Insulin allergy: clinical manifestations and management strategies
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Allergy 2008: 63: 148–155 2008 The Authors
Journal compilation 2008 Blackwell Munksgaard
DOI: 10.1111/j.1398-9995.2007.01567.x
Review article
Insulin allergy: clinical manifestations and management strategies
Insulin allergy in patients with diabetes mellitus on insulin treatment is a rare L. Heinzerling1,2, K. Raile3,
condition. It is suspected upon noticing immediate symptoms following insulin H. Rochlitz4, T. Zuberbier1, M. Worm1
injections. The immediate vital implications for the patient call for prompt 1
Department of Dermatology and Allergy, Charit
diagnosis and management of insulin allergy.We review current knowledge and Universittsmedizin, Berlin, Germany; 2Harvard
procedures based on four diabetic patients who presented in our clinic. Insulin School of Public Health, Boston, MA, USA;
allergy was suspected as they showed immediate symptoms after insulin injection Departments of 3Pediatric Endocrinology and
Diabetes; 4Endocrinology, Diabetes and Nutrition,
(urticaria, rash, angioedema, hypotension, dyspnea). A detailed allergologic Charit Universittsmedizin, Berlin, Germany
work-up was performed and adequate therapy was initiated. In three of the four
patients, a specific immunotherapy was started whereas in one patient a switch Key words: drug reaction; IgE; skin prick test; specific
to oral antidiabetics was possible and consequently initiated. By standard prick immunotherapy; tolerance; type 1 allergic reaction.
testing and measurement of specific IgE antibodies, a type 1 IgE-mediated
allergy was confirmed. After initiation of insulin immunotherapy, the symptoms Lucie Heinzerling
completely resolved in two out three of patients and significantly improved in the Harvard School of Public Health
third patient. The fourth patient was successfully switched to oral antidiabet- 677 Huntington Avenue
Boston
ics.Insulin allergy is a rare but severe condition that calls for immediate aller- MA 02115
gological work-up. It can be managed well in close cooperation between the USA
diabetologist and the allergologist. Specific immunotherapy is efficient and
should be considered. Accepted for publication 19 September 2007
Adverse reactions to insulin have significantly decreased at hand. Rarely, insulin allergy can be fatal despite
since the introduction of human insulin preparations (1). appropriate interventions (8).
However, cases with insulin allergy continue to present in In this review, the diagnostic procedures and manage-
the clinic. Symptoms range from local injection site ment options for insulin allergy are reviewed in the light
reactions to severe generalized anaphylactic reactions (2). of four severe cases of IgE-mediated allergic reaction to
Allergic reactions to insulin include immediate type insulin and/or insulin components. We suggest a detailed
IgE-mediated reactions, type 3 immune complex type allergological work-up and discuss a management proto-
(Arthus reaction-localized or serum sickness-generalized) col.
or delayed type hypersensitivity reactions. Furthermore,
reactions with a delayed onset, i.e. 6 h after injection of
insulin may develop (3). These delayed reactions include
Clinical presentation
induration at the injection site with histological signs of
leukocytoclastic vasculitis (4). Finally, some reactions are The clinical presentation of insulin allergy can range
even more delayed with onset after 8–24 h and may be on from minor local symptoms to a severe generalized
account of delayed hypersensitivity. This has been allergic reaction. IgE-mediated symptoms occur imme-
reported most frequently for insulin preparations con- diately after insulin injection. Skin reactions vary from
taining zinc (5) or protamine (6). It is important to local erythema and swelling at the injection site to
distinguish insulin allergy that manifests with allergic generalized reactions like urticaria and angioedema
symptoms from immune-complex mediated insulin resis- (9, 10). Interestingly, flare reactions can also be elicited
tance due to IgG antibodies that bind to insulin to at the former injection sites upon insulin injection (11).
produce a nonfunctional complex (7). Furthermore, pruritus of soles and palms, generalized
This review focuses on the type 1 allergy with an flushing, and itching can occur (12). In rare severe cases,
immediate reaction to insulin preparations. As insulin is a anaphylaxis with dyspnea and hypotension has been
vital drug for the insulin-dependent patients, a quick observed (2, 13). In one case, a diabetic patient
diagnostic work-up and adequate management is critical developed a severe anaphylactic reaction in which
for diabetic patients presenting with symptoms suspected symptoms could not be managed, despite attempts to
to be of allergic origin. Upon diagnosis, most patients can desensitize and the patient succumbed upon reintroduc-
be satisfactorily managed with various treatment options tion of insulin (8).
