Experimental testing of skin reactions to insulin detemir in diabetes patients naïve to insulin detemir.

Abstract

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.

MATERIAL AND METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

• Authors: Kenichiro O'goshi, Jørgen Serup, Bente Blaaholm, Henrik Klem Thomsen, Peter Rossing, Lise Tarnow
• Journal: Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI) (Skin Res Technol) Vol. 17 Issue 4 Pg. 411-9 (Nov 2011) ISSN: 1600-0846 [Electronic] England
• PMID: 21729174 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 John Wiley & Sons A/S.

Chemical References

• Antibodies
• Hypoglycemic Agents
• Insulin, Long-Acting
• Insulin Detemir
• Histamine

Topics

• Adult
• Antibodies (metabolism)
• Colorimetry
• Diabetes Mellitus, Type 1 (drug therapy)
• Diabetes Mellitus, Type 2 (drug therapy)
• Drug Eruptions (diagnosis, immunology, pathology)
• Female
• Histamine (metabolism)
• Humans
• Hypersensitivity, Delayed (diagnosis, immunology, pathology)
• Hypersensitivity, Immediate (diagnosis, immunology, pathology)
• Hypoglycemic Agents (administration & dosage, adverse effects, immunology)
• Injections, Intradermal
• Insulin Detemir
• Insulin, Long-Acting (administration & dosage, adverse effects, immunology)
• Laser-Doppler Flowmetry
• Male
• Middle Aged
• Skin (blood supply, drug effects, immunology)