“…Studies from several laboratories have reported that (i) circulating levels of ET-1 are elevated in insulin resistance associated with aging [Sayama et al, 1999], metabolic syndrome X [Ferri et al, 1997], obesity [Ferri et al, 1995[Ferri et al, , 1997, polycystic ovary syndrome [DiamantiKandarakis et al, 2001], and type 2 diabetes [Takahashi et al, 1990;Ferri et al, 1997]; (ii) ET-1 administration in vivo leads to insulin resistance in rats [Juan et al, 1996;Wilkes et al, 2003], and humans [Teuscher et al, 1998]; (iii) blockade of the endothelin type-A (ET-A) receptor prevents ET-1-induced reduction in insulin sensitivity in humans [Ottosson-Seeberger et al, 1997], as well as in vitro [Chou et al, 1994;Jiang et al, 1999;Idris et al, 2001;Ishibashi et al, 2001] and in vivo [Teuscher et al, 1998;Wilkes et al, 2003] models of ET-1-induced insulin resistance; and (iv) key signal transduction mechanisms of insulin action in skeletal muscle [Idris et al, 2001;Wilkes et al, 2003], smooth muscle [Jiang et al, 1999], and fat [Chou et al, 1994;Idris et al, 2001;Ishibashi et al, 2001] cells are impaired following chronic ET-1 treatment. The results of our studies are in full agreement with these observations and further demonstrate ET-1-induced defects in lipid membrane, actin cytoskeletal, and signaling events regulating GLUT4 trafficking.…”