Abstract 5038: Enhanced Endothelial-specific Insulin Sensitivity Regulates Whole Body Glucose Homeostasis and Endothelial Function

Abstract

Accumulating evidence now suggests that insulin resistance may promote atherosclerosis through a closely coupled association with endothelial dysfunction, and that the relationship between insulin resistance and endothelial function is reciprocal. However the role of the endothelium in whole body glucose regulation until now has remained unclear. SHIP2 is a lipid phosphatase which acts as a negative regulator of insulin signalling. In this study Cre-Lox technology is used to generate an endothelial-specific SHIP2 haploinsuffient mouse, as a model of enhanced endothelial-specific insulin sensitivity. We have investigated both the metabolic and vascular phenotype of this model to determine whether enhanced insulin signalling in endothelium modulates vascular function and whole body glucose regulation. Results described are from male EC-SHIP2 +/− offspring compared with control sex-matched littermates at 12–16 weeks of age. EC-SHIP +/− mice were morphologically indistinguishable from control littermates, exhibited normal development and body and organ masses were similar in both groups. No significant differences were observed in heart rate or blood pressure. Glucose tolerance after glucose challenge was found to be significantly better in EC-SHIP +/− than controls (p = <0.05), with no differences in plasma insulin concentrations; fasted or after glucose challenge. Improved insulin sensitivity was confirmed in EC-SHIP +/− mice in insulin tolerance tests (p = <0.05). e x vivo vasomotor studies in aorta revealed no significant differences between EC-SHIP +/− and controls in contractile responses to phenylephrine or maximal relaxation to sodium nitroprusside and ACh. However, basal phosphorylation of eNOS (Ser-1177) was greater in EC-SHIP +/− aorta than controls. In conclusion; the results suggest endothelial partial deletion of SHIP2 confers important effects on metabolic homeostasis and endothelial function. In particular, improved glucose tolerance and insulin sensitivity in EC-SHIP +/− mice support a critical role for insulin signalling in endothelial cells in whole body glucose regulation.