Mechanisms of extra-pancreatic effects of oral anti-diabetic agents

点击翻译按钮获取中文摘要

1) Demonstration of the specific binding sites fo glibenclamide in rat liver membrane. The characters of the binding sites for [^3H]glibenclamide in rat crude liver membrane fraction were analyzed. The binding was specific, time- and temperature-dependent, and reversible. The calculated dissociation constant (Kd=1.1muM) was higher that those reported in beta-cell tumors or brain. The binding sites in the liver, however, seemed to play some roles because the stimulation of fructose-2,6-bisphosphate (F-2,6-P_2) production and inhibition of phosphoenolpyruvate carboxykinase (PEPCK) were observed in these concentrations of sulfonylurea(SU) drugs.2) Non-SU anti-diabetic drug, CS-045, has no stimulatory effect on insulin secretion from the beta-cells. The hypoglycemic effect should be based on "extra-pancreatic" action. We demonstrated that CS-045 stimulates F-2,6-P_2 production by the similar mechanism to tolbutamide. The fact may suggest that CS-045 reduces blood glucose by facilitating glycolysis in the liver.3) We showed that tolbutamide inhibits the activity of PEPCK, the key enzyme in gluconeogenesis, in rat hepatoma cell line H4-IIE cells. The inhibition is caused by reduction of mRNA for PEPCK in the cells.