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Diabetes 52:1904-1909, 2003
© 2003 by the American Diabetes Association, Inc.

Chronic Endothelin-1 Treatment Leads to Insulin Resistance In Vivo

Jason J. Wilkes1, Andrea Hevener2, and Jerrold Olefsky3

1 Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California
2 San Diego VA HealthCare System, Research Service, San Diego, California
3 Whittier Diabetes Institute, La Jolla, California

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 ETA receptors, because a specific ETA 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 ~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.

Address correspondence and reprint requests to Jason Wilkes, Department of Medicine (0673), UCSD, 9500 Gilman Dr., La Jolla, CA 92093. E-mail: jawilkes{at}ucsd.edu


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