Salhanick A I, Konowitz P, Amatruda J M
Diabetes. 1983 Mar;32(3):206-12. doi: 10.2337/diab.32.3.206.
Although sulfonylureas have been used extensively in the treatment of non-insulin-dependent (type II) diabetes, controversy exists as to whether these agents act primarily by increasing insulin secretion or by enhancing insulin action. To determine whether sulfonylureas potentiate insulin action in the liver, we evaluated the ability of the sulfonylurea tolazamide to affect insulin-sensitive lipogenesis utilizing primary cultures of hepatocytes prepared from both normal and nonketotic streptozotocin-diabetic rats. Hepatocytes were cultured for 16 h in serum-free media with no additions, tolazamide alone (0.3 mg/ml), or insulin (10(-10) to 10(-7)M) in the absence and presence of tolazamide. Following culture, lipogenesis and specific insulin binding were assessed. Dose-dependent increases in lipogenesis were found in hepatocytes from both normal and diabetic rats after the chronic exposure to insulin. In hepatocytes from diabetic rats, the basal and the maximal insulin-stimulated rates of lipogenesis were only 27% and 13% of normal, respectively, establishing this as a model of hepatic insulin resistance. In the presence of tolazamide, significant potentiation of insulin action was found in hepatocytes from normal and diabetic rats although hepatocytes from diabetic animals remained relatively resistant to insulin when compared with those from nondiabetic animals. While exposure to tolazamide increased insulin responsiveness in both groups of cells, no changes in insulin sensitivity (ED50) were observed. Tolazamide significantly increased insulin binding (12%) in hepatocytes from normal rats cultured in the absence of insulin, but no alterations in insulin binding were found under incubation conditions in which tolazamide potentiated insulin action. These results give the first direct evidence for an insulin-dependent action of a sulfonylurea on the liver from both normal and diabetic rats and indicate that the enhancement of insulin responsiveness occurs through postbinding mechanisms.
尽管磺脲类药物已被广泛用于治疗非胰岛素依赖型（II型）糖尿病，但关于这些药物主要是通过增加胰岛素分泌还是增强胰岛素作用存在争议。为了确定磺脲类药物是否能增强肝脏中的胰岛素作用，我们利用从正常和非酮症链脲佐菌素诱导的糖尿病大鼠制备的原代肝细胞培养物，评估了磺脲类药物甲苯磺丁酰胺影响胰岛素敏感性脂肪生成的能力。肝细胞在无添加物、仅含甲苯磺丁酰胺（0.3mg/ml）或胰岛素（10⁻¹⁰至10⁻⁷M）的无血清培养基中培养16小时，有无甲苯磺丁酰胺均进行培养。培养后，评估脂肪生成和特异性胰岛素结合情况。慢性暴露于胰岛素后，正常和糖尿病大鼠的肝细胞中脂肪生成均呈剂量依赖性增加。在糖尿病大鼠的肝细胞中，基础和最大胰岛素刺激的脂肪生成率分别仅为正常的27%和13%，从而将其确立为肝胰岛素抵抗模型。在甲苯磺丁酰胺存在的情况下，正常和糖尿病大鼠的肝细胞中均发现胰岛素作用显著增强，尽管与非糖尿病动物的肝细胞相比，糖尿病动物的肝细胞对胰岛素仍相对抵抗。虽然暴露于甲苯磺丁酰胺可增加两组细胞中的胰岛素反应性，但未观察到胰岛素敏感性（ED50）的变化。甲苯磺丁酰胺显著增加了在无胰岛素培养的正常大鼠肝细胞中的胰岛素结合（12%），但在甲苯磺丁酰胺增强胰岛素作用的培养条件下未发现胰岛素结合的改变。这些结果首次直接证明了磺脲类药物对正常和糖尿病大鼠肝脏具有胰岛素依赖性作用，并表明胰岛素反应性的增强是通过结合后机制发生的。
