The Insulin Analog Aspart: A Safe Alternative in Insulin Allergy

The introduction of human recombinant insulin has considerably lowered, but not eliminated, adverse reactions to insulin administration. Several reports indicate that human recombinant insulin can also induce IgE- and non–IgE-mediated local or systemic reactions (1,2). However, in most patients with allergy to human recombinant insulin, insulin lispro—a genetically engineered insulin analog (Humalog; Lilly, Indianapolis, IN)—is well tolerated and can be safely used (3,4,5). Although the main immunogenic insulin epitopes remain unchanged in the lispro molecule, it has been suggested that this analog has reduced immunogenicity because of its rapid dissociation in monomers (6).

Here we report the case of cutaneous hypersensitivity to human insulin, successfully treated with the human insulin analog aspart (NovoRapid; Novo Nordisk, Bagsværd, Denmark). This rapid-acting insulin analog is produced by recombinant technology that replaces the proline at position 28 on the β-chain of insulin with negatively charged aspartic acid. Insulin aspart exists as examers that rapidly dissociate into monomers and dimers after the subcutaneous injection (7); therefore, it should be less immunogenic than human recombinant insulin.

A 45-year-old man was referred to our division for the management of uncontrolled diabetes. Type 2 diabetes had been diagnosed 2 years before and was treated with glyburide and metformin. Recently, non-Hodgkin’s lymphoma was diagnosed, and a combination chemotherapy was started. The use of glucocorticoids worsened glycemic control, and two daily injections of premixed human insulin (30% regular and 70% intermediate-acting) were prescribed. After a few days, the patient noticed local wheal and flare reactions immediately after the injection at the injection site. The flare reached a diameter of 3–5 cm and was followed by an indurated lesion that lasted for 3–5 days. Treatment with cetirizine (10 mg daily) provided relief from pruritus. No previous history of atopy was known. Serum total IgE was 3.1 kU/l (UniCAP; Pharmacia, Uppsala, Sweden). The search for insulin-specific IgE antibodies in the serum was positive (0.7 kU/l, class I, UniCAP); conversely, no latex-specific IgE could be detected. Skin prick tests were performed with several human recombinant insulins at commercial concentrations, using saline solution and histamine as negative and positive controls. The skin tests with Humulin R, Humulin I, Humulin 30/70 (Lilly), Actrapid, Protaphane, and Actraphane 30/70 (Novo Nordisk) were positive, with an immediate wheal and flare reaction that cleared up within 40 min. The skin prick test for insulin lispro (Humalog by Lilly) was weakly positive, whereas the skin prick test with insulin aspart (NovoRapid; Novo Nordisk) was negative. To confirm the results of skin prick tests, in vitro basophil histamine release was evaluated after challenge with different types of insulin. Leukocyte suspensions, prepared by dextran sedimentation of peripheral venous blood and containing 7 × 10⁴ basophils/ml, were incubated with different insulins (final concentration 5 units/ml for all types) and polyclonal goat IgG anti-IgE (final concentration 10 μg/ml; Sigma Chemical, St. Louis, MO) as a control. After incubation for 40 min at 37°C, the reaction was stopped by the addition of ice-cold buffer solution and centrifugation. The supernatants were assayed for histamine concentration by a commercially available radioimmunoassay (Immunotech, Marseille, France). Net histamine release was calculated as the percentage of total histamine content, after subtraction of spontaneous release. A 5% net release cutoff value was used. Insulin analogs (Humalog and NovoRapid) did not induce any significant histamine release (<1%), whereas a histamine release >5% was found after stimulation with Humulin I, Protaphane, and Actraphane 30/70 (6.9, 5.4, and 5.5%, respectively). Humulin R and Actrapid provoked a weak and nonsignificant in vitro histamine release (3%).

Because the results of the skin prick tests and in vitro basophil histamine release suggested that insulin aspart could be tolerated, we decided to start this type of insulin, which was administered in three premeal doses. The patient tolerated subcutaneous insulin aspart without any evidence of allergy. Subsequently, metformin was added at 1.0 g daily in two divided doses.

Several case reports suggest that insulin lispro may be an option in treating patients with insulin allergy. Our report indicates that the insulin analog aspart can be considered as an alternative treatment in patients with allergic reactions to human recombinant insulin.