CS-045, A NEW ORAL ANTIDIABETIC AGENT, STIMULATES FRUCTOSE-2,6-BISPHOSPHATE PRODUCTION IN RAT HEPATOCYTES

Fructose-2,6-bisphosphate is a potent activator of 6-phosphofructo-1-k inase, a key enzyme in glycolysis. We previously revealed that sulfony lureas stimulate fructose-2,6-bisphosphate production in the rat liver by activating 6-phosphofructo-2-kinase. In the present study, we show that CS-045, a new antidiabetic agent, activated 6-phosphofructo-2-ki nase and raised fructose-2,6-bisphosphate levels in dispersed rat hepa tocytes. This action was time- and dose-dependent. Ten micromolar CS-0 45 raised the fructose-2,6-bisphosphate content linearly to the submax imal level in 20 min. Dose dependency was observed in the range of 1-3 0 muM. Thirty micromolar CS-045 completely reversed the inhibitory eff ect of 0.1 nM glucagon on fructose-2,6-bisphosphate production. CS-045 activated 6-phosphofructo-2-kinase by decreasing the K(m) value for t he substrate (fructose-6-phosphate) without affecting the V(max). The combination of suboptimal doses of CS-045 and tolbutamide increased fr uctose-2,6-bisphosphate content more than that induced by each agent a lone. These results indicate that CS-045 may reduce plasma glucose by facilitating glycolysis in the liver.