Vascular insulin/insulin-like growth factor-1 resistance in female obese Zucker rats.
Because insulin resistance/diabetes may cause inordinate vascular complications in females, we have investigated the effects of insulin and insulin-like growth factor (IGF-1) on vascular reactivity in 12-week-old female Zucker obese (Ob) rats, a rodent model of insulin resistance and its lean (Ln) age-matched counterpart. Endothelium intact aortic rings from Ob animals and their Ln littermates (12 weeks of age) were subjected to contractile concentration responses to phenylephrine (PE) followed by relaxation to isoproterenol (Iso), with and without preincubation for 2 hours with cholera toxin (CTX; 1 microg/mL) or pertussis toxin (PTX; 2 microg/mL) and before and after incubation with either insulin or IGF-1 (100 nmol/L) for 1 hour. Systolic blood pressure was higher (138 +/- 3 v. 109 +/- 4 mm Hg; P <.0001) in the 12-week-old Ob rats. Contractile responses to PE were similar in both groups; however, both insulin and IGF-1 induced a paradoxical increase (P <.001) in contraction in Ob vasculature (929 +/- 92 v. 679 +/- 25 mg, respectively). CTX alone decreased contraction in the Ob (P <.02) and PTX in the Ln (P <.02), but there were no interactions between either IGF-1 or insulin and the toxins. Marked impairment of relaxation to Iso was seen in aortic rings of these female Ob rats (ED(50) = 2.6 micromol/L v. 418 nmol/L, P =.0002), an effect exacerbated by preincubation with either insulin or IGF-1 (P =.0001). Again, no role for G-proteins could be demonstrated. Insulin-dependent glucose uptake was severely impaired (P <.05) in aortic segments of the Ob insulin-resistant rats. Insulin receptor binding, tyrosine kinase activity (TKA), and abundance of several G-protein alpha subunits (inhibitory and stimulatory) in solubilized arterial membrane preparations (assessed by Western blot) were comparable in the 2 groups. These results indicate that resistance to the vascular actions of insulin/IGF-1 in female Ob rats is a postreceptor event that parallels glucose uptake resistance and is independent of G-proteins.
Walsh
M F
MF
Division of Endocrinology, Diabetes, and Hypertension, SUNY Health Science Center at Brooklyn, and Veterans Administration Medical Center (VAMC) Brooklyn, Brooklyn, NY, USA.
Ali
S S
SS
Sowers
J R
JR
D000818:Animals; D001011:Aorta; D002772:Cholera Toxin / Q000494:pharmacology; D003847:Deoxyglucose / Q000378:metabolism; D004351:Drug Resistance; D004730:Endothelium, Vascular; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology*; D009765:Obesity / Q000503:physiopathology*; D037342:Pertussis Toxin; D010656:Phenylephrine / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000378:metabolism; D014316:Tritium; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D010566:Virulence Factors, Bordetella; D014316:Tritium; D010656:Phenylephrine; D007334:Insulin-Like Growth Factor I; D002772:Cholera Toxin; D003847:Deoxyglucose; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D019204:GTP-Binding Proteins; D007545:Isoproterenol