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

口服抗糖尿病药物的胰外作用机制

• 批准号: 04671482
• 负责人: INOUE Yasushi
• 金额: $ 1.28万
• 依托单位: Yamaguchi University, School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1992
• 资助国家: 日本
• 起止时间: 1992 至 1993
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671482/
• 关键词: Liver; Sulfonylurea; Glibenclamide; Tolbutamide; Fructose-2,6-bisphosphate; Phosphenolpyruvate carboxykinase; Glycolysis; Gluconeogenesis; スルフォニル尿素剤; フォスフォエノールピルビン酸カルボキシナーゼ; スルフォニルウレア; CS-045; PEPCK

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.

1)格列本脲在大鼠肝细胞膜上特异性结合位点的证明。分析了[^3H]格列本脲在大鼠肝细胞膜粗组分中结合位点的特征。结合是特异性的，时间和温度依赖性的，可逆的。计算的解离常数（Kd= 1.1 μ M）高于β细胞肿瘤或脑中报道的解离常数。2）非磺酰脲类降糖药CS-045对胰岛β细胞分泌胰岛素无刺激作用，但对胰岛β细胞分泌胰岛素无刺激作用。降血糖作用应以“胰外”作用为基础。我们证明CS-045刺激F-2，6-P_2产生的机制与甲苯磺丁脲相似。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）我们表明甲苯磺丁脲抑制大鼠肝癌细胞系H4-IIE细胞中的PEPCK活性，PEPCK是细胞生成的关键酶。这种抑制是由细胞中PEPCK的mRNA减少引起的。

项目成果

村野 健兒他: "CS-045のラット肝解糖系促進作用 -肝F-2,6-P_2産生におよぼす効果-" 糖尿病. 35 supple.1. 216 (1992)

Kenji Murano 等人：“CS-045 对大鼠肝糖酵解的促进作用 - 对肝脏 F-2,6-P_2 产生的影响”糖尿病 35 suple.1 (1992)。

Y.Inoue et al.: "Insulin Resistance in Human Disease" Excerpta Medica (分担265-268), 412 (1993)

Y. Inoue 等人：“人类疾病中的胰岛素抵抗”医学摘录（贡献 265-268），412（1993）

K.Murano, Y.Inoue, K.Kaku, & T.Kaneko: "CS-045, a new oral antidiabetic agent, stimulates fructose-2,6-bisphosphate production in rat hepatocytes" Eur.J.Pharmacol. (in press). (1994)

K.Murano、Y.Inoue、K.Kaku、

M.Emoto et al.: "The inhibitory effect of tolbutamide on〜" Biochem.Biophys.Res.Commun.191. 465-471 (1993)

M.Emoto 等人：“甲苯磺丁脲对〜”的抑制作用 Biochem.Biophys.Res.Commun.191（1993）。

K.Murano et al.: "CS-045,a new oral antidiabetic agent,stimulates 〜" Eur.,J.Pharmacol.(in press).

K. Murano 等人：“CS-045，一种新型口服抗糖尿病药，刺激 ~”Eur.，J. Pharmacol（出版中）。