148Insulin allergy
hypoglycemia with human
The four patients presented in this review were between
Improvement of symptoms,
but worse perception of
12 and 87 years of age with different types of diabetes
Cessation of symptoms
Cessation of symptoms
Cessation of symptoms
insulin preparation
mellitus and varying local and systemic symptoms
(Table 1).
Outcome
Diagnostic work-up
The presence of an insulin sensitization can be proven by
human insulin (Insuman Rapid)
insulin analogue (Novo-Rapid)
skin prick test and determination of specific IgE (14). A
Specific immunotherapy with
Specific immunotherapy with
Specific immunotherapy with
Change to oral antidiabetics
human insulin (Huminsulin
diagnostic algorithm in suspected insulin allergy has been
suggested by Jaeger et al. (15) including intradermal skin
testing, quantification of insulin-specific IgG and IgE in
the serum, and analysis of the time-dependent binding/
Management
dissociation curves of the insulin-neutralizing antibodies
normal)
in an ex vivo/in vitro assay.
Diagnostic work-up for the four patients included skin
prick testing, assessment of specific IgE and IgG4, and
Immediate monitoring in hospital
diagnostic tests to exclude other causes of the allergic
Infusat/Actrapid), NPH-insulin
Change of insulin preparation,
Change of insulin preparation
(Protaphane), insulin aspart,
pump, symptomatic therapy
glargine), change to insulin
symptoms. Skin prick testing included the insulin prep-
symptomatic therapy with
insulin lispro, and insulin
Symptomatic therapy with
(regular insulin (Insuman
with antihistamines and
arations used, alternative insulin preparations, additives
and the components of the skin test kits provided by the
pharmaceutical companies (Sanofi aventis, Bad Soden am
corticosteroids
antihistamines
antihistamines
Taunus, Germany; Novo Nordisc, Bagsvaerd, Denmark). Trial attempts
Positivity was defined as wheal diameter of more than
3 mm after 15 min. Histamine (10 mg/ml) and diluent
(0.9% NaCl) served as positive and negative control.
Insulin-specific IgG antibodies were assessed with the
mite, grass, birch), food allergy
and continuous treatment with
Allergic rhinitis (cat, house dust
Sickle cell anemia (splenectomy
CentAK anti-IA (Medipan, Selchow, Germany) which
(hazelnut, oat flour), allergic
Hypertension, coronary artery
Allergic rhinitis (cat, grass),
determines specific antibodies against human insulin. The
drug reaction to penicillin
disease, apoplexapoplexy
Other (allergic) conditions
allergic drug reaction to
estimate for normal values determined by Jaeger et al.
low dose penicillin)
(15) was around 0.038 mU/ml (95% CI 0.025–0.052 mU/
ml). Additionally, specific IgE against latex, protamine
and penicilloyl G and V were assessed (CAP system;
penicillin
Pharmacia, Uppsala, Sweden).
injection site, diplopic images,
Urticaria, pruritus, angioedema,
angioedema, dyspneadyspnoe
confusion, paresthesia (hands
Management
macular exanthema, insulin
Urticaria, pruritus, erythema,
Table 1. Patient characteristics, symptoms, management, and outcome
Urticaria, pruritus, erythema
induration and swelling at
Urticaria, nausea, paleness,
malaise with palpitations,
and mouth), induration at
diplopic images, general
First line management of insulin allergy besides symp-
injection site, maculous
tomatic therapy with antihistamines calls for a switch to a
Symptoms
insulin resistance
different insulin preparation. Especially in patients that
show allergic reactions to components of the preparation
resistance
a switch to a preparation which does not contain the
specific agent can lead to a cessation of symptoms (16).
