Kang S, Brange J, Burch A, Vølund A, Owens D R
Department of Medicine, University of Wales College of Medicine, Cardiff, United Kingdom.
Diabetes Care. 1991 Nov;14(11):1057-65. doi: 10.2337/diacare.14.11.1057.
The subcutaneous absorption and resulting changes in plasma insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations after subcutaneous bolus injection of three soluble human insulin analogues (AspB9GluB27, monomeric; AspB28, mixture of monomers and dimers; and AspB10, dimeric) and soluble human insulin were evaluated.
Fasting healthy male volunteers (n = 7) were studied on five occasions 1 wk apart randomly receiving 0.6 nmol.kg-1 s.c. 125I-labeled AspB10 or soluble human insulin (Novolin R, Novo, Copenhagen); 1st study and 0.6 nmol.kg-1 s.c. 125I-labeled AspB28, AspB9GluB27 or soluble human insulin (2nd study). Residual radioactivity at the injection site was measured over 8 h with frequent venous sampling for plasma immunoreactive insulin or analogue, glucose, C-peptide, and blood intermediary metabolite concentrations.
The three analogues were absorbed 2-3 times faster than human insulin. The mean +/- SE time to 50% residual radioactivity was 94 +/- 6 min for AspB10 compared with 184 +/- 10 min for human insulin (P less than 0.001), 83 +/- 8 min for AspB28 (P less than 0.005), and 63 +/- 9 min for AspB9GluB27 (P less than 0.001) compared with 182 +/- 21 min for human insulin. delta Peak plasma insulin analogue levels were significantly higher after each analogue than after human insulin (P less than 0.005). With all three analogues, the mean hypoglycemic nadir occurred earlier at 61-65 min postinjection compared with 201-210 min for the reference human insulins (P less than 0.005). The magnitude of the hypoglycemic nadir was greater after AspB9GluB27 (P less than 0.05) and AspB28 (P less than 0.001) compared with human insulin. There was a significantly faster onset and offset of responses in C-peptide and intermediary metabolite levels after the analogues than after human insulin (P less than 0.05).
The rapid absorption and biological actions of these analogues offer potential therapeutic advantages over the current short-acting neutral soluble insulins.
评估皮下推注三种可溶性人胰岛素类似物（天冬酰胺B9-谷氨酸B27，单体；天冬酰胺B28，单体和二聚体混合物；以及天冬酰胺B10，二聚体）和可溶性人胰岛素后皮下吸收情况以及血浆胰岛素或类似物、葡萄糖、C肽和血液中间代谢物浓度的变化。
对7名空腹健康男性志愿者进行了5次研究，每次间隔1周，随机接受0.6 nmol·kg-1皮下注射125I标记的天冬酰胺B10或可溶性人胰岛素（诺和灵R，诺和诺德公司，哥本哈根）；第1次研究以及0.6 nmol·kg-1皮下注射125I标记的天冬酰胺B28、天冬酰胺B9-谷氨酸B27或可溶性人胰岛素（第2次研究）。在8小时内测量注射部位的残留放射性，并频繁采集静脉血样以检测血浆免疫反应性胰岛素或类似物、葡萄糖、C肽和血液中间代谢物浓度。
这三种类似物的吸收速度比人胰岛素快2至3倍。天冬酰胺B10达到50%残留放射性的平均±标准误时间为94±6分钟，而人胰岛素为184±10分钟（P<0.001）；天冬酰胺B28为83±8分钟（P<0.005），天冬酰胺B9-谷氨酸B27为63±9分钟（P<0.001），相比之下人胰岛素为182±21分钟。每种类似物注射后血浆胰岛素类似物峰值水平均显著高于人胰岛素注射后（P<0.005）。使用所有三种类似物时，平均低血糖最低点出现在注射后61 - 65分钟，早于参比人胰岛素的201 - 210分钟（P<0.005）。与人类胰岛素相比，天冬酰胺B9-谷氨酸B27（P<0.05）和天冬酰胺B28（P<0.001）注射后低血糖最低点的幅度更大。与人类胰岛素相比，类似物注射后C肽和中间代谢物水平的反应起效和消退明显更快（P<0.05）。
这些类似物的快速吸收和生物学作用相对于目前的短效中性可溶性胰岛素具有潜在的治疗优势。
