Abstract 11247: Expression of a Non-Functioning Igf-1 Receptor on the Vascular Endothelium: A Novel Approach to Manipulating Whole Body and Endothelial Insulin Sensitivity?
Introduction: Work published by our group has shown that expression of insulin like growth factor-1 receptors (IGF-1R) in the endothelium may play a role in determining endothelial cell insulin sensitivity and NO bioavailability. To further investigate this we have generated a transgenic mouse which expresses a non-functional IGF-1R solely on the vascular endothelium (MIGFREO).
Results: MIGFREO mice have preserved glucose tolerance but enhanced insulin sensitivity (mean [SEM] % of baseline blood glucose 30 minutes following insulin injection MIGFREO 55.99 [2.31], wild type 68.04 [2.43] p<0.001). Leptin and insulin levels are comparable between the wild type and MIGFREO mice; FFA were significantly lower in MIGFREO mice (mean [SEM] plasma FFA nmol/μl wild type 0.43 [0.07], MIGFREO 0.23 [0.03] p<0.05). MIGFREO mice are resistant to the endothelial dependent vasodilatory effect of insulin as measured by maximum constriction in response to phenylephrine in the presence of insulin (Figure 1) (mean [SEM] maximum constriction in grams (g), wild type 0.54 [0.06], MIGFREO 0.75 [0.06] p<0.05). Endothelial function assessed by vasorelaxation in the presence of acetylcholine in the MIGFREO mice is comparable with wild type mice. Exposure to catalase (H2O2) in the organ bath significantly reduces vasorelaxation to acetylcholine in MIGFREO mice (mean [SEM] maximal relaxation with and without H2O2 respectively, wild type 89.29% [3.27} vs. 86.02% [8.56] MIGFREO 86.85% [3.02] vs. 73.36% [5.97] p=0.05) a finding not demonstrated in wild type mice. This suggests that MIGFREO mice may have elevated levels of H2O2 in comparison with wild type controls.
Conclusion: Mutation of the IGF-1R specific to the vascular endothelium has divergent effects on whole body and endothelial insulin sensitivity, measured by assessing vasomotor response to insulin. Preliminary data suggests that MIGFREO mice have a higher basal level of H2O2 than the wild type controls.
- © 2013 by American Heart Association, Inc.