Liver sinusoidal endothelial cells link hyperinsulinemia to hepatic insulin resistance.
Insulin signaling in vascular endothelial cells (ECs) is critical to maintain endothelial function but also to mediate insulin action on peripheral glucose disposal. However, gene knockout studies have reached disparate conclusions. Thus, insulin receptor inactivation in ECs does not impair insulin action, whereas inactivation of Irs2 does. Previously, we have shown that endothelial ablation of the three Foxo genes protects mice from atherosclerosis. Interestingly, here we show that mice lacking FoxO isoforms in ECs develop hepatic insulin resistance through excessive generation of nitric oxide (NO) that impairs insulin action in hepatocytes via tyrosine nitration of insulin receptors. Coculture experiments demonstrate that NO produced in liver sinusoidal ECs impairs insulin's ability to suppress glucose production in hepatocytes. The effects of liver sinusoidal ECs can be mimicked by NO donors and can be reversed by NO inhibitors in vivo and ex vivo. The findings are consistent with a model in which excessive, rather than reduced, insulin signaling in ECs predisposes to systemic insulin resistance, prompting a reevaluation of current approaches to insulin sensitization.
Naomi Berrie Diabetes Center and Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Kyoichiro
K
Tsuchiya
Domenico
D
Accili
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006946:Hyperinsulinism / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D051858:Forkhead Transcription Factors; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D011972:Receptor, Insulin