Download PDF
Exp Clin Endocrinol Diabetes 2004; 112(8): 416-421
DOI: 10.1055/s-2004-821186
Article

J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York

Diagnostic Algorithm and Management of Immune-Mediated Complications Associated with Subcutaneous Insulin Therapy[*]

C. Jaeger1 , M. Eckhard1 , M. D. Brendel1 , R. G. Bretzel1
  • 1Third Medical Department and Policlinic, Justus-Liebig University of Giessen, Germany
Further Information

Publication History

Publication Date:
16 September 2004 (online)

Also available at
    Permissions and Reprints

Abstract

Immune mediated complications associated with subcutaneous insulin therapy such as insulin neutralizing antibodies and/or skin reactions are rare conditions since human insulin is in general use. Nevertheless, if it occurs, a stepwise diagnostic approach is essential for differential diagnosis and consecutive treatment of these complications. Here we suggest a diagnostic algorithm to deal with e.g. insulin antibody formation of the IgG and/or IgE type and/or severe skin reactions resulting in poor metabolic control and often “brittle diabetes” in affected patients. This diagnostic algorithm includes step 1: Intradermal skin testing with positive and negative controls, additives and different insulin preparations; step 2: Quantification of insulin specific IgG and IgE in the serum, and step 3: Analysis of the time dependent binding/dissociation curves of the insulin neutralizing antibodies in an ex vivo/in vitro assay to assess the clinical significance of these antibodies. Based on 158 insulin treated control subjects and four patients with typical symptoms and signs representing the spectrum of immune-mediated complications subsequent to subcutaneous insulin therapy we demonstrate that the proposed stepwise approach leads to a definite diagnosis as a prerequisite for individual and successful therapy.

Key words

Insulin antibodies - insulin allergy - insulin resistance - brittle diabetes - insulin therapy

