Caro J F, Ittoop O, Sinha M K
Department of Medicine, School of Medicine, East Carolina University, Greenville, NC 27858-4354.
Metabolism. 1989 Jul;38(7):606-11. doi: 10.1016/0026-0495(89)90095-4.
To test the hypothesis that sulfonylureas enhance insulin action by activating the insulin receptor tyrosine kinase, the effects of glyburide, a second generation sulfonylurea, and ciglitazone, a nonsulfonylurea hypoglycemic agent, were determined in primary cultures of rat hepatocytes on insulin action and insulin receptor structure and function. Twenty hours of preincubation with glyburide (1 microgram/mL) resulted in increased insulin (1 X 10(-7) mol/L) stimulation of [14C] acetate incorporation into lipids and [14C] alpha-aminoisobutyric acid uptake without any change in basal activity. Ciglitazone (1 microgram/mL) was without any effect. Glyburide's actions were mediated without altering the following: (1) 125I-insulin binding; (2) the electrophoretic mobility of the affinity labeled alpha-subunit or the autophosphorylated beta-subunit of the insulin receptor; and (3) the insulin-stimulated insulin receptor kinase activity using histone or the beta-subunit of the insulin receptor as phosphoacceptors. These data suggest that the action of sulfonylureas is distal to the insulin receptor tyrosine kinase. Ciglitazone in vitro is ineffective in the liver, which suggests the peripheral tissues as the possible site of action.
为了验证磺脲类药物通过激活胰岛素受体酪氨酸激酶增强胰岛素作用这一假说，研究了第二代磺脲类药物格列本脲以及非磺脲类降糖药环格列酮对原代培养大鼠肝细胞胰岛素作用、胰岛素受体结构和功能的影响。用格列本脲（1微克/毫升）预孵育20小时后，胰岛素（1×10⁻⁷摩尔/升）对[¹⁴C]乙酸掺入脂质及[¹⁴C]α-氨基异丁酸摄取的刺激作用增强，而基础活性无变化。环格列酮（1微克/毫升）则无任何作用。格列本脲的作用是通过以下方式介导的：（1）不改变¹²⁵I-胰岛素结合；（2）不改变胰岛素受体亲和标记α亚基或自身磷酸化β亚基的电泳迁移率；（3）不改变以组蛋白或胰岛素受体β亚基作为磷酸受体时胰岛素刺激的胰岛素受体激酶活性。这些数据表明磺脲类药物的作用发生在胰岛素受体酪氨酸激酶的下游。环格列酮在体外肝脏中无效，提示外周组织可能是其作用部位。
