The role of Methylglyoxal in the pathogenesis of endothelial insulin resistance and vascular damage in type 2 diabetes

Cecilia Nigro
It has now become evident that insulin exerts a direct action on vascular cells, thereby conditioning the outcome and progression of vascular complication associated with diabetes. However, the mechanisms through which insulin signaling is impaired in the vascular endothelium remain still unclear. Chronic hyperglycaemia per se promotes insulin resistance and plays a pivotal role in the outcome and progression of diabetes-associated vascular complications. Hyperglycaemia may act through
more » ... ct through different mechanisms, including generation of advanced glycation end products (AGEs). In this work we evaluated the role of the AGEs precursor methylglyoxal (MGO) in the generation of endothelial insulin-resistance in cellular and animal models. Time-courses experiments were performed on bovine aortic endothelial cells (BAEC) incubated with different concentrations of MGO. The glyoxalase 1 inhibitor "SpBrBzGSHCp2" was used to increase the endogenous levels of MGO. For the in vivo study, C57bl6 mice were intraperitoneally injected with a MGO solution at steadily increasing concentrations (50 to 75mg/kg) for 7 weeks. MGO incubation induces a 50% reduction of IRS1 phosphorylation, the loss of IRS1-p85 interaction and of the downstream Akt activation in response to insulin, whilst MAPK is more active in BAEC treated with MGO. The insulin-induced Akt activation is reverted by the inhibition of ERK through the use of MEK inhibitor U0126 in BAEC treated with MGO. Furthermore, downstream Akt, MGO is able to inhibit eNOS activation in response to insulin, and this was paralleled by a 60% decrease of insulin-induced NO production in BAEC. Similar results were obtained in BAEC treated with SpBrBzGSHCp2 compared to controls. Intraperitoneally administration of MGO to mice caused insulin resistance (ITT AUC: C57MGO 10163±1979 vs C57 7787±1174 mg/dl/120', p=0.01) and reduced serum NO by 2.5-fold compared to untreated mice. Western blots of lysates of aortae from MG-treated mice revealed a reduction of insulin-induced Akt activation. In conclusio [...]
doi:10.6092/unina/fedoa/8778 fatcat:b2vlg6zn6bg2po5vumxkkslyje