Impaired insulin-mediated vasorelaxation in a nonobese model of type 2 diabetes: role of endothelin-1.
Insulin resistance involves decreased phosphorylation of insulin receptor substrate (IRS) proteins and (or) Akt. In the vasculature, modulated Akt phosphorylation may cause impaired vasorelaxation via decreased eNOS activation. Diet-induced insulin resistance enhances endothelin-1(ET-1)-mediated vasoconstriction and prevents vasodilatation to insulin. Presently, we evaluated insulin-mediated vascular relaxation, assessed molecular markers of the insulin signaling pathway, and determined the involvement of ET-1 in response to insulin by using selective ETA- or ETB-receptor blockade in a lean model of type 2 diabetes. Dose-response curves to insulin (0.01-100 ng/mL) were generated with wire myograph using thoracic aorta rings from control Wistar or diabetic Goto-Kakizaki (GK) rats (n=3-11). Maximal relaxation (Rmax) to insulin was significantly impaired and insulin sensitivity was decreased in the GK group. Preincubation with 1 micromol/L BQ-123 or BQ-788 for ETA- and ETB-receptor blockade, respectively, resulted in improved insulin sensitivity. Immunoblotting for native and phosphorylated Akt and IRS-1 revealed a decrease in Akt activation in the GK group. In vivo hyperinsulinemic euglycemic clamp studies showed decreased glucose utilization in GK rats, indicative of insulin resistance. These findings provide evidence that vascular insulin resistance occurs in a nonobese model of diabetes and that both ET receptor subtypes are involved in vascular relaxation to insulin.
Program in Clinical and Experimental Therapeutics, University of Georgia College of Pharmacy, Augusta, GA 30912, USA.
Mostafa M
MM
Elgebaly
Aisha
A
Kelly
Alex K
AK
Harris
Hazem
H
Elewa
Vera
V
Portik-Dobos
Pimonrat
P
Ketsawatsomkron
Mario
M
Marrero
Adviye
A
Ergul
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000502:physiology*; D015309:Glucose Clamp Technique; D066298:In Vitro Techniques; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D011972:Receptor, Insulin / Q000502:physiology; D015398:Signal Transduction; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D019332:Endothelin-1; D007328:Insulin; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D011972:Receptor, Insulin