[ Diabetes Type 1 ]

IgE-mediated allergy to recombinant human insulin in a diabetic – Baur – 2003 – Allergy

Patients with long-standing diabetes frequently demonstrate gastric hypersensitivity with an unknown mechanism. The mean values for the migration index (M.I. Hypersensitivity to insulin has considerably been reduced with the introduction of human insulin produced by recombinant deoxyribonucleic acid technology. This was associated with a decrease in the antioxidant capacity and an increase in the sensitivity of these DFs to hydrogen peroxide-induced necrotic cell death. Mechanical hypersensitivity was assessed by the monofilament and paw pressure tests. Overnight, fever developed and the rash evolved into an erythematous morbilliform eruption affecting the torso. The exact mechanism of such discrepancies is unknown.

These are important areas for research in the future. Imaeda, K, Takano, H, Koshita, M, Yamamoto, Y, Joh, T, and Suzuki, H (1998). In all treatment groups, SCS resulted in reversal of mechanical hypersensitivity and a clinically relevant reduction was achieved in 70% of animals. In addition, the nonselective beta-blockers (e.g., propranolol, pindolol, timolol) may inhibit catecholamine-mediated glycogenolysis, thereby potentiating insulin-induced hypoglycemia and delaying the recovery of normal blood glucose levels. insulin S Hoechst (porcine; Bad Soden, Germany), Novo Rapid (bovine), Hoechst (bovine), Lantus (human) Aventis Pharma), Humanlog (recombinant human) Lilly. Furthermore, protamine (0.02 mg/ml) also caused a wheal and flare reaction. With the exception of a borderline response to the house dust mite Dermatophagoides pteronyssinus, 12 common environmental allergens did not yield positive results.

Consider more frequent assessment for patients who are already routinely monitored for ocular conditions. The hemodynamic status should be closely monitored before and after the dose. sensitization to each insulin product as well as, to a lesser extent, to protamine (porcine insulin 7.5 kU/l, bovine insulin 5.0 kU/l, recombinant human insulin 6.7 kU/l and protamine 1.0 kU/l). Complete immunological cross-reactivity of IgE antibodies to human, porcine and bovine insulin could be proved by inhibition tests (Table 1) whereas IgE binding to protamine was independent of insulin reactivity, i.e. it could be inhibited only by itself or by Protophan HM (recombinant human insulin with protamine); 20 μg of both resulted in an inhibition of 100%, whereas insulin S Hoechst (porcine), Novo Rapid (bovine), insulin Hoechst (bovine) or Humalog (recombinant human; Lilly) only led to an inhibition of ≤8%. Commercially available insulin products and protamine were used as inhibitors (25 μg protein each). They were dissolved in 50 μl phosphate-buffered saline (PBS), mixed with 50 μl of patient’s serum and incubated for 16 h prior to routine CAP analysis.

IgG antibodies to recombinant human insulin (CAP) as well as to natural human insulin [commercially available enzyme-linked immunosorbent assay (ELISA)] could not be detected. Islet-cell antibodies [radioimmunoassay (RIA)] were not found either. After incubation for 40 min at 37°C, the reaction was stopped by the addition of ice-cold buffer solution and centrifugation. Local hypersensitivity reactions occur in 15–55% (1), and systemic reactions in 0.1–2% (1–4). Although there are hints of cross-reactivity between different insulin products (5), detailed information is not yet available. This case clearly shows that treatment with recombinant human insulin was associated with a nearly identical IgE-antibody response to porcine and bovine insulin. Corticosteroids do have a number of side effects like weight gain, sudden mood swings, and acne, especially when taken for a long period of time.

Our nonatopic patient also developed immediate-type sensitization to protamine [neutral protamine Hagedorn (NPH)], derived from salmon milt which is used to prolong insulin metabolism and its therapeutic effect. Protamine consists of basic proteins with 30 amino acids (67% arginine) and has a molecular weight of 4.5 kDa. Protamine sensitization was reported in approximately 50% of NPH-insulin treated subjects (6–8). Stewart et al. (6) showed that 27% of these subjects developed major allergic reactions during cardiac catheterization when heparin coagulation was reversed by intravenous protamine injection. Corresponding outcomes including life-threatening reactions or even death were observed during cardiac and other surgeries (9–12). See medicine and doctors for further information regarding the insight of a medical degree and awareness of the drug industry influence on naive doctors.

However, the subject tolerated regular human and Lente insulin suggesting that his hypersensitivity reaction was caused by protamine. After a rest period of 15 min, the balloon was distended by 1 mmHg increments to assess the minimum distending pressure (MDP), which was defined as the pressure at which respiratory excursions were clearly discernable on the tracing. Immunotherapy with human insulin described in a case report did not result in an improvement after desensitization by Humulin but in a reduction of allergic symptoms after desensitization by regular and NPH insulin (18). The hydrated slides were immersed in Trilogy (Cell Marque Corporation, Rocklin, CA, USA) at 121 °C for 15 min for antigen retrieval. “I remember one fella said the 
observatory would make it rain when they wanted it to,” says Harold Crist, 
a 90-year-old Green Bank native who worked for the telescope at one time. The diabetes-related relevance of insulin antibodies is unknown, however. If diabetes worsens, treatment with anti-IgE antibodies (19, 20) might be an effective approach providing valuable information on the impact of IgE-mediated insulin auto-immune response.

We conclude that specific IgE antibodies registered after treatment with recombinant human insulin also induce allergy to porcine and bovine insulin because of immunological cross-reactivity. It is therefore no alternative treatment for such patients. Anti-IgE antibodies (Omalizumab) might be a new promising therapeutic approach. 11 Weiss ME, Nyhan D, Peng Z, Horrow JC, Lowenstein E, Hirshman C, Adkinson NF Jr. Association of protamine IgE and IgG antibodies with life-threatening reactions to intravenous protamine. N Engl J Med 1989;320: 886–892. 17 Galloway JA, De Shazo RD.

Complications of insulin treatment. In: EllenburgM, RifkinH, editors. Diabetes mellitus: theory and practice. New Hyde Park (NY): Medical Examination 1990;506–508. 18 Bollinger ME, Hamilton RG, Wood RA. Protamine allergy as a complication of insulin hypersensitivity: a case report. J Allergy Clin Immunol 1999;104: 462–465.

20 Milgrom H, Fick RB Jr, Su JQ, Reimann JD, Bush RK, Watrous ML, Metzger WJ. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med 1999;341: 1966–1973.

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