Rapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na transport

Abstract

Insulin resistance is associated with deficits in glucose metabolism. We tested whether the vascular and renal responses to insulin might contribute to insulin resistance. Generation of endothelial-derived vasodilator nitric oxide (NO), estimated after a 2-h period of insulin stimulation, was inhibited in the presence of high glucose. Immunoprecipitations indicated that insulin-induced endothelial signal transduction was mediated through an immediate complex formation of insulin receptor substrate (IRS) with phosphatidylinositol 3-kinase, which caused serine phosphorylation of a protein complex that was comprised of Akt kinase and endothelial NO synthase. The enzymatic complexes did not form when the endothelial insulin stimulation occurred in the presence of high glucose concentrations. By contrast, neither epithelial signal transduction nor sodium transport in renal epithelial cells was affected by high glucose. Hence, glucose does not appear to modulate either the epithelial IRS cascade or renal sodium retention. Dysfunction of the endothelial IRS cascade and NO generation, which suppresses efficient delivery of nutrients, may further exacerbate the metabolic syndrome of insulin resistance.

High glucose attenuates insulin-induced VEGF expression in bovine retinal microvascular endothelial cells

“…31 Besides, high glucose was also reported to inhibit insulin-stimulated nitric oxide production by impairing molecular (IRS-1, PI 3-kinase) and functional insulin signals in vascular endothelial cells. 32 These findings are consistent with the results of this study that show that high glucose may attenuate insulin-induced VEGF expression by impairing the PI 3-K signalling pathway.…”

Vanadyl sulfate inhibits NO production via threonine phosphorylation of eNOS.

“…Phosphorylation of Ser 1177 enhances eNOS activity, a mechanism shared by many NO agonists such as insulin (Montagnani et al 2001;Schnyder et al 2002), insulin-like growth factor-1 , VEGF (Brouet et al 2001;Dimmeler et al 2000;Fulton et al 1999;Michell et al 2001 (Boo et al 2002). In our study, VOSO 4 did not affect Ser phosphorylation of eNOS or Akt1.…”

Pathways from obesity to hypertension: from the perspective of a vicious triangle

“…Glucose levels between 11 and 16 mmol=l, not uncommon in the post-prandial state of obese subjects, could be sufficiently elevated to attenuate insulin-mediated NO release by endothelial cells. 102 Additional factors promoting sympathetic activation. A number of other factors may also contribute to the increased sympathetic activity of obesity.…”

“…117 Interestingly, large elevations in plasma glucose (25 mmol=l) that normally completely blunt insulin-mediated NO release by endothelial cells do not alter the increase in sodium transport induced by insulin in A6 cells, a model of the distal tubule. 102 If these observations can be extended to other factors causing insulin resistance, it would appear that insulin resistance might not affect insulin-mediated sodium retention whereas it clearly impairs endothelial function. In obesity, the vasodilatory effects of insulin would thus be blunted whereas the sodium-retaining properties of insulin would be well maintained.…”