Effect of Hypoglycemic Sulfonylureas on Hepatic Fructose Metabolism in the Rat[*]

Abstract

The metabolism of fructose in isolated perfused livers from fasting rats was affected by sulfonylureas (0.5 and 2.5 mM) as follows: 1. Net formation of glucose and ketone bodies was reduced by tolbutamide and chlorpropamide, while net production of lactate plus pyruvate was enhanced. 2. Hepatic oxygen uptake was reduced by the sulfonylurea drugs. 3. Surface fluorescence of reduced pyridine nucleotides decreased while surface fluorescence of flavine nucleotides increased, indicating a more oxidized state of the mitochondrial compartment. 4. None of these effects could be observed with carboxy-tolbutamide, the non-hypoglycemic metabolite of tolbutamide. 5. Within the freeze clamped tissue of livers perfused in a recirculating system, glibenclamide (0.002 mM) did reduce the contents of ATP, ADP and several triose phosphates. A shift in the 3-hydroxybutyrate/acetoacetate ratio towards oxidation associated with an unchanged lacatate/pyruvate ratio confirmed a more oxidized state of the mitochondrial compartment, as indicated by the fluorescence tracings. 6. It is suggested that sulfonylureas affect hepatic metabolism by reducing mitochondrial ATP production, possibly by impairing pyruvate transport through the mitochondrial membrane. In addition the known inhibitory effect of sulfonylureas on intrahepatic lipolysis does contribute to the observed effects.

Key words

Sulfonylureas - Liver - Fructose - Gluconeogenesis - Glycolysis - Oxygen Consumption - Adenine Nucleotides Surface Fluorescence

1 Supported by the Deutsche Forschungsgemeinschaft

1 Supported by the Deutsche Forschungsgemeinschaft

2 Present address: Medizinische Klinik der Universität Würzburg, D-87 Würzburg, Josef-Schneider-Str. 2