To offer alternatives to the patient allergic to insulin
analogues, lispro, aspart and glargine with the exchange
Diabetes
mellitus
of two (B28-proline and B29-lysine), one (B28-aspartate)
Type II
Type II
Type I
Type I
or the exchange of one (A21-glycine) and addition of two
amino acids (B31-arginine and B32-arginine), respec-
tively, have been used (17–20). Although these represent
gender (M/F)
options for patients with allergy to insulin (21) they have
60, M
36, F
13, F
83, F
Age,
also been known to provoke hypersensitivity reactions
including type 1 allergies in clinical practice (22–25).
Detemir, a long-acting insulin analogue, differs from
Patient
native insulin by the deletion of amino acid B30 and
Nr.
addition of a myristic acid residue at B29 and has also
1
2
3
4
149Heinzerling et al. been reported to elicit allergic reactions (26, 27). One insulin injections. Additionally, the local injection site report even implied the potential of insulin analogues to showed an induration upon physical examination. Fur- be more allergenic than insulin (28), which led to a debate thermore, intermittent diplopia without periorbital edema on this preposition (29). was present. Insulin therapy with human insulin was One method to induce tolerance is the application of increasingly less effective in controlling the glucose level insulin as continuous subcutaneous insulin infusion and showed progressively more intense side effects. The (CSII). Several case reports describe the beneficial effect following insulin preparations had been used: regular of this form of application in allergic diabetic patients insulin (Insuman Infusat or Actrapid), NPH-insulin (30–34). Furthermore, the use of specific immunotherapy (Protaphane), insulin aspart, insulin lispro, and insulin for the treatment of insulin allergy has been reported glargine. At the time of admission to our unit, the patient previously and was successful in many cases (35). In our was treated with porcine regular insulin (Actrapid suis patients, prior to the specific immunotherapy, various MC) in an infusion pump. Besides the acute symptoms, treatment options including change of insulin, change of the patient had a seasonal allergic rhinoconjunctivitis insulin application and symptomatic therapy with anti- with sensitization to grass pollen and a history of allergic histamines had been attempted (Table 1). Specific immu- reaction to penicillin. The immunological evaluation notherapy consists of successive subcutaneous injections revealed: (1) positive skin testing for the additives zinc of insulin under close monitoring with preparation for and protamine, and insulin preparations Insulin novo emergency intervention in an in-patient setting. The semilente, Insuman rapid, and insulin glargine in intra- initial dose for the specific immunotherapy depends on cutaneous testing. The porcine insulin Actrapid suis MC the grade of sensitization and the duration is usually up to showed a reaction, though of insufficient magnitude to be 2 days. In our patients who presented with severe classified as positive. (2) High titers of insulin-specific IgE symptoms, the initial dose was 0.00001 units, with with CAP class 4 (30.6 kU/l) but no protamine-specific subsequent doses progressively increasing 10-fold up to IgE (
Insulin allergy
allergy. Currently, insulin pump treatment with insulin insulin that provoked symptoms despite intensive anti-
aspart continues and metabolic control is good. histamine therapy, a specific immunotherapy with regular
insulin (Insuman Rapid) was performed. After the 2-day
course the symptoms did not recur.
Patient #3
An 83-year-old female patient with type 2 diabetes [body
mass index (BMI), 25] received insulin treatment for
Results
10 months with regular and NPH-insulin (Actrapid and
Protaphane). She had hypertension, coronary artery dis- At our department, we diagnosed four patients with a
ease, and had previously suffered from an apoplexy. The type 1 sensitization towards insulin (Table 2) and allergic
leading allergic symptoms were erythematous reactions, symptoms in clinical use of insulin. Respective insulin IgE
urticaria, and pruritus immediately after injection. Addi- antibodies were present in these four patients (Table 2).
tionally, her glucose levels were increasingly hard to Furthermore, all patients showed a positive skin prick test
control. Furthermore, the injection site showed induration. or intracutaneous test to insulin preparations and/or
Oral antihistamine treatment improved the condition but insulin analogues. Two patients presented with a sensi-
did not completely resolve it. Immunological evaluations tization to additives in the insulin preparations (one to
revealed: (1) positive skin prick testing for regular insulin protamine and zinc, and one to cresol). Three out of three
(Actrapid), mix insulin (Berlinsulin H 30/70, Huminsu- patients tested had IgE against penicillin and two patients
lin Profil 30/70), NPH-insulin (Basal Hoechst, Huminsulin had a history of allergic reactions to penicillin.
