Advantage of insulin lispro in suspected insulin allergy


R ecently, Lluch-Bernal et al. discussed insulin lispro as an alternative therapy in type 1 diabetes mellitus with insulin hypersensitivity ( 1). Here we report on the treatment by insulin lispro of a 54-year-old woman with type 2 diabetes mellitus, and insulin and protamine hypersensitivity.

Our patient developed gestational diabetes mellitus, which was treated by diet alone, during her first pregnancy at 23 years of age in 1968. After the delivery, her diabetes mellitus was classified as type 2 diabetes. Her good metabolic control was achieved by diet only. In 1978, oral antidiabetic agent therapy became necessary. She had adverse reactions to chromium, pollen, dust, penicillin, acarbose, and metformin. Since she had an adverse reaction to metformin, therapy with sulfonylurea (glibenclamid) was introduced.

In 1998, the metabolic control maintained by diet and sulfonylurea treatment weakened (HbA1c level of 9.1%), and a commonly used combined therapy with daytime administration of sulfonylurea and bedtime administration of insulin was initiated. The administration of Humulin N insulin (Lilly) had to be discontinued because of allergic skin reaction. The patient developed local painless, nonitching, urticariform erythema with a wheal diameter of 15 mm immediately after the injection on the injection site. This lesion cleared up in a few hours. However, by 2–3 h after the injection, painful itching and induration appeared at the injection site, lasting for a few days.

We performed intradermal tests with human, bovine, and porcine insulin, as well as with various additives of insulin preparations (protamine, paraben, phenol, metacresol, zinc, and isophane), using the Novo Insulin Allergy Kit (Novo Nordisk). We also did an intradermal test with the new insulin analog, insulin lispro (Humalog, Lilly). We tested for the presence of the human insulin-specific IgE and IgG antibodies in the patient's plasma, using the indirect avidin-biotin and indirect immunofluorescence methods, respectively.

The intradermal tests were positive for all types of regular insulin tested and for protamine, but the reactions were different. There was an immediate reaction (urticariform erythema) to insulins and a delayed-type one to protamine (induration). These two types of reactions were similar to the adverse reactions previously described and produced by Humulin N insulin containing human insulin and protamine. The intradermal test was negative for insulin lispro. No circulating insulin-specific IgE or IgG antibodies were found in the patient's plasma.

Since the intradermal test with insulin lispro was negative, we chose it for the patient's therapy. Because of the delayed adverse reaction to protamine, bedtime sulfonylurea treatment was chosen instead of NPH insulin therapy for nighttime metabolic control. Good metabolic control was achieved with this combination (HbA1c level of 5.48%). Insulin lispro therapy was well tolerated in our patient with insulin and protamine hypersensitivity.

Insulin lispro is a rapid-acting insulin analog identical to human insulin except at positions B28 and B29. This structural modification of human insulin greatly reduced its self-association characteristic, causing very rapid absorption. There have been only a few immunologic studies on insulin lispro ( 1–7). In view of the published reports, we suggest that the reduced immunogenicity of insulin lispro is related more to its faster absorption rate than to any changes in the immunogenic epitopes.


  1. Successful treatment of type 2 diabetes mellitus with allergy to human insulin.