OBJECTIVE:We investigated the impact of two different injection strategies on the pharmacokinetics and pharmacodynamics of insulin aspart in vivo in an open-label, two-period crossover study and verified changes in the surface-to-volume ratio ex vivo. RESEARCH DESIGN AND METHODS:Before the clinical trial, insulin aspart was injected ex vivo into explanted human abdominal skin flaps. The surface-to-volume ratio of the subcutaneous insulin depot was assessed by microfocus computed tomography that compared 1 bolus of 18 IU with 9 dispersed boluses of 2 IU. These two injection strategies were then tested in vivo, in 12 C-peptide-negative type 1 diabetic patients in a euglycemic glucose clamp (glucose target 5.5 ± 1.1 mmol/L) for 8 h after the first insulin administration. RESULTS:The ex vivo experiment showed a 1.8-fold higher mean surface-to-volume ratio for the dispersed injection strategy. The maximum glucose infusion rates (GIR) were similar for the two strategies (10 ± 4 vs. 9 ± 4; P = 0.5); however, times to reach maximum GIR and 50% and 10% of the maximum GIR were significantly reduced by using the 9 × 2 IU strategy (68 ± 33 vs. 127 ± 93 min; P = 0.01; 38 ± 9 vs. 49 ± 16 min; P < 0.01; 23 ± 6 vs. 30 ± 10 min; P < 0.05). For 9 × 2 IU, the area under the GIR curve was greater during the first 60 min (219 ± 89 vs. 137 ± 75; P < 0.01) and halved until maximum GIR (242 ± 183 vs. 501 ± 396; P < 0.01); however, it was similar across the whole study period (1,361 ± 469 vs. 1,565 ± 527; P = 0.08). CONCLUSIONS:A dispersed insulin injection strategy enhanced the effect of a fast-acting insulin analog. The increased surface-to-volume ratio of the subcutaneous insulin depot can facilitate insulin absorption into the vascular system.

译文

目的:我们在开放标签,两期交叉研究中研究了两种不同的注射策略对体内门冬胰岛素的药代动力学和药效学的影响,并验证了离体表面积与体积比的变化。
研究设计和方法:在临床试验之前,将门冬胰岛素离体注射到植入的人腹部皮肤皮瓣中。皮下胰岛素贮存库的表面体积比是通过微焦点计算机断层扫描技术评估的,该技术比较了1个大剂量的18 IU与9个分散的大剂量的2 IU。然后在首次胰岛素给药后的正常血糖葡萄糖钳位(葡萄糖靶标5.5±1.1 mmol / L)中,在12名C肽阴性1型糖尿病患者体内测试了这两种注射策略。
结果:离体实验显示,分散注射策略的平均表面体积比高1.8倍。两种策略的最大葡萄糖输注速率(GIR)相似(10±4 vs. 9±4; P = 0.5);但是,通过使用9×2 IU策略,达到最大GIR以及达到最大GIR的时间分别减少了50%和10%(68±33 vs. 127±93 min; P = 0.01; 38±9 vs. 49± 16分钟; P <0.01; 23±6 vs. 30±10分钟; P <0.05)。对于9×2 IU,在最初的60分钟内GIR曲线下的面积更大(219±89对137±75; P <0.01),并且减半直到最大GIR(242±183对501±396对; P < 0.01);但是,在整个研究期间,情况相似(1,361±469对1,565±527; P = 0.08)。
结论:分散胰岛素注射策略增强了速效胰岛素类似物的作用。皮下胰岛素贮存库增加的表面积与体积之比可以促进胰岛素吸收进入血管系统。

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