Basal, Berlinsulin Basal), zinc insulin (Novo Ultratard), During the specific immunotherapy regimen that each
insulin aspart and insulin lispro. Skin prick testing for the of the three patients underwent, no complications
compounds with the Novo Nordisc insulin allergy kit was occurred and symptoms improved in one patient and
negative. Intracutaneous testing was positive for porcine, completely disappeared in the other two patients. In the
bovine and more positive for human insulin. (2) Insulin- fourth patient, a change to oral antidiabetics was suffi-
specific IgE against human CAP class 2 (2.39 kU/l), bovine cient to control blood glucose and insulin treatment could
CAP class 2 (2.06 kU/l) and porcine CAP class 1 (2.61 be stopped with no further allergic symptoms.
kU/l) insulin were present. Insulin-specific IgG were
normal. The patient was successfully transferred from
insulin to oral antidiabetics (metformin and repaglinide)
Immunologic mechanisms
and allergic symptoms resolved completely.
Type 1 allergic reactions are mediated by IgE against
insulin or components of the insulin preparations. These
Patient #4
immunologic reactions can be elicited by different anti-
A 60-year-old male patient with type 2 diabetes was treated genic determinants in the recombinant proteins, which
with insulin for 5 months and presented to our outpatient are not present in the endogenous human insulin (37) or
department because of the onset of urticaria, erythema, they may also be on account of the immunogenicity of
flush, and pruritus. He had been treated with insulin one of the nonprotein components (38). It has also been
glulisine. After the symptoms started he was switched to assumed that some modification of insulin, such as
insulin aspart. However, the allergic symptoms did not aggregation, may lead to the immunologic reactions (39,
improve. Since 1 month he received NPH-insulin (Prota- 40). In rare cases, the IgE is directed to the endogenous
phane) in addition. Oral antihistamines had improved the insulin of the patient (41, 42). The following additives in
symptoms but not resolved them. Additionally, he suffered insulin preparations have been observed to induce allergic
from allergic rhinitis and asthma and reported a drug reactions or sensitizations: zinc, protamine (42, 43), and
reaction to penicillin. The immunological evaluations cresol (44). Protamine can act as adjuvant (45), and the
revealed the following: (1) positive skin testing showed an crystalline zinc solutions can alter immunogenicity by
urticaria factitia with equally positive reactions for NaCl, changing the structure of the B-chain (46, 47). Interest-
human insulin, and cresol. (2) Quantification of insulin- ingly, Madero et al. report a case of a diabetic patient
specific antibodies showed insulin-specific IgE CAP class 1 with IgE-mediated allergic reactions to recombinant
(0.43 kU/l) while insulin-specific IgG was normal. Inter- human insulin and a positive skin test for glargine
estingly, the patient showed penicillin-specific antibodies: possibly mediated by specific IgG4 (48).
penicilloyl V CAP class 1 (0.56 kU/l), ampicilloyl CAP The route of administration also determines whether
class 1 (0.47 kU/l) as well as latex-specific antibodies allergic symptoms occur as described in a patient by
CAP class 2 (2.24 kU/l) with a total IgE of 210 kU/l. Asai et al. who showed no symptoms upon intravenous
Other triggers for the urticaria, e. g. Helicobacter pylori injection of insulin, whereas symptoms on subcutaneous
infection were excluded. Furthermore, the patient had injection persisted (36).
sensitizations to house dust mite, grass pollen, cat and Specific immunotherapy induces tolerance in many
birch. Because of a suspected IgE-mediated allergy to patients with IgE-mediated immediate allergic reactions.
151Heinzerling et al.
