Chronic endothelin-1 treatment leads to insulin resistance in vivo.
We determined whether chronic endothelin-1 (ET-1) treatment could lead to in vivo insulin resistance. Like insulin, ET-1 acutely stimulated glucose transport in isolated soleus muscle strips of WKY rats. ET-1 pretreatment (1 h) decreased insulin-stimulated glucose transport in muscle strips (-23%). Both ET-1-mediated effects were generated through ET(A) receptors, because a specific ET(A) receptor antagonist (BQ610) blocked these effects of ET-1. Osmotic minipumps were used to treat normal rats with ET-1 for 5 days. Subsequent hyperinsulinemic-euglycemic clamps showed that ET-1 treatment led to an approximately 30% decrease in insulin-stimulated glucose disposal rates in male and female rats. In addition, ex vivo study of soleus muscle strips showed decreased glucose transport into muscle from ET-1-treated animals. With respect to insulin signaling, chronic in vivo ET-1 treatment led to a 30-40% decrease in IRS-I protein content, IRS-I-associated p110(alpha), and AKT activation. In summary, 1) in vitro ET-1 pretreatment leads to decreased insulin-stimulated glucose transport in skeletal muscle strips; 2) chronic ET-1 administration in vivo leads to whole-body insulin resistance, with decreased skeletal muscle glucose transport and impaired insulin signaling; and 3) elevated ET-1 levels may be a cause of insulin resistance in certain pathophysiologic states.
Wilkes
Jason J
JJ
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA. jawilkes@ucsd.edu
Hevener
Andrea
A
Olefsky
Jerrold
J
D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D005947:Glucose / Q000493:pharmacokinetics; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D019332:Endothelin-1; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C526296:Irs1 protein, rat; C494920:Akt1 protein, rat