BACKGROUND AND PURPOSE: Thiazolidinediones (TZD) are known to ameliorate fatty liver in type 2 diabetes. To date, the underlying mechanisms of their hepatic actions remain unclear. EXPERIMENTAL APPROACH: 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. KEY 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.
BACKGROUND AND PURPOSE:Thiazolidinediones (TZD) are known to ameliorate fatty liver in type 2 diabetes. To date, the underlying mechanisms of their hepatic actions remain unclear. EXPERIMENTAL APPROACH: 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. KEY 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: C F Burant; S Sreenan; K Hirano; T A Tai; J Lohmiller; J Lukens; N O Davidson; S Ross; R A Graves Journal: J Clin Invest Date: 1997-12-01 Impact factor: 14.808
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Authors: Carlos M González-Casimiro; Beatriz Merino; Elena Casanueva-Álvarez; Tamara Postigo-Casado; Patricia Cámara-Torres; Cristina M Fernández-Díaz; Malcolm A Leissring; Irene Cózar-Castellano; Germán Perdomo Journal: Biomedicines Date: 2021-01-17