Human insulin is beneficial for most diabetic patients for whom insulin therapy is indispensable. However, some patients suffer from insulin allergy. Insulin allergies are immunologic reactions to exogenous insulin, which cause local or systemic symptoms. Here we report that insulin aspart, a human insulin analog, alleviated local and generalized insulin allergy in the absence of anti-allergic agents in a Japanese patient.
A 59-year-old woman (60 kg body wt, BMI 24.4 kg/m2) with bronchial asthma was admitted to our hospital in December 2000 for the treatment of uncontrolled diabetes. She was first diagnosed as having type 2 diabetes in 1996 and started on treatment with oral hypoglycemic agents. However, hyperglycemia was difficult to control, and treatment with human insulin was started in July 1999. After subcutaneous injection of human regular insulin, she developed a skin rash, itching, and slight stridor. Although she had been treated with anti-allergic drugs (anatomize 75 mg, chlorpheniramine maltase 6 mg per day) along with regular/NPH insulin, her allergic reaction to insulin continued. The percentage of eosinophils in the peripheral white blood cell count was 9.8% (normal <7%). On further examination, she also showed a high level of total IgE (2,368 IU/ml; normal range <270 IU/ml) and human insulin–specific IgE in RAST (radioallergosorbent test; 8.04 AU/ml; normal range <0.34). Drug-induced lymphocyte stimulation tests for regular and NPH insulin were negative.
The patient demonstrated both local and generalized allergic reactions to different kinds of human insulin, including human regular insulin, NPH insulin, and crystalline zinc-insulin suspension, not only after systemic injection but also after intradermal test. She also demonstrated similar allergic reactions to bovine and porcine insulin. There was no evidence of allergic reactions to concomitant materials or any preservatives. To test the possibility of treating the patient with insulin analogs, we examined skin reactions to the two rapid-acting insulin analogs aspart (B28Asp human insulin) and lispro (B28Lys-B29Pro human insulin). Although insulin lispro also caused localized allergic reactions, insulin aspart alone did not induce local or systemic allergic reactions. Moreover, during the 6 months after the start of treatment with insulin aspart, diabetic control was improved, as shown by a reduction in HbA1c values from 8.9 to 7.6%. Although total IgE was not changed (from 2,368 to 2,254 IU/ml), the level of human insulin–specific IgE in RAST was significantly reduced from 8.04 to 4.37 AU/ml.
Insulin aspart is a new rapid-acting human insulin analog. It is characterized with rapid uptake, higher insulin peak, and rapid decline. The B26-B30 region is not particularly critical for insulin receptor recognition and has been a preferred site for structural modifications aimed at modifying the pharmacokinetic profile of the insulin molecule. In human insulin–transgenic mice, antibodies against insulin were not elicited by injection of B28Asp insulin (insulin aspart), in comparison with other analogs (1). It appears that insulin aspart had a reduced antigenicity. This is supported by the fact that no allergic reaction was induced in our patient when injected with insulin aspart. Although it was not found in this case, insulin lispro has also been reported to not induce insulin allergy (2). Taken together, the data suggest that position B28 may be a common immunogenic epitope in insulin allergy. Therefore, the modification of insulin at position B28 allows not only acceleration of the rate of absorption from injection sites but also suppression of insulin allergy.
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Address correspondence and reprint requests to Masao Nagata, MD, PhD, Division of Internal and Geriatric Medicine, Department of Development and Aging, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan. E-mail: [email protected].
