: Forearm blood flow (FBF) and forearm glucose uptake (FGU) were determined. Glucose uptake and molecular signaling were determined in cultured skeletal muscle cells. Results: ETA/ETB receptor blockade increased FGU by 63% (P < 0.05). Coadministration of insulin caused a further 2-fold increase in FGU (P < 0.001). ETA/ETB receptor blockade combined with insulin resulted in greater FGU than insulin infusion alone (P < 0.005). ETA/ETB receptor blockade increased FBF by 30% (P < 0.05), with a further 16% increase (P < 0.01) during insulin coinfusion. ET-1 decreased basal FBF by 35% without affecting FGU. ET-1 impaired basal and insulin-stimulated glucose uptake in cultured muscle cells (P < 0.01) via an effect that was prevented by ETA/ETB receptor blockade. Conclusion: ETA/ETB receptor blockade enhances basal and insulin-stimulated glucose uptake in IR subjects. ET-1 directly impairs glucose uptake in skeletal muscle cells via a receptor-dependent mechanism. These data suggest that ET-1 regulates glucose metabolism via receptor-dependent mechanisms in IR subjects. Endothelin-1 regulates glucose metabolism via receptor-dependent mechanisms in insulin resistant subjects.