Abstract
Sulfonylurea drugs are widely used for the treatment of non-insulin-dependent diabetes mellitus. As this treatment sometimes leads to hyperinsulinemia and obesity these are not always the ideal oral agents for the treatment of diabetes mellitus.
Clinically, we often encounter the necessity of developing oral hypoglycemic agents with different modes of action from those currently available. Therefore to provide some insight into such a type of agents, we studied the effects of 3-phenylpyruvate (3-PPA) on hepatic glucose metabolism by using isolated rat hepatocytes. The following results were obtained. 1) 3-PPA caused significant suppression of hepatic glucose output without inhibition of β-oxidation from alanine, glycerol, lactate and pyruvate but not from fructose. 2) In the presence of pyruvate and palmitate, 3-PPA decreased hepatic ketone body production and reduced the βhydroxybutyrate/acetoacetate ratio in a dosedependent manner. 3) Ten millimolar 3-PPA showed an antigluconeogenic effect similar to that of 3 mM tolbutamide and 1 mM buformin. However, the mode of action of 3-PPA was different from those of sulfonylurea and biguanide. 4) The oxidation of [14C (U)] alanine, [1-14C] palmitate and [1-14C] glutamate was increased by 3-PPA.
Therefore it is suggested that the inhibitory effect of 3-PPA on gluconeogenesis and ketogenesis involves increased activity of the TCA cycle as one of its mechanisms.
