Soman V, Felig P
J Clin Invest. 1977 Jul;60(1):224-32. doi: 10.1172/JCI108759.
To investigate the role of glucagon and insulin receptor binding in the glucagon hypersensitivity and insulin resistance which characterize the glucose intolerance of uremia, liver plasma membranes were prepared from control rats (blood urea nitrogen [BUN] 15+/-1 mg/100 ml, creatinine 0.7+/-0.2 mg/100 ml), and from 70% nephrectomized rats (BUN 30+/-2 mg/100 ml, creatinine 2.2+/-0.2 mg/100 ml), and from 90% nephrectomized rats (BUN 46+/-3 mg/100 ml, creatinine 4.20+/-0.7 mg/100 ml), 4 wk after surgery. As compared to controls, the 90% nephrectomized rats had significantly higher levels of plasma glucose (95+/-4 vs. 125+/-11 mg/100 ml), plasma insulin (28+/-9 vs. 52+/-11 muU/ml), and plasma glucagon (28+/-5 vs. 215+/-18 pg/ml). Similar, but less marked, elevations were observed in the 70% nephrectomized animals. In liver plasma membranes from nephrectomized rats, specific binding of (125)I-glucagon was increased by 80-120%. Furthermore, glucagon (2 muM)-stimulated adenylate cyclase activity in nephrectomized rats was twofold higher than in controls. In contrast, fluoridestimulated adenylate cyclase activity was similar in both groups of rats. In marked contrast to glucagon binding, specific binding of (125)I-insulin to liver membranes from nephrectomized rats was reduced by 40-50% as compared to controls. Data analysis suggested that the changes in both glucagon and insulin binding are a consequence of alterations in binding capacity rather than changes in affinity. Liver plasma membranes from nephrectomized rats degraded (125)I-glucagon and (125)I-insulin to the same extent as control rats. THESE RESULTS DEMONSTRATE THAT: (a) the 70 and 90% nephrectomized rats simulate the hyperglycemia, hyperinsulinemia, and hyperglucagonemia observed in clinical uremia; (b) in these animals specific binding of glucagon to liver membranes is increased and is accompanied by higher glucagon-stimulated adenylate cyclase activity; and (c) specific binding of insulin is markedly decreased. These findings thus provide evidence of oppositely directed, simultaneous changes in glucagon and insulin receptor binding in partially nephrectomized rats. Such changes may account for the hypersensitivity to glucagon and may contribute to resistance to insulin observed in the glucose intolerance of uremia.
为研究胰高血糖素与胰岛素受体结合在胰高血糖素超敏反应及胰岛素抵抗（这是尿毒症患者糖耐量异常的特征）中所起的作用，分别从对照组大鼠（血尿素氮[BUN]15±1mg/100ml，肌酐0.7±0.2mg/100ml）、70%肾切除大鼠（BUN 30±2mg/100ml，肌酐2.2±0.2mg/100ml）以及90%肾切除大鼠（BUN 46±3mg/100ml，肌酐4.20±0.7mg/100ml）（术后4周）制备肝细胞膜。与对照组相比，90%肾切除大鼠的血糖水平（95±4 vs. 125±11mg/100ml）、血浆胰岛素水平（28±9 vs. 52±11μU/ml）及血浆胰高血糖素水平（28±5 vs. 215±18pg/ml）显著升高。70%肾切除动物也观察到类似但程度较轻的升高。在肾切除大鼠的肝细胞膜中，(125)I-胰高血糖素的特异性结合增加了80 - 120%。此外，胰高血糖素（2μM）刺激的肾切除大鼠腺苷酸环化酶活性比对照组高两倍。相比之下，两组大鼠中氟化物刺激的腺苷酸环化酶活性相似。与胰高血糖素结合形成鲜明对比的是，与对照组相比，肾切除大鼠肝细胞膜上(125)I-胰岛素的特异性结合减少了40 - 50%。数据分析表明，胰高血糖素和胰岛素结合的变化是结合能力改变的结果，而非亲和力变化。肾切除大鼠的肝细胞膜对(125)I-胰高血糖素和(125)I-胰岛素的降解程度与对照大鼠相同。这些结果表明：(a) 70%和90%肾切除大鼠模拟了临床尿毒症中观察到的高血糖、高胰岛素血症和高胰高血糖素血症；(b) 在这些动物中，胰高血糖素与肝细胞膜上的特异性结合增加，并伴有更高的胰高血糖素刺激的腺苷酸环化酶活性；(c) 胰岛素的特异性结合显著降低。因此，这些发现提供了部分肾切除大鼠胰高血糖素和胰岛素受体结合同时发生相反方向变化的证据。这种变化可能解释了对胰高血糖素的超敏反应，并可能导致尿毒症患者糖耐量异常中观察到的胰岛素抵抗。
