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
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.
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.