Sherwin R S, Bastl C, Finkelstein F O, Fisher M, Black H, Hendler R, Felig P
J Clin Invest. 1976 Mar;57(3):722-31. doi: 10.1172/JCI108330.
To evaluate the mechanism and role of hyperglucagonemia in the carbohydrate intolerance of uremia, 19 patients with chronic renal failure (12 of whom had undergone chronic hemodialysis for at least 11 mo) and 35 healthy control subjects were studied. Plasma glucagon, glucose, and insulin were measured in the basal state, after glucose ingestion (100 g), after intravenous alanine (0.15 g/kg), and during a 3-h continuous infusion of glucagon (3 ng/kg per min) which in normal subjects, raised plasma glucagon levels into the upper physiological range. Basal concentrations of plasma glucagon, the increment in glucagon after infusion of alanine, and post-glucose glucagon levels were three- to fourfold greater in uremic patients than in controls. The plasma glucagon increments after the infusion of exogenous glucagon were also two- to threefold greater in the uremics. The metabolic clearance rate (MCR) of glucagon in uremics was reduced by 58% as compared to controls. In contrast, the basal systemic delivery rate (BSDR) of glucagon in uremics was not significantly different from controls. Comparison of dialyzed and undialyzed uremics showed no differences with respect to plasma concentrations, MCR, or BSDR of glucagon. However, during the infusion of glucagon, the increments in plasma glucose in undialyzed uremics were three- to fourfold greater than in dialyzed uremics or controls. When the glucagon infusion rate was increased in controls to 6 ng/kg per min to produce increments in plasma glucagon comparable to uremics, the glycemic response remained approximately twofold greater in the undialyzed uremics. The plasma glucose response to glucagon in the uremics showed a direct linear correlation with oral glucose tolerance which was also improved with dialysis. The glucagon infusion resulted in 24% reduction in plasma alanine in uremics but had no effect on alanine levels in controls. It is concluded that (a) hyperglucagonemia in uremia is primarily a result of decreased catabolism rather than hypersecretion of this hormone; (b) sensitivity to the hyperglycemic effect of physiological increments in glucagon is increased in undialyzed uremic patients; and (c) dialysis normalizes the glycemic response to glucagon, possibly accounting thereby for improved glucose tolerance despite persistent hyperglucagonemia. These findings thus provide evidence of decreased hormonal catabolism contributing to a hyperglucagonemic state, and of altered tissue sensitivity contributing to the pathophysiological action of this hormone.
为评估高胰高血糖素血症在尿毒症碳水化合物不耐受中的机制及作用，对19例慢性肾衰竭患者（其中12例已接受慢性血液透析至少11个月）和35名健康对照者进行了研究。在基础状态下、摄入葡萄糖（100克）后、静脉注射丙氨酸（0.15克/千克）后以及在3小时持续输注胰高血糖素（3纳克/千克每分钟）期间，测定血浆胰高血糖素、葡萄糖和胰岛素水平，在正常受试者中，该输注可使血浆胰高血糖素水平升至生理范围上限。尿毒症患者血浆胰高血糖素的基础浓度、输注丙氨酸后胰高血糖素的增量以及葡萄糖后胰高血糖素水平比对照组高3至4倍。尿毒症患者输注外源性胰高血糖素后血浆胰高血糖素的增量也比对照组高2至3倍。与对照组相比，尿毒症患者胰高血糖素的代谢清除率（MCR）降低了58%。相比之下，尿毒症患者胰高血糖素的基础全身输送率（BSDR）与对照组无显著差异。透析和未透析的尿毒症患者在胰高血糖素的血浆浓度、MCR或BSDR方面无差异。然而，在输注胰高血糖素期间，未透析的尿毒症患者血浆葡萄糖的增量比透析的尿毒症患者或对照组高3至4倍。当将对照组的胰高血糖素输注速率提高到6纳克/千克每分钟以产生与尿毒症患者相当的血浆胰高血糖素增量时，未透析的尿毒症患者的血糖反应仍比其高约两倍。尿毒症患者对胰高血糖素的血浆葡萄糖反应与口服葡萄糖耐量呈直接线性相关，透析后口服葡萄糖耐量也有所改善。胰高血糖素输注使尿毒症患者血浆丙氨酸降低了24%，但对对照组的丙氨酸水平无影响。得出的结论是：（a）尿毒症中的高胰高血糖素血症主要是该激素分解代谢减少而非分泌过多的结果；（b）未透析的尿毒症患者对胰高血糖素生理增量的高血糖作用敏感性增加；（c）透析使对胰高血糖素的血糖反应正常化，这可能是尽管持续存在高胰高血糖素血症但葡萄糖耐量仍改善的原因。因此，这些发现提供了证据，证明激素分解代谢减少导致高胰高血糖素血症状态，以及组织敏感性改变导致该激素的病理生理作用。
