The Human Insulin Analogue Aspart Is Not the Almighty Solution for Insulin Allergy

Although human insulin is beneficial for most diabetic patients, some patients suffer from an allergy to exogenous insulin. Human insulin analogues, lispro or aspart, have been well tolerated in cases of insulin allergy. However, we report herein the first case of allergy to both lispro and aspart.

A 53-year-old woman with a history of type 2 diabetes for the past 3 years consulted our hospital for management of uncontrolled diabetes. Her postprandial blood glucose level was 12.9 mmol/l, and her HbA_1c level was 10.2%. She was initially treated with oral hypoglycemic agents (voglibose, glimepiride, metformin, and pioglitazone), which led to a decrease in her HbA_1c to 6.8%. However, her hyperglycemia became difficult to control over the next year (HbA_1c 7.6%), and treatment with intermediate-acting human insulin (Novolet N; Novo Nordisk, Bagsværd, Denmark) was begun. Two months after starting insulin injections, the patient noticed a skin rash and itching at the injection sites, so her insulin was changed to the analogues aspart and lispro, in succession. The local reactions continued, however, and the insulin analogue injections were suspended.

The patient had no previous history of any allergy. The percentage of eosinophils in her peripheral white blood cell count was 8.0%. She showed a high level of total IgE (748 IU/ml; normal, <400 IU/ml) and human insulin-specific IgE (19.80 IU/ml; normal, <0.34) measured by radioallergosorbent test. She had a positive test for anti-insulin antibodies (52%; normal, <7%). Prick tests were positive for lispro, aspart, human insulin, and porcine insulin, as well as for an additive of insulin preparations, protamine, using the Novo insulin allergy kit (Novo Nordisk), for which in vitro drug-induced lymphocyte stimulation tests were all positive. A biopsied specimen of the skin with prick tests revealed subcutaneous edema with infiltrated cells, including eosinophils. Her illness was diagnosed as insulin allergy.

Because the anti-allergenic drug ebastine did not reduce the allergic reaction, insulin and insulin analogues had to be discontinued. Since the patient’s hospitalization, administration of oral hypoglycemic agents with intensification of nutrition therapy and exercise has conveniently led to an HbA_1c of 5.5%.

The human insulin analogues aspart (B28Asp human insulin) and lispro (B28Lys-B29Pro human insulin) have been reported to be beneficial for the reduction of allergic reactions to insulin because of less antigenicity due to increased clearance of insulin analogue monomers from injection sites. Aspart has been confirmed to be less immunogenic for development of antibodies against human insulin (1). Lispro and aspart have been available internationally since 1996 and 1999, respectively; and both analogues, especially aspart, certainly seem to be beneficial for patients with insulin allergy (2,3). To our knowledge, there has been no report that aspart is intolerable in cases of insulin allergy. However, our patient showed an allergic reaction to both insulin analogues. Therefore, these analogues are not necessarily tolerated as alternatives when insulin allergy has already developed. We need follow-up of patients treated with insulin analogues that focuses on the evocation of insulin allergy.