Insulin human
Summary
Insulin supplementation is a life-saving treatment for insulin-requiring diabetes mellitus (DM) patients. Production of human insulin for DM treatment is based on recombinant DNA technology. Epidemiological studies indicate a significant decrease in insulin allergy prevalence since the introduction of recombinant human insulin, with current estimates at less than 3% of patients receiving this treatment. However, hypersensitivity reactions to insulin, which include immediate IgE-mediated reactions, are notable concerns given the vital character of insulin treatment and the broad range of differential diagnosis. Immediate reactions to insulin range from mild local symptoms at injection sites to severe anaphylactic responses. Diagnosing insulin allergy involves taking a detailed history, examining injection sites, performing skin and serum specific IgE tests with insulin and additives, and excluding other possible causes. Management of insulin allergy involves switching to a different insulin formulation, using antihistamines or corticosteroids, desensitization protocols, and addressing allergic reactions to additives or preservatives.
Epidemiology
Worldwide distribution
Adverse reactions to human insulin can occur in response to the insulin molecule (regular or HIAs), to preservatives and additives contained in pharmaceutical preparations of insulin (protamine, zinc, or metacresol), and to components of the medical devices employed for insulin injection, such as rubber latex. Adverse reactions to insulin may result from various mechanisms, such as hypersensitivity including IgE-dependent and IgE-independent reactions, as well as immune-mediated lipoatrophy and the generation of insulin auto-antibodies.
Hypersensitivity reactions to human insulin preparations may affect 0.1 to 3% of patients, in contrast with up to 50% - 60% with animal-derived (bovine, porcine) insulin preparations in use before recombinant human insulin became available. Allergic reactions to human insulin preparations are quite uncommon; among 90 million insulin-treated patients worldwide, possible allergic reactions were estimated at about 800,000 cases. In addition to recombinant human insulin and HIAs, additives and preservatives, like metacresol, protamine or zinc, contained in the insulin formulation are frequent hypersensitivity elicitors. Immediate hypersensitivity reactions to human insulin are mostly due to insulin-specific IgE antibodies.
In a retrospective cohort study from France, 52 patients with suspected insulin allergy were classified as clinically likely, clinically possible, and clinically unlikely of having insulin allergy using different diagnostic approaches. Following an insulin challenge test, likely insulin allergy was found in 50% (26/52) of patients, while 17% (9/52) were reported to have possible insulin allergy and 33% (17/52) were declared unlikely to have insulin allergy. In contrast, intradermal skin tests found 92% (24/26) likely insulin allergy cases. A retrospective study in Denmark involving 144 patients suspected of insulin allergy reported that about 24% (34 patients) had specific IgE for insulin.
In another Danish retrospective analysis, confirmation using intradermal testing was obtained in 41% of 22 patients suspected of allergy to insulin preparation.
Risk factors
Intravenous administration is associated with a lowered risk of hypersensitivity reactions to human insulin compared with subcutaneous injection. Similarly, the administration of gradually increasing doses rather than a unique total dose is associated with lower risk. Together, these observations form the basis for rapid insulin desensitization protocols allowing for treatment administration using a fractionated or continuous subcutaneous insulin infusion.
Pediatric issues
Pediatric case reports on human insulin hypersensitivity are scarce, however, they suggest patterns similar to those observed in adults, with immediate IgE-mediated reactions to human insulin supported by positive intradermal tests, localized delayed reactions involving memory T cells, and reactions to metacresol.
Route of Exposure
The main route of exposure to insulin to the patients is via injection, either subcutaneous or intravenous. Interest in noninvasive alternatives has led to the approval of pulmonary route/inhaled insulin, with additional routes under investigation.
Clinical Relevance
Human insulin-induced hypersensitivity reactions are rare but carry significant clinical relevance. These reactions vary from local injection site reactions such as erythema and swelling to generalized reactions like urticaria and angioedema, and even intense anaphylactic reactions. These reactions include immediate type I reactions mediated by IgE, type III immune complex reactions presenting as localized Arthus reactions or generalized serum sickness, and type IV or delayed-type hypersensitivity reactions. Moreover, there are reports of delayed reactions with histological signs of leukocytoclastic vasculitis. In addition to long-term insulin treatment of patients with type 1 or type 2 DM, insulin allergy has been reported in insulin-requiring patients with gestational DM.
