Kang S, Brange J, Burch A, Vølund A, Owens D R
Department of Medicine, University of Wales College of Medicine, Cardiff, United Kingdom, Research Institute.
Diabetes Care. 1991 Nov;14(11):942-8. doi: 10.2337/diacare.14.11.942.
To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans.
Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting.
The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and 68.9 +/- 3.5 from 2.5 h onward; and hexameric insulin 20.7 +/- 1.9 from 0 to 2 h, 45.6 +/- 5.0 from 2.5 to 5 h, and 70.6 +/- 6.3 from 5 h onward.
Association state is a major determinant of rates of absorption of insulin and insulin analogues. The lag phase and the subsequent increasing rate of subcutaneous soluble insulin absorption can be explained by the associated state of native insulin in pharmaceutical formulation and its progressive dissociation into smaller units during the absorption process.
研究分子聚集对皮下胰岛素吸收速率的影响，并试图阐明传统可溶性人胰岛素在人体中的吸收机制。
本研究纳入7名年龄在22 - 43岁、未服用任何药物的健康男性志愿者。本研究为单盲随机对照试验，比较等摩尔剂量的125I标记的可溶性六聚体2 Zn2+人胰岛素以及处于不同缔合状态的人胰岛素类似物（AspB10，二聚体；AspB28，单体与二聚体混合物；AspB9，GluB27，单体）在药物浓度下的情况。经过一夜禁食和1小时的基础期后，在相隔1周的4个不同日期，皮下注射0.6 nmol/kg的125I标记的人可溶性胰岛素（Actrapid HM U - 100）或125I标记的类似物。通过外部γ计数测量注射部位的残余放射性来评估吸收情况。
四种制剂的平均±标准误初始分数消失率分别为20.7±1.9（六聚体可溶性人胰岛素）、44.4±2.5（二聚体类似物AspB10）、50.6±3.9（类似物AspB28）和67.4±7.4%/小时（单体类似物AspB9，GluB27）。二聚体类似物的吸收明显快于六聚体人胰岛素（P<0.001）；单体胰岛素类似物AspB9，GluB27的吸收明显快于二聚体类似物AspB10（P<0.01）。缔合状态与初始分数消失率之间存在负线性相关（r = -0.98，P<0.02）。在对数线性尺度上对消失数据进行分析表明，只有单体类似物在整个过程中具有单指数过程。二聚体的吸收速率确定有两个阶段，六聚体人胰岛素有三个阶段。通过对数线性回归分析计算的分数消失率（%/小时）为：单体73.3±6.8；二聚体在0至2小时为44.4±2.5，在2.5小时及以后为68.9±3.5；六聚体胰岛素在0至2小时为20.7±1.9，在2.5至5小时为45.6±5.0，在5小时及以后为70.6±6.3。
缔合状态是胰岛素和胰岛素类似物吸收速率的主要决定因素。皮下可溶性胰岛素吸收的延迟期和随后增加的速率可以通过药物制剂中天然胰岛素的缔合状态及其在吸收过程中逐渐解离为较小单元来解释。