Even though the mechanism of specific immunotherapy
negative; helicobacter pylori: negative;
IgG insulin antibodies: positive; tyrosinInsulin allergy
Immediate symptoms after
insulin injection: Delayed/prolonged symptoms
• Urticaria after insulin injection:
• Angioedema • Induration at injection site
• Rash • Erythematous burning lesions
• Nausea/diarrhea at injection site
• Cardiovascular symptoms • Nausea/diarrhea
• Dyspnea
Skin prick test/ Assessment of Assessment of Epicutaneous skin
Exclude other
intracutaneous test: specific IgE: specific IgG: test:
reasons for
• Insulin preparations • Insulin • Insulin • Additives
symptoms
• Insulin additives • Protamine
Negative Positive Positive Positive Positive
Immune-
IgE-mediated Delayed
complex mediated
insulin allergy hypersensitivity
reaction
Possibly associated with
insulin resistance
Figure 1. Diagnostic approach in suspected insulin allergy.
Table 3. Insulin preparations with respective additives
Additives
Duration of
Name of insulin Type of insulin Zinc Protamine Cresol Other action
Actrapid Human · · Glycerol 2–8 h
Berlinsulin H Normal Human · Glycerol 2–8 h
Huminsulin Normal Human · Glycerol 2–8 h
Insuman Rapid Human · Glycerol 2–8 h
Insulin B Braun Human (enzymatically produced · Glycerol 2–8 h
from porcine insulin)
Velosulin Human · · Glycerol 2–8 h
Insulin S Berlin-Chemie Porcine Methyl-4-hydroxybenzoat 2–8 h
Insulin S.N.C. Berlin-Chemie Porcine · Glycerol 2–8 h
Novorapid r-DNA insulin aspart · · Phenol, glycerol 2–5 h
Apidra optiset Analogum (glulisin) · Trometamol 2–5 h
Humalog Analogum (lispro) · · Glycerol 2–5 h
Actraphane Human · · · Phenol, glycerol Up to 24 h
Berlinsulin H Human · · · Phenol, glycerol Up to 24 h
Huminsulin Basal for pen Human · · Phenol, glycerol Up to 24 h
Huminsulin Basal Human · · · Phenol, glycerol Up to 24 h
Huminsulin Profil Human · · Phenol, glycerol Up to 24 h
Insulin B Braun Basal Human (enzymatically produced · · · Phenol, glycerol Up to 24 h
from porcine insulin)
Protaphane Human · · · Phenol Up to 24 h
Insuman Basal Human · · · Phenol, glycerol Up to 24 h
Monotard Human · Methyl-4-hydroxybenzoat Up to 24 h
B Insulin S Porcine Methyl-4-hydroxybenzoat, Aminoquinurid Up to 24 h
Insulin Novo Semilente MC Porcine · Methyl-4-hydroxybenzoat Up to 24 h
Humalog Mix Analogum (lispro) · · · Phenol, glycerol Up to 24 h
NovoMix 30 Insulin aspart-protamin cristals · · · Phenol Up to 24 h
Levemir Insulindetemir · · Phenol Up to 24 h
Ultratard Human · Methyl-4-hydroxybenzoat More than 24 h
Lantus Analogum (glargin) · · Glycerol More than 24 h
153Heinzerling et al.
been associated with anaphylaxis during reversal of (32, 33, 60) and surprisingly one case of intravenous
intraoperative heparin anticoagulation by protamine in therapy (36). The specific immunotherapy regimen was
cardiac catheterization (42, 56, 57). Treatment options effective and well tolerated. However, a few cases of
for insulin allergy include the symptomatic therapy with ineffective specific immunotherapy (61) and short dura-
antihistamines. However; sensitization may be accentu- tion of effect have also been reported (9). A rare
ated over time. Especially when local symptoms are complication has been described in the induction of
increasing in intensity they may precede systemic reac- insulin IgG antibodies leading to insulin resistance (62).
tions. When symptomatic therapy is not sufficient, and In conclusion, insulin allergy is a rare condition that
change of insulin preparation not feasible due to calls for a quick allergological work-up. It can be
multiple sensitizations or difficulties in stabilizing the managed well in close cooperation between the diabetol-
blood sugar with a certain insulin preparation, specific ogist and the allergologist. Specific immunotherapy
immunotherapy is a good option for the patient. In should be considered if a type 1 allergy to insulin is
severe cases it has previously been combined with diagnosed and may lead to a complete resolution of
prednisolone (35, 58). symptoms.
