title: Effect of N-acetyl-l-cysteine on insulin resistance caused by prolonged free fatty acid elevation.
abstract: Circulating free fatty acids (FFAs) are elevated in obesity and cause insulin resistance. The objective of the current study was to determine whether the antioxidant N-acetyl-l-cysteine (NAC) prevented hepatic and peripheral insulin resistance caused by prolonged elevation of plasma FFAs. Chronically cannulated Wistar rats received saline (SAL), Intralipid plus heparin (IH), IH plus NAC, or NAC i.v. infusion for 48 h. Insulin sensitivity was determined using the hyperinsulinemic-euglycemic clamp with tritiated glucose tracer. IH induced hepatic and peripheral insulin resistance (P<0.05). NAC co-infusion did not prevent insulin resistance in the liver, although it was able to prevent peripheral insulin resistance. Prolonged IH infusion did not appear to induce oxidative stress in the liver because hepatic content of protein carbonyl, malondialdehyde, and reduced to oxidized glutathione ratio did not differ across treatment groups. In alignment with our insulin sensitivity results, IH augmented skeletal muscle protein carbonyl content and this was prevented by NAC co-infusion. Taken together, our results indicate that oxidative stress mediates peripheral, but not hepatic, insulin resistance resulting from prolonged plasma FFA elevation. Thus, in states of chronic plasma FFA elevation, such as obesity, antioxidants may protect against peripheral but not hepatic insulin resistance.
authors.affiliation: Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pereira
authors.affiliation: Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Anu
authors.initials: A
authors.lastname: Shah
authors.affiliation: Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo
authors.forename: I
authors.initials: I
authors.lastname: George Fantus
authors.affiliation: Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada.
authors.forename: Jamie W
authors.initials: JW
authors.lastname: Joseph
authors.affiliation: Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo, Waterloo, Ontario, Canada Department of PhysiologyUniversity of Toronto, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8Department of MedicineUniversity of Toronto, Toronto, Ontario, CanadaToronto General Research InstituteUniversity Health Network, Toronto, Ontario, CanadaBanting and Best Diabetes CentreUniversity of Toronto, Toronto, Ontario, CanadaInstitute of Medical ScienceUniversity of Toronto, Toronto, Ontario, CanadaSchool of PharmacyUniversity of Waterloo
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers; D001786:Blood Glucose; D004655:Emulsions / Q000008:administration & dosage; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage; D007333:Insulin Resistance / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010743:Phospholipids / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013024:Soybean Oil / Q000008:administration & dosage*
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D004655:Emulsions; D005230:Fatty Acids, Nonesterified; D016166:Free Radical Scavengers; D010743:Phospholipids; C545823:soybean oil, phospholipid emulsion; D013024:Soybean Oil; D006493:Heparin; D005947:Glucose; D000111:Acetylcysteine
keywords: N-acetyl-l-cysteine; free fatty acids; insulin resistance; liver