Insulin


Immunological responses to insulin are responsible for 2 principal syndromes: insulin allergy and insulin resistance. The prevalence of insulin allergy has decreased considerably since human recombinant insulins became available.
 
Incidence
Historically: 50% of patients using impure insulin preparation.
 
Less than 1% of de novo human insulin treated patients.
 
Risk factors
Atopy (controversial).
 
Previous allergies (controversial).
 
Insulin factors: purity, species (bovine > pork > human), physical properties (pH), retarding agents (Zn, protamine).
 
Individual factors: age, immunological background (HLA DR 2, 3, 4), presence of insulin antibodies.
 
Mode of insulin administration: SC > IV, insulin pumps, interrupted insulin therapy.
 
Clinical manifestations
I/ Local (2-3% in patients treated with highly purified pork or human insulin).
  • Immediate (within minutes of injection): pain + itching accompanied by erythema and swelling < 1 hour.
     
  • Biphasic (immediate + late phase response): starting at 4 hours and persisting 1-3 days. 
     
  • Intermediate (Arthus reaction): onset at 4-8 hours, peaks at 12 hours, induration with pruritus.
     
  • Delayed (tuberculin-like): onset at 12 hours, peaks at 24-48 hours, induration with erythema and pruritus.
II/ Systemic.
 
Anaphylactic shock.
 
Bronchospasm.
 
General urticaria, angioedema, periorbital edema.
 
Serum sickness, generalized lymphadenopathy.
 
Immunological insulin resistance.
 
Diagnostic methods
Cutaneous testing
 
(40% of patients receiving insulin without clinical allergy develop positive immediate skin-tests to the insulin used for treatment).
 
Cutaneous testing allows assessment of the less immunogenic insulin.
 
Skin-prick tests: insulins 40 UI/ ml, protamine sulfate 10 mg/ ml .
 
Intradermal skin-tests: 0.02 to 0.05 ml of different insulins (5 U/ ml).
 
Specific IgE (RAST, ELISA)
 
Low concentrations of IgE anti-insulin are present in the serum of many patients treated with insulin and do not correlate with allergic reactions.
 
High titers of IgE are frequently present in systemic insulin allergy.
 
Protamine-specific IgE (UniCAPâ/Pharmacia CAP Systemä) are positive in a few patients with allergy to insulins containing protamine.
 
Specific IgG (ELISA)
 
High titers of insulin IgG antibodies are found in patients with insulin resistance.
 
This requires a quantitative assay of the insulin binding capacity of the serum (if greater than 5 U/l of plasma = insulin resistance)
 
Mechanisms
IgE-mediated hypersensitivity (local reactions: immediate or biphasic; general reactions: anaphylactic shock, urticaria).
 
Type III reactions (antigen-antibody initiated complement fixation, leukocyte attraction and inflammatory response): Arthus, adenopathies, serum sickness, immunological insulin resistance).
 
Type IV reactions: rare.
 
Antigenic characteristics.
  • Differences in primary amino acid sequence from human insulin
     
  • Altered tertiary structure
     
  • Dimer and aggregate formations
     
  • Non-insulin protein contaminants (proinsulin, peptides, glucagon, microbial contaminants)
     
  • Non-protein additives (zinc, protamine, preservatives, buffers). 
Antigenicity of human semi-synthetic insulin is probably due to a tertiary structure change and to shared antigen determinants with pork and beef insulins. Most cases of allergy to human insulin have histories of animal insulin exposure.
 
Differences in amino acid sequences of the various exogenous is one of the major contributors to exogenous insulin allergy. Porcine and bovine insulins differ from human insulin by 1 and 3 amino acids. Allergy occurs more often with bovine insulin than with porcine insulin therapy.
 
The insulin molecule has well-identified immunogenic epitopes which map at A.A positions A1, A6, A chain loop (A8-A11), A19-20-21, B-3 and B-30.
 
A few papers reported allergy to protamine, present in NPH insulin and protamine-zinc insulin as the cause of generalized allergic reactions to insulin (clinically: absence of previous local reactions, severity of reactions, refractory period of weeks or months between reactions).
 
Insulin syringes and insulin vial stoppers containing latex and may lead to allergic reactions in patients with diabetes.
 
Different from contact allergy due to glue components in infusion sets of insulin pumps: epoxyresin.
 
Management
I/ Local reactions.
 
Reassure the patient, use antihistamines, use several injection sites, switch to a more purified form of insulin.
 
II/ Generalized reactions.
 
If insulin treatment is absolutely necessary and skin-tests are positive; desensitize to the least reactive regular insulin preparation.
 
If the patient is medically stable: give 1/2 dose of insulin.in- crease insulin dose 5 Uq 12 h until control is achieved.continue NPH or lente insulin q12 h
 
If the patient is medically unstable: rapid desensitization protocol; for example:
 
0.02 ml (0.05 U/ ml) ID to 0.08 ml (50 U/ ml); then follow with double dose SC q 4 h until control is established.
 
LISPRO (analog of human insulin) with reversed position of amino acids lysine 28 and proline 29 on the insulin Beta chain, remains in a monomeric state and has lowest immunogenicity. It has been successfully used in allergy to other insulins and in immune-mediated insulin resistance cases.

References

  1. Frigerio C, Aubry M, Gomez F, Graf I, Dayer E, de Kalbermatten N, Gaillard R.C, Spertini F, "Desensitization-resistant insulin allergy", Allergy, 1997; 52 (2): 238-9
  2. Kumar D, "Lispro analog for treatment of generalized allergy to human insulin", Diabetes Care. , 1997; 20 (9): 1357-9
  3. Lebovitz H.E, "Insulin allergy and insulin resistance", Curr. Ther. Endocrinol. Metab., 1997; 6: 500-4
  4. Blanco C, Castillo R, Quiralte J, Delgado J, Garcia I, de Pablos P, Carrillo T, " Anaphylaxis to subcutaneous neutral protamine Hagedorn insulin with simultaneous sensitization to protamine and insulin", Allergy, 1996; 51 (6): 421-4
  5. Goldfine A.B, Kahn C.R, "Insulin allergy and insulin resistance", Curr. Ther. Endocrinol. Metab., 1994; 5: 461-4
  6. Dykewicz M.S, Kim H.W, Orfan N, Yoo T.J, Lieberman P, "Immunologic analysis of anaphylaxis to protamine component in neutral protamine Hagedorn human insulin", J. Allergy. Clin. Immunol., 1994; 93 (1.1): 117-25
  7. Schernthaner G, "Immunogenicity and allergenic potential of animal and human insulins", Diabetes Care., 1993; 16 Suppl 3: 155-65

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.