In accordance with results from other groups (31, 35),
specific immunotherapy was effective in reducing symp-
toms of type 1 allergy to insulin or insulin components in
Acknowledgements
all three patients described here. It was also associated
with a decrease in IgE titers as has been described before We thank Dr Elsbeth Oestmann and Dr Christian Hessel from the
(59). Our regimen used several ascending single doses, Charité University Hospital, Department of Dermatology and
whereas there are also reports of successful specific Allergy, for patient care. We also thank Jeff Berens for language
editing of the manuscript.
immunotherapy with continuous subcutaneous infusion
References
1. Fernandez L, Duque S, Montalban C, 8. Kaya A, Gungor K, Karakose S. Severe 16. Rajpar SF, Foulds IS, Abdullah A,
Bartolome B. Allergy to human insulin. anaphylactic reaction to human insulin Maheshwari M. Severe adverse cutane-
Allergy 2003;58:1317. in a diabetic patient. J Diabetes Com- ous reaction to insulin due to cresol
2. Blanco C, Castillo R, Quiralte J, plications 2007;21:124–127. sensitivity. Contact Dermatitis
Delgado J, Garcı́a I, de Pablos P et al. 9. Chng HH, Leong KP, Loh KC. Primary 2006;55:119–120.
Anaphylaxis to subcutaneous neutral systemic allergy to human insulin: 17. Airaghi L, Lorini M, Tedeschi A. The
protamine Hagedorn insulin with recurrence of generalized urticaria after insulin analog aspart: a safe alternative
simultaneous sensitization to successful desensitization. Allergy in insulin allergy. Diabetes Care
protamine and insulin. Allergy 1995;50:984–987. 2001;24:2000.
1996;51:421–424. 10. Gonzalo MA, de Argila D, Revenga F, 18. Kumar D. Lispro analog for treatment
3. deShazo RD, Boehm TM, Kumar D, Garcia JM, Diaz J, Morales F. Cutane- of generalized allergy to human insulin.
Galloway JA, Dvorak HF. Dermal ous allergy to human (recombinant Diabetes Care 1997;20:1357–
hypersensitivity reactions to insulin: DNA) insulin. Allergy 1998;53:106– 1359.
correlations of three patterns to their 107. 19. Lluch-Bernal M, Fernandez M, Herrera-
histopathology. J Allergy Clin Immunol 11. Wessbecher R, Kiehn M, Stoffel E, Moll Pombo JL, Sastre J. Insulin lispro, an
1982;69:229–237. I. Management of insulin allergy. alternative in insulin hypersensitivity.
4. Mandrup-Poulsen T, Molvig J, Pildal J, Allergy 2001;56:919–920. Allergy 1999;54:186–187.
Rasmussen AK, Andersen L, Skov BG 12. Baur X, Bossert J, Koops F. IgE- 20. Moriyama H, Nagata M, Fujihira K,
et al. Leukocytoclastic vasculitis induced mediated allergy to recombinant Yamada K, Chowdhury SA,
by subcutaneous injection of human human insulin in a diabetic. Allergy Chakrabarty S et al. Treatment with
insulin in a patient with type 1 diabetes 2003;58:676–678. human analog (GlyA21, ArgB31,
and essential thrombocytemia. Diabetes 13. Scheer BG, Sitz KV. Suspected insulin ArgB32) insulin glargine (HOE901)
Care 2002;25:242–243. anaphylaxis and literature review. J Ark resolves a generalized allergy to human
5. Feinglos MN, Jegasothy BV. ‘‘Insulin’’ Med Soc 2001;97:311–313. insulin in type 1 diabetes. Diabetes Care
allergy due to zinc. Lancet 1979;1:122– 14. Lee AY, Chey WY, Choi J, Jeon JS. 2001;24:411–412.
124. Insulin-induced drug eruptions and reli- 21. Panczel P, Hosszufalusi N, Horvath
6. Raap U, Liekenbrocker T, Kapp A, ability of skin tests. Acta Derm Venereol MM, Horvath A. Advantage of insulin
Wedi B. Delayed-type hypersensitivity to 2002;82:114–117. lispro in suspected insulin allergy.
protamine as a complication of insulin 15. Jaeger C, Eckhard M, Brendel MD, Allergy 2000;55:409–410.
therapy. Contact Dermatitis 2005;53:57– Bretzel RG. Diagnostic algorithm and 22. Barranco R, Herrero T, Tornero P,
58. management of immune-mediated com- Barrio M, Frutos C, Rodriguez A et al.
