Abstract 778: Vascular Endothelial KO of Insulin Receptors Confirm a Critical Role of Endothelial Insulin Signaling in Regulating Myocardial Glucose Utilization
We previously showed that hearts with cardiomyocyte-restricted KO of insulin receptors (CIRKO) increase myocardial glucose utilization (MGU) upon insulin stimulation, an effect that is abolished when IRs are deleted in myocytes and endothelial cells (ECs), or by blocking insulin-stimulated NO generation. We have now evaluated the effect of endothelial insulin signaling on MGU in mice that lack IRs exclusively in ECs, but express IRs in cardiomyocytes (VENIRKO). Insulin stimulated glycolysis was 6364±492, 7076±254 and 5619±358* nmol/ min/g in WT, CIRKO and VENIRKO hearts respectively (*p<0.05 vs. WT), indicating that absence of IRs in ECs, impaired insulin stimulated glucose uptake in the heart, despite preserved IR expression in cardiomyocytes. Insulin increased myocardial content of cGMP by 1.9 and 1.6-fold in WT and CIRKO hearts respectively (p<0.03), but did not stimulate cGMP production in VENIRKO hearts. The relationship between insulin-stimulated glucose uptake and NO-generated cGMP suggested that insulin-stimulated glucose uptake in the heart was mediated via effects on vascular perfusion. We therefore perfused WT hearts with the vasodilator papaverine10μM ±insulin, or with10nM of the vasoconstrictor thromboxane agonist, U46619 ±insulin. These concentrations modulated coronary flow but had minimal effects on cardiac contractility. As shown in the table⇓, papaverine increased glycolysis and cGMP to the same extent as insulin and the effects were not additive. U46619 blocked the vasodilatory effects of insulin and papaverine and completely prevented the increase in glycolysis despite preservation of their stimulatory effect on cGMP. Thus vascular insulin signaling plays a central role in the regulation of insulin-stimulated MGU by coordinating substrate delivery with utilization.