Abstract 18289: New Roles of the Interplay Between Endothelin and Insulin-like Growth Factor 1 in the Regulation of Vascular Redox State in Patients With Type 2 Diabetes and Coronary Atherosclerosis

Background: Insulin resistance (IR) is associated with increased cardiovascular risk. Given that plasma endothelin (ET) is elevated in IR, we explored whether the variations in ET levels mediate the vascular complications of type 2 diabetes (T2DM), by exploring its links with vascular redox state in human vessels. Methods: The study population consisted of 383 patients undergoing coronary bypass surgery (CABG), 30% with T2DM. Levels of ET, insulin growth factor 1 (IGF1), insulin and glucose (to calculate HOMA-IR as an index of insulin resistance) were measured in plasma, while vascular superoxide (O2) was measured in saphenous vein segments obtained during surgery. Results: Patients with untreated T2DM had elevated plasma ET, contrary to treated patients with T2DM (A). A positive association was observed between plasma endothelin and IGF1 levels in non-T2DM, which was reversed in T2DM (B). Elevated plasma ET was associated with increased NADPH-stimulated O2- (indicative of higher NADPH oxidase activity) and more LNAME inhibitable O2- (suggestive of more eNOS uncoupling) in human vessels (C, D). Conclusions: We demonstrate that circulating ET is elevated in untreated T2DM but its levels are normalised after intensive glycaemic control. We also document a striking effect of DM on the balance between ET and IGF1, and we demonstrate for the first time in humans, that elevated plasma ET is associated with increased O2- generation in the vascular wall through activation of NADPH-oxidase and uncoupling of eNOS. This study shows that ET and its interplay with IGF1 is possibly a key mechanism linking T2DM with its vascular complications in humans