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

1)论证了格列本脲在大鼠肝膜上的特异性结合位点。分析了[^3H]格列本脲在大鼠粗肝膜组分中的结合位点特征。这种结合具有特异性、时间和温度依赖性和可逆性。计算的解离常数（Kd=1.1muM）高于β细胞肿瘤或脑中的解离常数。然而，肝脏中的结合位点似乎发挥了一定的作用，因为在这些浓度的磺脲类药物中观察到果糖-2,6-二磷酸（f -2,6- p_2）的产生和磷酸烯醇丙酮酸羧激酶（PEPCK）的抑制。2)非su降糖药CS-045对β细胞分泌胰岛素无刺激作用。降糖作用应基于“胰腺外”作用。我们证明了CS-045刺激f -2,6- p_2产生的机制与甲苯丁胺相似。这一事实可能表明CS-045通过促进肝脏中的糖酵解来降低血糖。3)甲苯丁胺抑制大鼠肝癌细胞系H4-IIE细胞糖异生关键酶PEPCK的活性。抑制作用是由细胞中PEPCK mRNA的减少引起的。

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.