1 In honour of Prof. Dr. Drs. h.c. K. Federlin on the occasion of his 75th birthday

References

  • 1 Airaghi L, Lorini M, Tedeschi A. The insulin analog aspart: a safe alternative in insulin allergy.  Diabetes Care. 2001;  24 2000
    PubMedSearch in Google Scholar
  • 2 Christiansen A H. Radioimmunoelectrophoresis in the determination of insulin binding to IgG. Methodological studies.  Horm Metabol Res. 1973;  5 147-154
    PubMedSearch in Google Scholar
  • 3 Discher T, Seipke G, Friedmann E, Velcovsky H G, Federlin K. Recurrent hypoglycemia in the insulin autoimmune syndrome.  Dtsch Med Wochenschr. 1990;  115 1950-1955
    PubMedSearch in Google Scholar
  • 4 Dixon K. Measurement of antibodies to insulin in serum.  Clin Chem. 1974;  20 1275-1281
    PubMedSearch in Google Scholar
  • 5 Eapen S S, Connor E L, Gern J E. Insulin desensitization with insulin lispro and an insulin pump in a 5-year-old child.  Ann Allergy Asthma Immunol. 2000;  18 395-397
    PubMedSearch in Google Scholar
  • 6 Federlin K. Diabetes mellitus and immunology - a manifold interrelation.  Immun Infekt. 1985;  13 1893-1899
    PubMedSearch in Google Scholar
  • 7 Francis A J, Hanning I, Alberti K GGM. The influence of insulin antibody levels on the plasma profiles and action of subcutaneously injected human and bovine short acting insulins.  Diabetologia. 1985;  28 330-334
    PubMedSearch in Google Scholar
  • 8 Galloway J A, deShazo R D. Complications of insulin treatment. Ellenberg M, Rifkin H Diabetes Mellitus: Theory and Practice. New Hyde Park; NY Med Exam 1990: 506-508
    Search in Google Scholar
  • 9 Ganz M G, Untermann T, Roberts M, Uy R, Sahgal S, Samter M, Grammer L C. Resistance and allergy to recombinant human insulin.  J Allergy Clin Immunol. 1990;  86 45-52
    PubMedSearch in Google Scholar
  • 10 Hobler H, Zoltobrocki M, Schernthaner G, Schnack C, Federlin K. Formation of protamine, insulin, and native NPH-human insulin antibodies in diabetic patients treated with NPH-human insulin. One year observation study.  Diab Nutr Metab. 1991;  4 275-281
    PubMedSearch in Google Scholar
  • 11 Jaeger C, Hatziagelaki E, Stroedter A, Becker F, Scherer S, Petzoldt R, Federlin K, Bretzel R G. The Giessen-Bad Oeynhausen family study: improved prediction of type 1 diabetes in a low incidence population of relatives using combinations of islet autoantibodies in a dual step model.  Exp Clin Endocrinol Diabetes. 1999;  107 496-505
    PubMedSearch in Google Scholar
  • 12 Kerp L, Steinhilber S, Kasemir H. Ein Verfahren zum Nachweis insulinbindender Antikörper durch Differentialadsorption.  Klin Wschr. 1966;  90 806-814
    PubMedSearch in Google Scholar
  • 13 Kumar D. Lispro analog for the treatment of generalized allergy to human insulin.  Diabetes Care. 1997;  20 1337-1359
    PubMedSearch in Google Scholar
  • 14 Kuzuya H, Blix P M, Horwitz D L, Steiner D F, Rubenstein A H. Determination of free and total insulin and c-peptide in insulin treated diabetics.  Diabetes. 1977;  26 22-29
    PubMedSearch in Google Scholar
  • 15 Lahtela J T, Knip M, Paul R, Antonen J, Salmi J. Severe antibody-mediated human insulin resistance: successful treatment with the insulin analog lispro. A case report.  Diabetes Care. 1997;  20 71-73
    PubMedSearch in Google Scholar
  • 16 Lohmann T, Kratzsch J, Kellner K, Witzigmann H, Hauss J, Paschke R. Severe hypoglycemia due to insulin autoimmune syndrome with insulin autoantibodies crossreactive to proinsulin.  Exp Clin Endocrinol Diabetes. 2001;  109 245-248
    PubMedSearch in Google Scholar
  • 17 Moriyama H, Nagata M, Fujihira K, Yamada K, Chowdhury S A, Chakrabarty S, Zhenzi J, Yasuda H, Ueda H, Yokono K. Treatment with human analog insulin glargine resolves a generalized allergy to human insulin in type 1 diabetes.  Diabetes Care. 2001;  24 411-412
    PubMedSearch in Google Scholar
  • 18 Näf S, Esmatjes E, Recasens M, Valero A, Halperin I, Levy I, Gomis R. Continous subcutaneous insulin infusion to resolve an allergy to human insulin.  Diabetes Care. 2002;  25 634-635
    PubMedSearch in Google Scholar
  • 19 Nagai T, Nagai Y, Tomizawa T, Mori M. Immediate-type human insulin allergy successfully treated by continuous subcutaneous insulin infusion.  Intern Med. 1997;  36 575-578
    PubMedSearch in Google Scholar
  • 20 Schernthaner. Immunogenicity and allergic potential of animal and human insulins.  Diabetes Care. 1993;  16 155-165
    CrossrefPubMedSearch in Google Scholar
  • 21 Van Haeften T W, Heiling V J, Gerich J E. Adverse effects of insulin antibodies on postprandial plasma glucose and insulin profiles in diabetic patients without immune insulin resistance. Implications for intensive insulin regimens.  Diabetes. 1987;  36 305-309
    PubMedSearch in Google Scholar
  • 22 Van Haeften T W. Clinical significance of insulin antibodies in insulin-treated diabetic patients.  Diabetes Care. 1989;  12 641-648
    PubMedSearch in Google Scholar
  • 23 Velcovsky H G, Federlin K. Insulin-specific IgG and IgE antibody response in type 1 diabetic subjects exclusively treated with human insulin (recomibinant DNA).  Diabetes Care. 1982;  5 126-128
    PubMedSearch in Google Scholar
  • 24 Von Kriegstein E, Schatz H. Insulin. Schatz H Diabetologie kompakt, Grundlagen und Praxis. 2nd ed. Berlin, Wien; Blackwell 2002: 86-101
    Search in Google Scholar
  • 25 Ziegler A G, Hummel M, Schenker M, Bonifacio E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study.  Diabetes. 1999;  48 460-468
    CrossrefPubMedSearch in Google Scholar

1 In honour of Prof. Dr. Drs. h.c. K. Federlin on the occasion of his 75th birthday

Dr. med. C. Jaeger

Third Medical Department and Policlinic
Justus-Liebig University of Giessen

Rodthohl 6

35392 Giessen

Germany

Phone: + 4906419942823

Fax: + 49 0 64 19 94 27 59

Email: clemens.jaeger@innere.med.uni-giessen.de