Insulin lispro, an alternative in insulin hypersensitivity
Authors: M Lluch‐Bernal, M Fernández, JL Herrera‐Pombo, J Sastre
Journal: Allergy (1999)

A dverse reactions to insulin have become less frequent since recombinant and semisynthetic types of human insulin have become available. A 28-year-old woman with type I diabetes had been using human insulins with no adverse reaction for several years. At the time of her first adverse reaction, she was taking Mixtard™ 30/70, a human recombinant insulin. This patient has recently developed local reactions; pruritus, erythema, and swelling had taken place minutes after the administration of different kinds of previously tolerated human insulins. These reactions cleared up in 30 min, but 2--3 h later a painful and palpable lesion appeared, lasting for several days. The reaction did not depend on the human insulin type or the injection site. We confirmed our patient's reaction when she injected herself with Mixtard 30/70, which immediately produced the reaction previously described. We treated our patient with lispro (Humalog™, Lilly), an analog characterized by the reversed positions of lysine 28-proline 29 on the insulin B-chain. We performed cutaneous tests with different human insulins – Actrapid HM™, Insulatard HM™, Mixtard, Monotard HM™, and Ultratard HM™ (Novo Nordisk); Humulina NPH™, Humulina ultralente™, and lispro Humalog™ (Lilly) – as well as various commonly used additives (protamine, phenol, cresol, zinc). For prick tests, additives and insulins were used at commercial concentration, and for intradermal tests, at a 1/100 dilution, saline solution and histamine were used as negative and positive controls. Detection of specific IgE was performed by CAP (Pharmacia) and specific IgG and IgE by ELISA, both for human insulins and lispro. A skin biopsy of a lesion was taken 4 h after the reaction with Mixtard. Cutaneous tests for lispro and additives were negative. Intradermal tests were positive for all human insulins tested, with an immediate reaction which cleared up in a few minutes and a delayed painful lesion which lasted for hours. Negative specific IgE and positive specific IgG were obtained for all the human insulins, including lispro. The histologic and immunofluorescence studies were negative in the biopsy. A lispro challenge test was negative, and this analog is currently being daily used by the patient with good tolerance. Lispro is an analog identical to human insulin, except at positions B28 and B29, where the sequence of the two residues has been reversed. These amino-acid substitutions interfere with the natural association of native monomers as hexamers ( 1), resulting in lispro more closely imitating the physiologic response in endogenous insulin secretion after meals ( 2). The hypersensitivity mechanism involved in our patient's dual reaction is not clear. Although the immediate intradermal tests suggest an IgE mechanism, this fact was not confirmed by in vitro methods. Clinical data and the delayed skin responses suggest that another non-IgE immunologic mechanism – humoral or cellular – may be implicated. Furthermore, the positive IgG detected for lispro and the human insulins does not explain why lispro was well tolerated by our patient or the immunologic difference between this analog and human insulins. Lispro has been a useful alternative treatment in some cases (4, 5). There are only a few immunologic studies on lispro; in monkeys, Zwickl ( 3) has demonstrated that lispro had lower immunogenicity than other insulins; in man, Frigerio ( 6) has suggested that the reversed positions 28–29 may alter the anti-insulin antibody affinity for this epitope and that the lispro monomeric state faculty may cause a lower pathogenicity, due to an altered immunocomplex formation. Kumar ( 7) has obtained very high titers of in vitro specific IgE and IgG for lispro and human insulins, which show complete cross-reactivity. For the latter author, the main immunogenic epitopes of the insulin remained unchanged in lispro; this analog may have a reduced immunogenicity due to its rapid dissociation in monomers, rather than to differences in binding epitopes. Further studies will be necessary to evaluate the usefulness of lispro as a therapeutic alternative in insulin adverse reactions as well as to determine how its structure affects the human immune response.