Regulation of glucose uptake by endothelin-1 in human skeletal muscle in vivo and in vitro.
BACKGROUND
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.


METHODS
Eleven subjects participated in three protocols using brachial artery infusion of: A) BQ123 (10 nmol/min) and BQ788 (10 nmol/min) (ET(A) and ET(B) 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).


METHODS
Forearm blood flow (FBF) and forearm glucose uptake (FGU) were determined. Glucose uptake and molecular signaling were determined in cultured skeletal muscle cells.


RESULTS
ET(A)/ET(B) receptor blockade increased FGU by 63% (P < 0.05). Coadministration of insulin caused a further 2-fold increase in FGU (P < 0.001). ET(A)/ET(B) receptor blockade combined with insulin resulted in greater FGU than insulin infusion alone (P < 0.005). ET(A)/ET(B) 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 ET(A)/ET(B) receptor blockade.


CONCLUSIONS
ET(A)/ET(B) 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.
Shemyakin
Alexey
A
Karolinska University Hospital Solna, Center for Molecular Medicine, L8:03, S-171 76, Stockholm, Sweden. alexey.shemyakin@ki.se
Salehzadeh
Firoozeh
F
Böhm
Felix
F
Al-Khalili
Lubna
L
Gonon
Adrian
A
Wagner
Henrik
H
Efendic
Suad
S
Krook
Anna
A
Pernow
John
J
D001692:Biological Transport; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D001916:Brachial Artery; D002097:C-Reactive Protein / Q000378:metabolism; D019332:Endothelin-1 / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D005542:Forearm / Q000098:blood supply; D005947:Glucose / Q000378:metabolism*; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007261:Infusions, Intra-Arterial; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D012039:Regional Blood Flow; D014280:Triglycerides / Q000097:blood
D001786:Blood Glucose; D002097:C-Reactive Protein; D019332:Endothelin-1; D005947:Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D014280:Triglycerides; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)