In the French retrospective cohort study presented above, patients with clinically likely insulin allergy exhibited mostly local reactions (73%; 19/26), while few experienced systemic reactions (27%; 7/26), including generalized urticaria/pruritus, laryngeal angioedema, or severe anaphylaxis. In this group, immediate-type reactions were more predominant than delayed reactions (77% vs. 23%). Patients with clinically possible insulin allergy experienced mainly immediate reactions such as pruritus at the injection sites (78%). In another study, all 34/144 patients with clinically suspected insulin allergy and specific IgE for human insulin exhibited only local symptoms at the injection sites, such as pruritus, nodules, localized dermatitis, and infiltration.
Several case reports of allergic reactions to insulin preparations have been published. In a clinical case of a 35-year-old male with type 1 DM (T1DM), hypersensitivity reactions manifested against subcutaneous insulin at the site of insulin injection as itchy subcutaneous nodules and erythema localized at the anterior abdominal and thigh regions. The levels of specific IgE were high and the patch test was positive to all insulin preparations. He was diagnosed with an allergy to exogenous human insulin preparations based on clinical findings and laboratory test results.
A case series presented four cases of hypersensitivity reactions to insulin in young patients with T1DM. Symptoms included skin reactions (erythematous nodules, eczematous plaques, and swelling), respiratory distress, and even severe anaphylaxis. Intradermal skin testing was positive for different insulin preparations. Management including premedication, tentative desensitization using gradual infusion, biologicals, or immunosuppressants had limited efficacy, leaving pancreas organ transplantation as the ultimate therapeutic option in some of these patients.
A study with 202 insulin-requiring DM patients from Denmark found no impact of insulin-specific antibodies, comprising insulin-specific IgE but also the more prevalent IgG and IgM, on the long-term glycemic control evaluated by glycated hemoglobin levels.
Diagnostics
Allergen avoidance is a challenging task for patients who need insulin, emphasizing the importance of a thorough diagnostic and treatment procedure. The diagnosis of insulin hypersensitivity must be given priority over most other suspected drug-induced hypersensitivity reactions, due to the vital character of insulin supplementation.
The diagnosis of insulin hypersensitivity involves thorough assessment of past and current symptoms, demonstration of insulin sensitization using both skin prick tests and intradermal tests, with serum insulin-specific IgE as an additional tool to assist in the diagnosis, and provocation tests required in some cases for definitive proof or ruling out the diagnosis.
Insulin-specific IgE determination is non-invasive and if negative it makes the diagnosis of IgE-dependent allergy to insulin highly unlikely. Conversely, insulin-specific IgE can be found in asymptomatic subjects. Insulin-specific IgE levels may be more elevated in patients experiencing systemic reactions, but this finding is inconsistently reported in the literature.
Testing for insulin-specific IgG as a step in the diagnosis of insulin hypersensitivity is currently not recommended, due to the lack of confirmed correlation between these antibodies and insulin hypersensitivity.
Prevention And Therapy
Prevention strategies
Patients allergic to insulin can often be managed without altering their treatment, for example adding premedication, biologics, or immunosuppressants, performing rapid desensitization protocols, or using continuous subcutaneous infusions via an insulin pump. Alternative approaches include changing for a different insulin preparation, switching to oral antidiabetic drugs if compatible with the patient’s status, or pancreas transplantation in selected cases.
Cross-Reactivity
In a patient usually receiving human insulin and who developed anaphylaxis following an accidental animal insulin injection, no cross-reactivity was found between bovine and porcine insulin-specific IgE and recombinant human insulin.
Recombinant human insulin and HIAs contain antigenic determinants which are partly shared with native insulin, and may interfere with human insulin immunoassays, which are based on monoclonal IgG antibodies to insulin. The potential impact of recombinant human insulin and HIA on insulin-specific IgE has not been evaluated.
Explained Results
Allergen information
Human Insulin, a rapid-acting treatment for T1DM and T2DM, is produced using recombinant DNA technology, and identical to native insulin. Modified human insulin analogs (HIAs) are available alongside traditional forms. Allergy to insulin preparations may occur in response to human insulin, to HIAs, to additives and preservatives contained in these preparations, and to medical devices used for insulin administration.
Clinical information
Insulin-induced allergic reactions, though rare, are clinically significant, ranging from local injection site reactions to severe anaphylaxis. These reactions encompass various types, including immediate IgE-mediated responses and delayed hypersensitivity, with studies and case reports highlighting both localized and systemic effects, underscoring the complexity and diversity of insulin allergies.
Cross-reactivity
Lack of cross-reactivity between recombinant human insulin-specific IgE and bovine or porcine-specific IgE has been reported.
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