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Diabetes 51:2363-2368, 2002
© 2002 by the American Diabetes Association, Inc.

Effects of Benfluorex on Fatty Acid and Glucose Metabolism in Isolated Rat Hepatocytes

From Metabolic Fluxes to Gene Expression

Claude Kohl1, Denis Ravel2, Jean Girard1, and Jean-Paul Pégorier1

1 Endocrinologie et Métabolisme, Institut Cochin, INSERM U567, Paris, France
2 Institut de Recherches Internationales Servier, Division Métabolisme, Courbevoie, France

The effects of benfluorex and two of its metabolites (S 422-1 and S 1475-1) on fatty acid and glucose metabolic fluxes and specific gene expression were studied in hepatocytes isolated from 24-h fasted rats. Both benfluorex and S 422-1 (0.1 or 1 mmol/l) reduced ß-oxidation rates and ketogenesis, whereas S 1475-1 had no effect. At the same concentration, benfluorex and S 422-1 were more efficient in reducing gluconeogenesis from lactate/pyruvate than S 1475-1. Benfluorex inhibited gluconeogenesis at the level of pyruvate carboxylase (45% fall in acetyl-CoA concentration) and of glyceraldehyde-3-phosphate dehydrogenase (decrease in ATP/ADP and NAD+/NADH ratios). Accordingly, neither benfluorex nor S 422-1 inhibited gluconeogenesis from dihydroxyacetone, but both stimulated gluconeogenesis from glycerol. In hepatocytes cultured in the presence of benfluorex or S 422-1 (10 or 100 µmol/l), the expression of genes encoding enzymes of fatty acid oxidation (carnitine palmitoyltransferase [CPT] I), ketogenesis (hydroxymethylglutaryl-CoA synthase), and gluconeogenesis (glucose-6-phosphatase, PEPCK) was decreased, whereas mRNAs encoding glucokinase and pyruvate kinase were increased. By contrast, Glut-2, acyl-CoA synthetase, and CPT II gene expression was not affected by benfluorex or S 422-1. In conclusion, this work suggests that benfluorex mainly via S 422-1 reduces gluconeogenesis by affecting gene expression and metabolic status of hepatocytes.


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P. Moulin, M. Andre, H. Alawi, L. C. dos Santos, A. K. Khalid, D. Koev, R. Moore, V. Serban, B. Picandet, and M. Francillard
Efficacy of Benfluorex in Combination With Sulfonylurea in Type 2 Diabetic Patients: An 18-week, randomized, double-blind study.
Diabetes Care, March 1, 2006; 29(3): 515 - 520.
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Copyright © 2002 by the American Diabetes Association.