7. Goldfine AB, Kahn CR. Insulin allergy plications associated with subcutaneous Systemic allergic reaction by a human
and insulin resistance. Curr Ther Endo- insulin therapy. Exp Clin Endocrinol insulin analog. Allergy 2003;58:
crinol Metab 1994;5:461–464. Diabetes 2004;112:416–421. 536–537.
154Insulin allergy
23. Durand-Gonzalez KN, Guillausseau N, 37. Schernthaner G. Immunogenicity and 50. Child DF, Johansson SG. IgE antibody
Pecquet C, Gayno JP. Glargine insulin is allergenic potential of animal and human studies in a case of generalized allergic
not an alternative in insulin allergy. insulins. Diabetes Care 1993;16(Suppl. reaction to human insulin. Allergy
Diabetes Care 2003;26:2216. 3):155–165. 1984;39:630–633.
24. JiXiong X, Jianying L, Yulan C, Huixian 38. Grammer L. Insulin allergy. Clin Rev 51. Bodtger U, Wittrup M. A rational clin-
C. The human insulin analog aspart can Allergy 1986;4:189–200. ical approach to suspected insulin al-
induce insulin allergy. Diabetes Care 39. Brange J, Andersen L, Laursen ED, lergy: status after five years and 22 cases.
2004;27:2084–2085. Meyn G, Rasmussen E. Toward under- Diabet Med 2005;22:102–106.
25. Takata H, Kumon Y, Osaki F, Kumagai standing insulin fibrillation. J Pharm Sci 52. Danne T, Niggemann B, Weber B, Wahn
C, Arii K, Ikeda Y et al. The human 1997;86:517–525. U. Prevalence of latex-specific IgE anti-
insulin analogue aspart is not the 40. Maislos M, Mead PM, Gaynor DH, bodies in atopic and nonatopic children
almighty solution for insulin allergy. Robbins DC. The source of the with type I diabetes. Diabetes Care
Diabetes Care 2003;26:253–254. circulating aggregate of insulin in 1997;20:476–478.
26. Blumer IR. Severe injection site reaction type I diabetic patients is therapeutic 53. Roest MA, Shaw S, Orton DI. Insulin-
to insulin detemir. Diabetes Care insulin. J Clin Invest 1986;77:717– injection-site reactions associated with
2006;29:946. 723. type I latex allergy. N Engl J Med
27. Darmon P, Castera V, Koeppel MC, 41. Alvarez-Thull L, Rosenwasser LJ, 2003;348:265–266.
Petitjean C, Dutour A. Type III allergy Brodie TD. Systemic allergy to endoge- 54. Velcovsky HG, Federlin KF. Insulin-
to insulin detemir. Diabetes Care nous insulin during therapy with re- specific IgG and IgE antibody response
2005;28:2980. combinant DNA (rDNA) insulin. Ann in type I diabetic subjects exclusively
28. Sola-Gazagnes A, Pecquet C, MÕBemba Allergy Asthma Immunol 1996;76:253– treated with human insulin (recombinant
J, Larger E, Slama G. Type I and type 256. DNA). Diabetes Care 1982;5(Suppl. 2):
IV allergy to the insulin analogue 42. Porsche R, Brenner ZR. Allergy to 126–128.
detemir. Lancet 2007;369:637–638. protamine sulfate. Heart Lung 55. Jegasothy BV. Allergic reactions to
29. Dejgaard A, Larsen J, Pedersen CR. 1999;28:418–428. insulin. Int J Dermatol 1980;19:139–
Type I and type IV allergy to insulin 43. Bollinger ME, Hamilton RG, Wood 141.
