c73 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.

Allergen         

Nature

Human insulin, also called regular insulin, is a rapid-acting insulin for treating DM patients requiring insulin supplementation. It is a peptide hormone with a sequence of 51 amino acids identical to native insulin (Aberuman 2021), produced by recombinant technology. Both recombinant and native human insulin consist of two amino acid chains linked covalently via a disulfide bond ( NIH-PubChem 2023), but the former tends to self-associate into multimers (Oh 2025). Human insulin analogs (HIAs) were developed as rapid and long-acting insulin analogs of natural insulin, bearing minor alterations to improve the pharmacokinetic properties (Bzowycky 2018, Abdi 2019, Oh 2025).

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 (Badik 2016, Bzowycky 2018, Oh 2025). 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 (Oh 2025).

Hypersensitivity reactions to human insulin preparations may affect 0.1 to 3% of patients (Badik 2016, Aberuman 2021, Oh 2025), in contrast with up to 50% - 60% with animal-derived (bovine, porcine) insulin preparations in use before recombinant human insulin became available (Bzowyckyj 2018). 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 (Sola-Gazagnes 2022). 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 (Yang 2023). Immediate hypersensitivity reactions to human insulin are mostly due to insulin-specific IgE antibodies (Shuster 2020).

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 (Sola-Gazagnes 2022). A retrospective study in Denmark involving 144 patients suspected of insulin allergy reported that about 24% (34 patients) had specific IgE for insulin (Haastrup 2018).

In another Danish retrospective analysis, confirmation  using intradermal testing was obtained in 41% of 22 patients suspected of allergy to insulin preparation (Bodtger 2005).

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 (Lijesh 2020, Yang 2023, Oh 2025).

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 (Wheeler 2012, Mastrorilli 2017, Alkhatib 2023, Oh 2025).

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 (Shah 2016).

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 (Heinzerling 2008, Ghazavi 2011). 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 (Akinci 2010). 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 (Kim 2015).

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%) (Sola-Gazagnes 2022). 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 (Haastrup 2018).

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 (Lijesh 2020).

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 (Alkhatib 2023).

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 (Toft-Hansen 2025).

Diagnostic Relevance

Allergen avoidance is a challenging task for patients who need insulin, emphasizing the importance of a thorough diagnostic and treatment procedure (Sola-Gazagnes 2022). 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 (Broyles 2020, Brockow 2023).

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 (Haastrup 2018, Brockow 2023, Oh 2025).

Insulin-specific IgE determination is non-invasive and if negative it makes the diagnosis of IgE-dependent allergy to insulin highly unlikely (Oh 2025). Conversely, insulin-specific IgE can be found in asymptomatic subjects (Oh 2025). Insulin-specific IgE levels may be more elevated in patients experiencing systemic reactions, but this finding is inconsistently reported in the literature (Haastrup 2018, Oh 2025).

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 (Oh 2025).

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 (Kim 2015, Haastrup 2018, Alkhatib 2023, Brockow 2023, Oh 2025).

Molecular Aspects

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 (Grammer 1989).

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 (Walch 2020). 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.

Compiled by Turacoz

Reviewed by Drs. Joana Vitte and Michael Spangfort