Impaired insulin-mediated vasorelaxation in a nonobese model of type 2 diabetes: Role of endothelin-1

Mostafa M. Elgebaly, Aisha Kelly, Alex K. Harris, Hazem Elewa, Vera Portik-Dobos, Pimonrat Ketsawatsomkron, Mario Marrero, Adviye Ergul

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20 Scopus citations

Abstract

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 μmol/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 insuhn 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.

Original languageEnglish (US)
Pages (from-to)358-364
Number of pages7
JournalCanadian Journal of Physiology and Pharmacology
Volume86
Issue number6
DOIs
StatePublished - Jun 1 2008

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Keywords

  • Endothelin-1
  • Type II diabetes
  • Vascular insulin resistance

ASJC Scopus subject areas

  • Physiology
  • Pharmacology
  • Physiology (medical)

Cite this

Elgebaly, M. M., Kelly, A., Harris, A. K., Elewa, H., Portik-Dobos, V., Ketsawatsomkron, P., Marrero, M., & Ergul, A. (2008). Impaired insulin-mediated vasorelaxation in a nonobese model of type 2 diabetes: Role of endothelin-1. Canadian Journal of Physiology and Pharmacology, 86(6), 358-364. https://doi.org/10.1139/Y08-034