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-kinase, a key enzyme in glycolysis. We previously revealed that sulfonylureas 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-kinase and raised fructose-2,6-bisphosphate levels in dispersed rat hepatocytes. This action was time- and dose-dependent. Ten micromolar CS-045 raised the fructose-2,6-bisphosphate content linearly to the submaximal level in 20 min. Dose dependency was observed in the range of 1-30 microM. Thirty micromolar CS-045 completely reversed the inhibitory effect of 0.1 nM glucagon on fructose-2,6-bisphosphate production. CS-045 activated 6-phosphofructo-2-kinase by decreasing the Km value for the substrate (fructose-6-phosphate) without affecting the Vmax. The combination of suboptimal doses of CS-045 and tolbutamide increased fructose-2,6-bisphosphate content more than that induced by each agent alone. These results indicate that CS-045 may reduce plasma glucose by facilitating glycolysis in the liver.
Murano
K
K
Third Department of Internal Medicine, Yamaguchi University School of Medicine, Ube, Japan.
Inoue
Y
Y
Emoto
M
M
Kaku
K
K
Kaneko
T
T
D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005635:Fructosediphosphates / Q000096:biosynthesis* / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014044:Tolbutamide / Q000494:pharmacology; D000077288:Troglitazone
D002839:Chromans; D005635:Fructosediphosphates; D013844:Thiazoles; D045162:Thiazolidinediones; C027652:fructose 2,6-diphosphate; D005934:Glucagon; D014044:Tolbutamide; D000242:Cyclic AMP; D000077288:Troglitazone