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.

[1]  K. Takahashi,et al.  Elevated plasma endothelin in patients with diabetes mellitus , 1990, Diabetologia.

[2]  C. Slaughter,et al.  Endothelin-1 Stimulates Leptin Production in Adipocytes* , 2001, The Journal of Biological Chemistry.

[3]  J. Olefsky,et al.  Chronic endothelin-1 treatment leads to heterologous desensitization of insulin signaling in 3T3-L1 adipocytes. , 2001, The Journal of clinical investigation.

[4]  A. Hevener,et al.  Exercise and thiazolidinedione therapy normalize insulin action in the obese Zucker fatty rat. , 2000, Diabetes.

[5]  J. Olefsky,et al.  The acute and chronic stimulatory effects of endothelin-1 on glucose transport are mediated by distinct pathways in 3T3-L1 adipocytes. , 2000, Endocrinology.

[6]  C. Polanczyk,et al.  Increased plasma levels of endothelin 1 and von Willebrand factor in patients with type 2 diabetes and dyslipidemia. , 2000, Diabetes care.

[7]  L. Monti,et al.  Relationship between endothelin-1 concentration and metabolic alterations typical of the insulin resistance syndrome. , 2000, Metabolism: clinical and experimental.

[8]  J. R. Mcneill,et al.  Altered paracrine effect of endothelin in blood vessels of the hyperinsulinemic, insulin resistant obese Zucker rat. , 2000, Cardiovascular research.

[9]  X. P. Liu,et al.  Treatment of atherosclerosis in apolipoprotein E-deficient mice with 4-(3-Bromobenzoyl)-6,7-dimethoxyquinazoline (WHI-P164), a potent inhibitor of triglyceride synthesis. , 2000, Journal of cardiovascular pharmacology.

[10]  Endothelin stimulates glucose uptake via activation of endothelin-A receptor in neonatal rat cardiomyocytes. , 2000, Journal of cardiovascular pharmacology.

[11]  J. Olefsky,et al.  Endothelin-1-induced GLUT4 Translocation Is Mediated via Gαq/11 Protein and Phosphatidylinositol 3-Kinase in 3T3-L1 Adipocytes* , 1999, The Journal of Biological Chemistry.

[12]  S. Chierchia,et al.  Endothelial and metabolic characteristics of patients with angina and angiographically normal coronary arteries: comparison with subjects with insulin resistance syndrome and normal controls. , 1999, Journal of the American College of Cardiology.

[13]  J. R. Wu-wong,et al.  Endothelin Stimulates Glucose Uptake and GLUT4 Translocation via Activation of Endothelin ETA Receptor in 3T3-L1 Adipocytes* , 1999, The Journal of Biological Chemistry.

[14]  G. Winkler,et al.  Elevated serum TNF‐α level as a link between endothelial dysfunction and insulin resistance in normotensive obese patients , 1999, Diabetic medicine : a journal of the British Diabetic Association.

[15]  J. Woodgett,et al.  Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. , 1998, The Biochemical journal.

[16]  J. R. Mcneill,et al.  Insulin increases endothelin-1-evoked intracellular free calcium responses by increased ET(A) receptor expression in rat aortic smooth muscle cells. , 1998, Diabetes.

[17]  G. Ahlborg,et al.  Exogenous endothelin-1 causes peripheral insulin resistance in healthy humans. , 1997, Acta physiologica Scandinavica.

[18]  C. Juan,et al.  Endothelin-1 induces insulin resistance in conscious rats. , 1996, Biochemical and biophysical research communications.

[19]  L. Monti,et al.  Hypertriglyceridemia and Hyperinsulinemia Are Potent Inducers of Endothelin-1 Release in Humans , 1996, Diabetes.

[20]  A. Bonen,et al.  Experimental approaches in muscle metabolism: hindlimb perfusion and isolated muscle incubations. , 1994, The American journal of physiology.

[21]  T. Hayama,et al.  Endothelin antagonistic peptide derivatives with high selectivity for ETA receptors , 1993 .

[22]  N. Iwasaki,et al.  Increased Plasma Endothelin in NIDDM Patients With Retinopathy , 1992, Diabetes Care.

[23]  M. Loeken,et al.  Stimulation of endothelin-1 gene expression by insulin in endothelial cells. , 1991, The Journal of biological chemistry.

[24]  P. Cobbold,et al.  Endothelin action in rat liver. Receptors, free Ca2+ oscillations, and activation of glycogenolysis. , 1991, The Journal of clinical investigation.

[25]  T. Sakurai,et al.  Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor , 1990, Nature.

[26]  M. Yanagisawa,et al.  The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Sadao Kimura,et al.  A novel potent vasoconstrictor peptide produced by vascular endothelial cells , 1988, Nature.

[28]  R. DeFronzo,et al.  The Effect of Insulin on the Disposal of Intravenous Glucose: Results from Indirect Calorimetry and Hepatic and Femoral Venous Catheterization , 1981, Diabetes.

[29]  R. Steele,et al.  INFLUENCES OF GLUCOSE LOADING AND OF INJECTED INSULIN ON HEPATIC GLUCOSE OUTPUT * , 1959, Annals of the New York Academy of Sciences.