title: Insulin resistance and liver microcirculation in a rat model of early NAFLD.
abstract: OBJECTIVE
  Insulin contributes to vascular homeostasis in peripheral circulation, but the effects of insulin in liver microvasculature have never been explored. The aim of this study was to assess the vascular effects of insulin in the healthy and fatty liver.
  
  
  METHODS
  Wistar rats were fed a control or a high fat diet (HFD) for 3days, while treated with a placebo, the insulin-sensitizer metformin, or the iNOS inhibitor 1400W. Vascular responses to insulin were evaluated in the isolated liver perfusion model. Insulin sensitivity at the sinusoidal endothelium was tested by endothelium-dependent vasodilation in response to acetylcholine in the presence or absence of insulin and by the level of liver P-eNOS after an insulin injection.
  
  
  RESULTS
  Rats from the HFD groups developed liver steatosis. Livers from the control group showed a dose-dependent hepatic vasodilation in response to insulin, which was blunted in livers from HFD groups. Metformin restored liver vascular insulin-sensitivity. Pre-treatment with insulin enhanced endothelium-dependent vasodilation of the hepatic vasculature and induced hepatic eNOS phosphorylation in control rats but not in HFD rats. Treatment with metformin or 1400W restored the capacity of insulin to enhance endothelium dependent vasodilation and insulin induced eNOS phosphorylation in HFD rats.
  
  
  CONCLUSIONS
  The administration of a HFD induces insulin resistance in the liver sinusoidal endothelium, which is mediated, at least in part, through iNOS upregulation and can be prevented by the administration of metformin. Insulin resistance at the hepatic vasculature can be detected earlier than inflammation or any other sign of advanced NALFD.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, CIBERrehd, University of Barcelona, Spain.
authors.forename: Marcos
authors.initials: M
authors.lastname: Pasarín
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
authors.forename: Aina
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.forename: Vincenzo
authors.initials: V
authors.lastname: La Mura
authors.forename: Joan Carles
authors.initials: JC
authors.lastname: García-Pagán
authors.forename: Jaime
authors.initials: J
authors.lastname: Bosch
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004727:Endothelium / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005234:Fatty Liver / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000098:blood supply* / Q000473:pathology / Q000503:physiopathology; D008102:Liver Circulation; D008297:Male; D008687:Metformin / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D014665:Vasodilator Agents; D008687:Metformin; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine