The effects of troglitazone and pioglitazone on glucose and fatty acid metabolism were studied in hepatocytes isolated from 24-h-starved rats. These thiazolidinediones inhibited long-chain fatty acid (oleate) oxidation and produced a very oxidized mitochondrial redox state. By contrast, thiazolidinediones did not affect the rate of medium-chain fatty acid (octanoate) oxidation or the activity of mitochondrial carnitine palmitoyltransferase (CPT) I. Thiazolidinediones inhibited selectively triglyceride synthesis but not phospholipid synthesis. The combined inhibition of oleate oxidation and esterification by troglitazone was due to a noncompetitive inhibition of mitochondrial and microsomal long-chain acyl-CoA synthetase (ACS) activities. It was suggested that troglitazone must be metabolized into its sulfo-conjugate derivative in liver cells to inhibit mitochondrial and microsomal ACS activities. Thiazolidinediones inhibited glucose production from lactate/pyruvate or from alanine. Analysis of gluconeogenic metabolite concentrations suggested that troglitazone would inhibit gluconeogenesis at the level of pyruvate carboxylase and glyceraldehyde-3-phosphate dehydrogenase reactions. It was concluded that 1) at a similar concentration, troglitazone was more efficient than pioglitazone to inhibit fatty acid metabolism and gluconeogenesis and 2) the inhibition of gluconeogenesis by troglitazone could be the result of the inhibition of long-chain fatty acid oxidation (decrease in acetyl-CoA, NADH-to-NAD+, and ATP-to-ADP ratios).
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Original Articles|
November 01 1996
Troglitazone Inhibits Fatty Acid Oxidation and Esterification, and Gluconeogenesis in Isolated Hepatocytes from Starved Rats
Jean-Pierre Fulgencio;
Jean-Pierre Fulgencio
Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement du CNRS
Meudon-Bellevue, France
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Claude Kohl;
Claude Kohl
Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement du CNRS
Meudon-Bellevue, France
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Jean Girard;
Jean Girard
Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement du CNRS
Meudon-Bellevue, France
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Jean-Paul Pégorier
Jean-Paul Pégorier
Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement du CNRS
Meudon-Bellevue, France
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Address correspondence and reprint requests to J.P. Pegorier, Ceremod, 9, rue J. Hetzel, 92190 Meudon-Bellevue, France.
Diabetes 1996;45(11):1556–1562
Article history
Received:
March 14 1996
Revision Received:
June 20 1996
Accepted:
June 20 1996
PubMed:
8866561
Citation
Jean-Pierre Fulgencio, Claude Kohl, Jean Girard, Jean-Paul Pégorier; Troglitazone Inhibits Fatty Acid Oxidation and Esterification, and Gluconeogenesis in Isolated Hepatocytes from Starved Rats. Diabetes 1 November 1996; 45 (11): 1556–1562. https://doi.org/10.2337/diab.45.11.1556
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