Jehle P M, Fussgaenger R D, Kunze U, Dolderer M, Warchol W, Koop I
Department of Internal Medicine, University of Ulm, Germany.
J Clin Endocrinol Metab. 1996 Jun;81(6):2319-27. doi: 10.1210/jcem.81.6.8964871.
The rapidly absorbed analog of human insulin, insulin lispro (LP), is characterized by a faster onset of action, a higher peak insulin level, and a shorter duration of action compared with regular insulin (RI). The aim of this study was to investigate whether intensified treatment with either LP or RI influences insulin receptor status. Twelve patients with insulin-dependent diabetes mellitus (IDDM) participating in a multicenter randomized cross-over trial were allocated to this study. Four patients began with LP, whereas eight patients started with RI. Each patient was switched to the other insulin after a 3-month treatment period. Competitive [125I]A-14-insulin binding studies were performed with isolated monocytes. Treatment with insulin lispro increased the total number of insulin binding sites from 9,400 +/- 2,200 (RI) to 20,300 +/- 3,000 (LP)/monocyte (P < 0.001). The insulin concentration required for a 50% competition of [125I]insulin binding (IC50) decreased from 0.6 +/- 0.2 (RI) to 0.1 +/- 0.03 (LP) nmol/L, indicating significantly higher affinity of insulin binding sites during LP treatment (P < 0.001). In additional experiments, the time course of insulin binding was determined after an oral meal. In LP-treated IDDM patients, the affinity and capacity of insulin binding showed a nadir 1 h after insulin injection and a regained binding affinity and capacity 5 h later. These changes observed after LP treatment were comparable to the effect of endogenous insulin secretion in healthy control subjects. In contrast, the IDDM patients who injected RI showed a decreasing insulin binding affinity and capacity, most markedly expressed after 5 h. The corresponding serum levels of insulin were inversely correlated with the affinity and capacity of insulin-binding sites. Pretreatment of cultured human IM-9 lymphoblasts with LP or RI yielded no difference in the down-regulation of insulin binding. In summary, intensified conventional insulin therapy with LP increased the number and affinity of insulin receptors on circulating monocytes to a level similar to that observed in healthy subjects. We conclude that the improved insulin receptor status observed during LP treatment is caused by its more physiological pharmacokinetic profile.
胰岛素类似物赖脯胰岛素（LP）吸收迅速，与常规胰岛素（RI）相比，其起效更快、胰岛素峰值水平更高、作用持续时间更短。本研究的目的是调查用LP或RI强化治疗是否会影响胰岛素受体状态。12名参与多中心随机交叉试验的胰岛素依赖型糖尿病（IDDM）患者被分配到本研究中。4名患者开始使用LP，而8名患者开始使用RI。每个患者在3个月的治疗期后改用另一种胰岛素。用分离的单核细胞进行竞争性[125I]A - 14胰岛素结合研究。赖脯胰岛素治疗使胰岛素结合位点总数从9400±2200（RI）增加到20300±3000（LP）/单核细胞（P<0.001）。[125I]胰岛素结合50%竞争所需的胰岛素浓度（IC50）从0.6±0.2（RI）降至0.1±0.03（LP）nmol/L，表明在LP治疗期间胰岛素结合位点的亲和力显著更高（P<0.001）。在额外的实验中，在口服餐后测定胰岛素结合的时间进程。在接受LP治疗的IDDM患者中，胰岛素注射后1小时胰岛素结合的亲和力和容量出现最低点，5小时后恢复结合亲和力和容量。LP治疗后观察到的这些变化与健康对照受试者内源性胰岛素分泌的效果相当。相比之下，注射RI的IDDM患者胰岛素结合亲和力和容量降低，5小时后最为明显。相应的血清胰岛素水平与胰岛素结合位点的亲和力和容量呈负相关。用LP或RI预处理培养的人IM - 9淋巴母细胞在胰岛素结合的下调方面没有差异。总之，用LP强化常规胰岛素治疗可使循环单核细胞上胰岛素受体的数量和亲和力增加到与健康受试者相似的水平。我们得出结论，LP治疗期间观察到的胰岛素受体状态改善是由其更符合生理的药代动力学特征引起的。