detemir. Lancet 2007;369:1926–1927. RA. Protamine allergy as a complication 56. Sharath MD, Metzger WJ, Richerson
30. Eapen SS, Connor EL, Gern JE. Insulin of insulin hypersensitivity: a case report. HB, Scupham RK, Meng RL, Ginsberg
desensitization with insulin lispro and an J Allergy Clin Immunol 1999;104:462– BH et al. Protamine-induced fatal ana-
insulin pump in a 5-year-old child. Ann 465. phylaxis. Prevalence of antiprotamine
Allergy Asthma Immunol 2000;85:395– 44. Clerx V, Van Den KC, Kochuyt A, immunoglobulin E antibody. J Thorac
397. Goossens A. Drug intolerance reaction Cardiovasc Surg 1985;90:86–90.
31. Moyes V, Driver R, Croom A, Mirakian to insulin therapy caused by metacresol. 57. Stewart WJ, McSweeney SM, Kellett
R, Chowdhury TA. Insulin allergy in a Contact Dermatitis 2003;48:162– MA, Faxon DP, Ryan TJ. Increased risk
patient with type 2 diabetes successfully 163. of severe protamine reactions in NPH
treated with continuous subcutaneous 45. Kahn CR, Rosenthal AS. Immunologic insulin-dependent diabetics undergoing
insulin infusion. Diabet Med 2006; reactions to insulin: insulin allergy, cardiac catheterization. Circulation
23:204–206. insulin resistance, and the autoimmune 1984;70:788–792.
32. Naf S, Esmatjes E, Recasens M, Valero insulin syndrome. Diabetes Care 58. Grant W, deShazo RD, Frentz J. Use of
A, Halperin I, Levy I et al. Continuous 1979;2:283–295. low-dose continuous corticosteroid
subcutaneous insulin infusion to resolve 46. Ratner RE, Phillips TM, Steiner M. infusion to facilitate insulin pump use in
an allergy to human insulin. Diabetes Persistent cutaneous insulin allergy local insulin hypersensitivity. Diabetes
Care 2002;25:634–635. resulting from high-molecular-weight Care 1986;9:318–319.
33. Nagai T, Nagai Y, Tomizawa T, Mori insulin aggregates. Diabetes 59. Mattson JR, Patterson R, Roberts M.
M. Immediate-type human insulin al- 1990;39:728–733. Insulin therapy in patients with systemic
lergy successfully treated by continuous 47. Yip CM, Brader ML, DeFelippis MR, insulin allergy. Arch Intern Med 1975;
subcutaneous insulin infusion. Intern Ward MD. Atomic force microscopy of 135:818–821.
Med 1997;36:575–578. crystalline insulins: the influence of se- 60. Pratt EJ, Miles P, Kerr D. Localized
34. Radermecker RP, Scheen AJ. Allergy quence variation on crystallization and insulin allergy treated with continuous
reactions to insulin: effects of continuous interfacial structure. Biophys J 1998;74: subcutaneous insulin. Diabet Med
subcutaneous insulin infusion and insu- 2199–2209. 2001;18:515–516.
lin analogues. Diabetes Metab Res Rev 48. Madero MF, Sastre J, Carnes J, Quirce 61. Frigerio C, Aubry M, Gomez F, Graf L,
2007;23:348–355. S, Herrera-Pombo JL. IgG(4)-mediated Dayer E, de Kalbermatten N et al.
35. Yokoyama H, Fukumoto S, Koyama H, allergic reaction to glargine insulin. Desensitization-resistant insulin allergy.
Emoto M, Kitagawa Y, Nishizawa Y. Allergy 2006;61:1022–1023. Allergy 1997;52:238–239.
Insulin allergy; desensitization with 49. Jutel M, Akdis M, Budak F et al. IL-10 62. Witters LA, Ohman JL, Weir GC,
crystalline zinc-insulin and steroid and TGF-beta cooperate in the regula- Raymond LW, Lowell FC. Insulin anti-
tapering. Diabetes Res Clin Pract tory T cell response to mucosal allergens bodies in the pathogenesis of insulin
2003;61:161–166. in normal immunity and specific immu- allergy and resistance. Am J Med
36. Asai M, Yoshida M, Miura Y. Immu- notherapy. Eur J Immunol 2003;33: 1977;63:703–709.
nologic tolerance to intravenously 1205–1214.
injected insulin. N Engl J Med
2006;354:307–309.
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