Emmanouel D S, Jaspan J B, Kuku S F, Rubenstein A H, Katz A I, Huen A H
J Clin Invest. 1976 Nov;58(5):1266-72. doi: 10.1172/JCI108581.
The pathogenesis of hyperglucagonemia and of the alterations in the pattern of circulating immunoreactive glucagon (IRG) associated with renal insufficiency was studied in rats in which a comparable degree of uremia was induced by three different methods, i.e., bilateral nephrectomy, bilateral ureteral ligation, and urine autoinfusion. Nephrectomized and ureteral-ligated rats were markedly hyperglucagonemic (575 +/- 95 pg/ml and 492 +/- 54 pg/ml, respectively), while IRG levels of urine autoinfused animals (208 +/- 35 pg/ml) were similar to those of control rats (180 +/- 26 pg/ml), indicating that uremia per se does not account for the hyperglucagonemia observed in renal failure. Similarly, plasma IRG composition in this group of animals was indistinguishable from that of controls, in which 88.2 +/- 5.9% of total IRG consisted of the 3,500-mol wt fraction. The same component was almost entirely responsible (82.6 +/- 4.1%) for the hyperglucagonemia observed in ligated rats, while it accounted for only 57.6 +/- 5.0% of the circulating IRG in nephrectomized animals. In the latter group, 36.8 +/- 6.6% of total IRG had a mol wt of approximately 9,000, consistent with a glucagon precursor. This peak was present in samples obtained as early as 2 h after renal ablation and its concentration continued to increase with time reaching maximal levels at 24 h. These results confirm that the kidney is a major site of glucagon metabolism and provide evidence that the renal handling of the various circulating IRG components may involve different mechanisms. Thus, the metabolism of the 3,500-mol wt fraction is dependent upon glomerular filtration, while the uptake of the 9,000-mol wt material can proceed in its absence, as long as renal tissue remains adequately perfused. This finding suggests that the 9,000-mol wt component may be handled by peritubular uptake.
采用三种不同方法在大鼠中诱导出程度相当的尿毒症，以此研究高胰高血糖素血症的发病机制以及与肾功能不全相关的循环免疫反应性胰高血糖素（IRG）模式改变。这三种方法分别是双侧肾切除、双侧输尿管结扎和尿液自身输注。肾切除和输尿管结扎的大鼠出现明显的高胰高血糖素血症（分别为575±95 pg/ml和492±54 pg/ml），而尿液自身输注动物的IRG水平（208±35 pg/ml）与对照大鼠（180±26 pg/ml）相似，这表明尿毒症本身并不能解释肾衰竭中观察到的高胰高血糖素血症。同样，该组动物的血浆IRG组成与对照组无法区分，对照组中总IRG的88.2±5.9%由分子量为3500的组分构成。在结扎大鼠中观察到的高胰高血糖素血症几乎完全由同一组分引起（82.6±4.1%），而在肾切除动物中，它仅占循环IRG的57.6±5.0%。在后一组中，总IRG的36.8±6.6%分子量约为9000，与胰高血糖素前体一致。该峰值在肾切除后最早2小时获取的样本中就已存在，其浓度随时间持续增加，在24小时达到最高水平。这些结果证实肾脏是胰高血糖素代谢的主要部位，并提供证据表明肾脏对各种循环IRG组分的处理可能涉及不同机制。因此，分子量为3500的组分的代谢依赖于肾小球滤过，而分子量为9000的物质的摄取在没有肾小球滤过的情况下也能进行，只要肾组织保持充分灌注。这一发现表明分子量为9000的组分可能通过肾小管周围摄取来处理。
