Nauck M A, Siegel E G, Creutzfeldt W
Department of Medicine, Georg-August-University, Goettingen, F.R.G.
Pancreas. 1991 Nov;6(6):645-52. doi: 10.1097/00006676-199111000-00005.
Release of immature secretory granules rich in incompletely processed proinsulin has been proposed to explain the relative hyperproinsulinemia in type 2 diabetic and insulinoma patients because of a constant secretory drive resulting from hyperglycemia and autonomous secretion, respectively. To test this hypothesis, insulin secretion was stimulated by a combination of hyperglycemia (11 mmol/L clamp), intravenous (i.v.) tolbutamide (1 g), and i.v. glucagon (initial bolus 10 micrograms/kg body weight, maintenance infusion 2 micrograms/kg body weight per hour) for 3 h. Circulating IR-insulin and IR-C-peptide concentrations increased 89-fold and 14-fold over basal values, respectively, but IR-proinsulin concentrations increased only ninefold over basal values. Estimation of the amount of insulin secreted (based on deconvolution analysis of plasma C-peptide values) showed that approximately 76 +/- 21 U were secreted during the stimulation period. This amount is a significant proportion of pancreatic insulin content in normal humans. In molar terms, IR-proinsulin (integrated incremental response multiplied by metabolic clearance rate of proinsulin) relative to IR-C-peptide (= insulin) secretion (deconvolution analysis) was estimated to be equal or even lower than the known proportion in islets (0.22 +/- 0.05%). Thus, using a near-maximal stimulation of insulin secretion maintained long enough to cause release of amounts of insulin approaching the estimated pancreatic content, no preferential release of proinsulin was observed in normal humans. Therefore, the hyperproinsulinemia of type 2 diabetes and in insulinoma patients may be caused by additional defects in the proinsulin to insulin conversion process.
富含未完全加工的胰岛素原的未成熟分泌颗粒的释放，已被提出用于解释2型糖尿病患者和胰岛素瘤患者中相对的高胰岛素原血症，其原因分别是高血糖导致的持续分泌驱动和自主分泌。为了验证这一假设，通过高血糖（11 mmol/L钳夹）、静脉注射甲苯磺丁脲（1 g）和静脉注射胰高血糖素（初始推注10微克/千克体重，维持输注2微克/千克体重/小时）联合刺激胰岛素分泌3小时。循环中的免疫反应性胰岛素（IR-胰岛素）和免疫反应性C肽（IR-C肽）浓度分别比基础值增加了89倍和14倍，但IR-胰岛素原浓度仅比基础值增加了9倍。根据血浆C肽值的反卷积分析估算胰岛素分泌量，结果显示在刺激期约分泌了76±21单位的胰岛素。这个量在正常人体内是胰腺胰岛素含量的很大一部分。以摩尔计算，相对于IR-C肽（=胰岛素）分泌（反卷积分析），IR-胰岛素原（胰岛素原的综合增量反应乘以胰岛素原的代谢清除率）估计等于甚至低于胰岛中的已知比例（0.22±0.05%）。因此，在正常人体内，使用接近最大程度的胰岛素分泌刺激并维持足够长的时间以导致胰岛素释放量接近估计的胰腺含量时，未观察到胰岛素原的优先释放。所以，2型糖尿病患者和胰岛素瘤患者的高胰岛素原血症可能是由胰岛素原向胰岛素转化过程中的其他缺陷引起的。
