Abstract 15422: Enhancing Endothelial Specific Insulin Signaling Confers Contrasting Temporal Effects on Vascular Function and Whole Body Glucose Homeostasis
Background: The effects of enhanced endothelial insulin signaling on whole body glucose regulation and vascular function are poorly characterized. We generated mice with downregulated activity of a negative regulator of insulin signaling (SHIP2) by deleting exons 18-19 of the ship 2 gene using Cre-Lox technology under the control of the Tie2 promoter to investigate whether enhanced endothelial insulin signaling modulates vascular function and whole body glucose regulation.
METHODS: Male mice heterozygous for the inactive protein (EC-SHIP2+/-) were compared with sex-matched littermate controls.
RESULTS: EC-SHIP+/- mice were morphologically indistinguishable from control littermates. At 8 weeks old EC-SHIP2+/- mice displayed increased glucose tolerance after glucose challenge (P=0.03) and improved insulin sensitivity (P=0.02) after insulin challenge compared to controls. At 40 weeks old this phenotype was reversed; EC-SHIP2+/- mice revealed significant insulin resistance 60 min after insulin challenge (P=<0.05) confirmed by euglycemic hyperinsulinemic clamping. In both groups young mice ex vivo aortic vasomotor studies revealed similar contractile responses to phenylephrine, decreased contraction after insulin incubation and increased contraction after NO synthase inhibitor LNMMA incubation. However, at 40 weeks old the vasodilatory aortic ring response to insulin in EC-SHIP2+/- mice was abolished (Emax controls 0.59
± 0.04g vs 0.47 ± 0.03g P=0.04, EC-SHIP2+/- 0.64 ± 0.04g vs 0.63 ± 0.06g P=0.9) and EC-SHIP2+/- displayed no increase in contraction to LNMMA incubation (Emax controls 0.59 ± 0.04g vs 0.82 ± 0.08g P=0.02, EC-SHIP2+/- 0.64 ± 0.04g vs 0.69 ± 0.07g P=0.5) indicating insulin resistance and lower basal NO production. Immunoblots from cultured endothelial cells and skeletal muscle from older mice reveal significantly (P=<0.05) increased levels of total eNOS suggesting a reduction in eNOS activation potential and the change in glucose homeostasis may be mediated by nitric oxide bioavailability.
Conclusions: Enhancement of endothelial insulin signaling augments whole body glucose disposal in the short term but chronically it attenuates whole body glucose disposal in older mice and significantly impairs vascular function.
- © 2013 by American Heart Association, Inc.