Correspondence

Immunologic Tolerance to Intravenously Injected Insulin

N Engl J Med 2006; 354:307-309January 19, 2006

Article

To the Editor:

Rosalyn Yalow, the inventor of radioimmunoassay, found that insulin treatments led to the production of antibodies against insulin.1 Initially, this phenomenon was thought to be due to slight immunogenicity induced by the refining of preparations or the difference in amino acid sequences between species. However, even today, when genetically engineered preparations of human insulin are used, anti–human insulin IgG subclasses still are frequently detected in patients treated with insulin. Why therapeutically used insulin molecules, despite having exactly the same primary structure as endogenous insulin, are immunogenic has not been fully clarified.

We describe the induction of immunologic tolerance with the use of intravenously injected insulin in a severely insulin-allergic patient with diabetes. In April 2003, a 24-year-old man with a three-year history of poorly controlled type 1 diabetes and with insulin allergy was referred to our institution. Skin tests performed with all forms of commercially available insulin and insulin analogues were positive, but skin tests were negative for solvent and additives. Attempted desensitization with the subcutaneous administration of insulin, with continuous subcutaneous injection of insulin lispro, or with oral antiallergic agents did not prevent frequent life-threatening allergic symptoms (e.g., systemic urticaria, shock, and dyspnea), especially after bolus injections with meals. However, when no allergic reactions were observed after intravenous injection of 0.05 U of regular insulin per patient, we gradually increased the dose.

We ultimately succeeded in administering all the required insulin intravenously with a portable parenteral-nutrition device (a central venous catheter, a subcutaneously embedded reservoir, and a portable infusion pump). All symptoms of an allergic reaction disappeared as soon as intravenous injection was begun. Oral antiallergic agents were no longer required. Within a year after the introduction of intravenously injected insulin, levels of anti–human insulin IgE returned to normal (decreasing from 2.51 to <0.34 U per milliliter), as did levels of anti–human insulin IgG bound/total (B/T) (from 42.6 to 9.2 percent), without any adverse effect on glucose control (Figure 1Figure 1Blood Levels of Glycosylated Hemoglobin, Anti–Human Insulin Antibodies, and Antiallergic Agents over Time.).

In July 2005, despite these changes in anti-insulin antibodies, subcutaneous injection of regular insulin still caused immediate allergic reactions in our patient. Thus, identical insulin molecules can behave in markedly different ways depending on the route of injection. Also, it is possible that the formation of anti–human insulin IgG is caused only by insulin molecules that are in contact with subcutaneous tissue. We assume that some modification of insulin, such as aggregation, leads to the immunologic reactions.2,3 We believe that the example of our patient not only indicates an option for the treatment of severe insulin allergy but also may help elucidate the pathogenesis of the immunologic response to therapeutic insulin.

Masato Asai, M.D., Ph.D.
Nagoya University Graduate School of Medicine and Hospital, Nagoya 466-8550, Japan
masato-a@mbc.ocn.ne.jp

Masanori Yoshida, M.D.
Toyota Memorial Hospital, Toyota 471-8513, Japan

Yoshitaka Miura, M.D., Ph.D.
Nagoya University Graduate School of Medicine and Hospital, Nagoya 466-8550, Japan

3 References

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   Maislos M, Mead PM, Gaynor DH, Robbins DC. The source of the circulating aggregate of insulin in type I diabetic patients is therapeutic insulin. J Clin Invest 1986;77:717-723
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Citing Articles (8)

Citing Articles

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   Masanori Yoshida, Masato Asai, Misaki Miyata, Koichiro Ogawa, Harumi Maeda, Yutaka Oiso. (2012) Combination therapy with liraglutide and sulfonylurea for a type 2 diabetic patient with high titer of anti-insulin antibodies produced by insulin therapy. Diabetes Research and Clinical Practice
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2. 2

   Mohammad K. Ghazavi, Graham A. Johnston. (2011) Insulin allergy. Clinics in Dermatology 29:3, 300-305
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   S. Hasani-Ranjbar, M. R. Fazlollahi, A. Mehri, B. Larijani. (2011) Allergy to human insulin and specific immunotherapy with glargine; case report with review of literature. Acta Diabetologica
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   Thomas Koroscil, Yasmin Kagzi, Dawn Zacharias. (2011) Failure of Multiple Therapies in the Treatment of a Type 1 Diabetic Patient with Insulin Allergy: A Case Report. Endocrine Practice 17:1, 91-94
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   (2010) Drug Allergy: An Updated Practice Parameter. Annals of Allergy, Asthma & Immunology 105:4, 259-273.e78
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   Baris Akinci, Serkan Yener, Firat Bayraktar, Sena Yesil. (2010) Allergic reactions to human insulin: a review of current knowledge and treatment options. Endocrine 37:1, 33-39
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   Kristen A Neville, Charles F Verge, Brynn K Wainstein, Helen J Woodhead, John B Ziegler, Jan L Walker. (2008) Insulin allergy desensitization with simultaneous intravenous insulin and continuous subcutaneous insulin infusion. Pediatric Diabetes 9:4pt2, 420-422
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   L. Heinzerling, K. Raile, H. Rochlitz, T. Zuberbier, M. Worm. (2008) Insulin allergy: clinical manifestations and management strategies. Allergy 63:2, 148-155
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