title: Mechanisms by which the thiazolidinedione troglitazone protects against sucrose-induced hepatic fat accumulation and hyperinsulinaemia.
abstract: OBJECTIVE
  Thiazolidinediones (TZD) are known to ameliorate fatty liver in type 2 diabetes. To date, the underlying mechanisms of their hepatic actions remain unclear.
  
  
  METHODS
  Hepatic triglyceride content and export rates were assessed in 2 week high-sucrose-fed Wistar rats treated with troglitazone and compared with untreated high-sucrose rodent controls. Fractional de novo lipogenesis (DNL) contributions to hepatic triglyceride were quantified by analysis of triglyceride enrichment from deuterated water. Hepatic insulin clearance and NO status during a meal tolerance test were also evaluated.
  
  
  RESULTS
  TZD significantly reduced hepatic triglyceride (P < 0.01) by 48%, decreased DNL contribution to hepatic triglyceride (P < 0.01) and increased postprandial non-esterified fatty acids clearance rates (P < 0.01) in comparison with the high-sucrose rodent control group. During a meal tolerance test, plasma insulin AUC was significantly lower (P < 0.01), while blood glucose and plasma C-peptide levels were not different. Insulin clearance was increased (P < 0.001) by 24% and was associated with a 22% augmentation of hepatic insulin-degrading enzyme activity (P < 0.05). Finally, hepatic NO was decreased by 24% (P < 0.05).
  
  
  CONCLUSIONS
  Overall, TZD show direct actions on liver by reducing hepatic DNL and increasing hepatic insulin clearance. The alterations in hepatic insulin clearance were associated with changes in insulin-degrading enzyme activity, with possible modulation of NO levels.
authors.affiliation: Metabolic Control Group, Center for Neurosciences and Cell Biology of Coimbra, Cantanhede, Portugal
authors.forename: Fátima O
authors.initials: FO
authors.lastname: Martins
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Delgado
authors.forename: Joana
authors.initials: J
authors.lastname: Viegas
authors.forename: Joana M
authors.initials: JM
authors.lastname: Gaspar
authors.forename: Donald K
authors.initials: DK
authors.lastname: Scott
authors.forename: Robert M
authors.initials: RM
authors.lastname: O'Doherty
authors.forename: M Paula
authors.initials: MP
authors.lastname: Macedo
authors.forename: John G
authors.initials: JG
authors.lastname: Jones
mesh_terms: D000818:Animals; D002839:Chromans / Q000627:therapeutic use*; D005234:Fatty Liver / Q000097:blood / Q000139:chemically induced* / Q000517:prevention & control*; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced* / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D020011:Protective Agents / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013395:Sucrose / Q000008:administration & dosage / Q000633:toxicity*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D020011:Protective Agents; D045162:Thiazolidinediones; D013395:Sucrose; C089946:2,4-thiazolidinedione; D000077288:Troglitazone