Rapid effects of glucose on the insulin signaling of endothelial NO generation and epithelial Na transport.
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.
Schnyder
Bruno
B
Institute of Physiology, University of Fribourg, Fribourg, Switzerland. bruno.schnyder@unifr.ch
Pittet
Martine
M
Durand
Jacques
J
Schnyder-Candrian
Silvia
S
D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects*; D012964:Sodium / Q000378:metabolism*; D013997:Time Factors
D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012964:Sodium; C526292:IRS1 protein, human; C496314:NOS3 protein, human; C494918:AKT1 protein, human