Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.
Skin Res Technol. 2011 Nov;17(4):411-9. doi: 10.1111/j.1600-0846.2011.00551.x. Epub 2011 Jul 6.
BACKGROUND/AIMS: Sporadic reports on immediate and delayed cutaneous reactions to insulin detemir, a modern insulin analogue, have raised unsupported claims of allergy of type I, III and IV. The purpose of this experimental study using a provocative design was to elucidate the potential mechanisms behind such skin reactions.
A total of 40 patients with type 1 diabetes or insulin-requiring type 2 diabetes, all naïve to insulin detemir, were injected on the thigh with 0.l mL of insulin detemir (Levemir(®)) administered with an 8 mm needle at three different depths, i.e. intradermal, subdermal and subcutaneously. Saline was injected as control. Any cutaneous reactions were assessed after 10 and 30 min, after 24 and 48 h and after 7 days. Histopathology of positive reactions on day 7 was obtained. The study was randomized, controlled, double-blinded, and conducted in accordance with ICH-GCP guidelines. Blood flow was recorded with the Periflux PF5010, and skin colour (a*) with the DSMII colorimeter.
Clinical reading, flowmetry and colorimetry consistently showed delayed reactions after intradermal insulin injection (35 of 40 patients reacted with mainly weak reactions, P<0.05), peaking after 48 h, contrasting no special reaction immediately after injection, except for reactions attributed to needle trauma. A total of 22 patients reacted on subdermal injection and 21 on subcutaneous injection. Histopathology on day 7 from 22 reactions in 15 patients showed a consistent pattern of inflammation with eosinophilia as typically observed in adverse skin reactions to a variety of medicines. Reactions were interpreted as non-specific biologic responses to the insulin different from direct toxic actions and classical allergic reaction patterns. Only one person registered itch/discomfort. A prick test vs. histamine reference excluded insulin detemir to be a pharmacological histamine releaser. Thus, provocative testing with insulin detemir produced delayed skin reaction but no immediate reaction. Measurement of circulating insulin detemir-specific antibodies by RIA before and after 3 months showed no increase.
Non-allergic delayed skin reactions from intradermal and, to a minor degree, subdermal and subcutaneous injections of insulin detemir were frequent in this experimental study and showed a consistent histology pattern of inflammation with eosinophilia. Immediate reactions were not produced. The reactions are unlikely to be specific for insulin detemir, and other insulins should be studied in a similar provocative design.
背景/目的：胰岛素类似物地特胰岛素的即时和迟发性皮肤反应的零星报告引起了对 I 型、III 型和 IV 型过敏的未经证实的说法。本实验研究采用激发设计，旨在阐明此类皮肤反应背后的潜在机制。
共纳入 40 名 1 型糖尿病或需要胰岛素的 2 型糖尿病患者，均对地特胰岛素（诺和平）无过敏史，用 8mm 针头在大腿处皮内、皮下和皮下注射 0.1ml 地特胰岛素。盐水作为对照。注射后 10 分钟和 30 分钟、24 小时和 48 小时以及 7 天后评估任何皮肤反应。第 7 天获得阳性反应的组织病理学。研究采用随机、对照、双盲设计，符合 ICH-GCP 指南。用 Periflux PF5010 记录血流，用 DSMII 比色计记录皮肤颜色（a*）。
临床阅读、流量测量和比色计均显示皮内注射胰岛素后出现迟发性反应（40 例患者中有 35 例出现主要为弱反应，P<0.05），48 小时达高峰，除了归因于针创伤的反应外，注射后即刻无特殊反应。22 例患者在皮下注射部位反应，21 例在皮下注射部位反应。来自 15 例患者 22 次反应的第 7 天组织病理学显示，炎症模式一致，伴有嗜酸性粒细胞增多，这是各种药物引起的不良皮肤反应的典型表现。反应被解释为与直接毒性作用和经典过敏反应模式不同的胰岛素的非特异性生物学反应。只有 1 人报告瘙痒/不适。与组胺参考物的划痕试验排除了地特胰岛素是药理学组胺释放剂。因此，用胰岛素地特胰岛素进行激发试验会导致迟发性皮肤反应，但不会导致即刻反应。用 RIA 在 3 个月前后测量循环中胰岛素地特胰岛素特异性抗体，未发现增加。
在这项实验研究中，皮内、皮下和皮下注射地特胰岛素会频繁引起非过敏性迟发性皮肤反应，且具有一致的炎症伴有嗜酸性粒细胞增多的组织病理学模式。未产生即刻反应。这些反应不太可能是地特胰岛素特异性的，应在类似的激发设计中研究其他胰岛素。
