Johns Hopkins Diabetes GuideClinical TestsImmunology

Insulin Antibodies

Shivam Champaneri, M.D., Christopher Saudek, M.D.

DESCRIPTION

  • Antibodies to exogenously delivered insulin are common with insulin treatment but are not often clinically significant.
  • IgG antibodies are the most common while IgE antibodies are the cause of insulin allergy [1].
  • At high titers, IgG antibodies may limit insulin action which could delay or diminish insulin action.
  • Rarely, antibodies can be agonists to the insulin receptor and cause hypoglycemia (usually postprandial hypoglycemia) [2].
  • The development of antibodies depends on the purity, molecular structure, and storage conditions of the insulin administered as well as patient factors such as age, HLA type, and delivery route [1].
  • Most common when patients are exposed to beef or pork insulin, rather than only to human or analog insulins [3].
  • Insulin auto-antibodies, in people not previously treated with insulin, are an indication of developing Type 1 Diabetes (See Insulin Initiation in Type 1 Diabetes and to LADA for more information).
  • React equally to analog insulin and unmodified human insulins.

ASSAYS

  • Radioligand binding (RLB) assays are the most common assay used for measurement of insulin antibodies [1].
  • Standard immunoprecipitation and agglutination analytic methods cannot measure insulin antibodies since insulin antibody immune complexes do not precipitate [1].
  • High sensitivity is required for evaluating autoantibodies which are in much lower concentration than antibodies to exogenous insulin [4].

INDICATIONS

  • Severe insulin resistance, unresponsive to high-dose insulin treatment.
  • Evaluation of possible insulin allergy: IgE antibodies are seen in rapid type 1 allergy, whereas IgG are seen in delayed type III hypersensitivity reaction [3].
  • Evaluation of possible factitious hypoglycemia: Surreptitious insulin administration in individuals without diabetes may be diagnosed by detecting insulin antibodies.
  • Diagnosing autoimmune hypoglycemia: a rare condition but one to be distinguished from insulinoma [2].

DIFFERENTIAL DIAGNOSIS

  • The presence of insulin antibodies does not prove that they are causing insulin resistance or hypoglycemia.
  • More soluble insulins, such as regular and semilente are less allergenic than intermediate or long acting insulins [5].
  • Circulating IgE antibodies to insulin may cause dermal and systemic allergic reactions to animal-source insulin [1].
  • Allergy to protamine and zinc (which help slow insulin absorption) need to be distinguished from allergy to insulin [6].
  • Autoimmune hypoglycemia can be due to endogenous antibodies to insulin or the insulin receptor [2].

INTERPRETATION

[General]

  • Most studies show no relationship between the presence of insulin antibodies and complications such as nephropathy, retinopathy, and neuropathy [1].
  • Rarely, antibodies bind differently to different insulins from different species; clinical improvement may result from switching insulin sources [7].
  • No relationship between insulin dose and development of antibodies has been shown in clinical trials; therefore, antibodies are only a cause of insulin resistance when found in unusually high titer [1].
  • For severely insulin resistant patients, positive antibody testing can lead to consideration of the following treatments: switching insulin formulations, glucocorticoid therapy, or rarely plasmaphoresis [8] [2].
  • Insulin allergy can be treated with antihistamines to control symptoms, switching insulin preparations, or immunotherapy in the form of desensitization [3].
  • Autoimmune hypoglycemia can be treated with tapering doses of corticosteroids to suppress endogenous insulin antibodies [9].

LIMITATIONS OR CONFOUNDERS

  • No standardization of the insulin antibody assay is available for proper quantification [1].
  • Diagnosis of insulin allergy is not established by presence of IgE alone as it can be found in patients with no apparent allergy [1].
  • Little evidence to show a causal relationship between presence of insulin antibodies and hypoglycemia in patients on insulin.
  • Can also be seen in patients with viral disorders, other autoimmune disorders, paraneoplastic syndromes or with a high likelihood of type 1 diabetes development [1].

EXPERT COMMENTS

  • As indicated, IgG insulin antibodies are rarely pathogenic, so attributing insulin resistance to antibodies is valid only when very high titer and only having ruled out more common causes.

References

  1. Fineberg SE et al: Immunological responses to exogenous insulin. Endocr Rev 28:625, 2007  [PMID:17785428]

    Comment: This reference provides an overview of the immunologic factors in the development of insulin antibodies and reviews its relationship toward diabetes complications.

  2. Koyama R et al: Hypoglycemia and hyperglycemia due to insulin antibodies against therapeutic human insulin: treatment with double filtration plasmapheresis and prednisolone. Am J Med Sci 329:259, 2005  [PMID:15894868]

    Comment: This article discusses the role of plasmapheresis and subsequent use of steroid therapy to lower insulin antibodies to achieve better glycemic control by insulin.

  3. Heinzerling L et al: Insulin allergy: clinical manifestations and management strategies. Allergy 63:148, 2008  [PMID:18186805]

    Comment: This review provides an overview of insulin allergy, including presentation, diagnosis, and immunotherapy.

  4. Greenbaum CJ et al: Insulin autoantibodies measured by radioimmunoassay methodology are more related to insulin-dependent diabetes mellitus than those measured by enzyme-linked immunosorbent assay: results of the Fourth International Workshop on the Standardization of Insulin Autoantibody Measurement. J Clin Endocrinol Metab 74:1040, 1992  [PMID:1569152]

    Comment: This summarizes the findings of the Fourth International Workshop on the Standardization of Insulin Autoantibody Measurement with the finding that the data suggest that insulin autoantibodies measured by radioimmunoassay are more disease related than those measured by enzyme-linked immunosorbent assay.

  5. Chance RE, Root MA, Galloway JA: The immunogenicity of insulin preparations. Acta Endocrinol Suppl (Copenh) 205:185, 1976  [PMID:793278]

    Comment: This review assessed antibody formation from differently prepared insulins (porcine and bovine) with the finding that more purely prepared insulins had less immunogenecity.

  6. Feinglos MN, Jegasothy BV: "Insulin" allergy due to zinc. Lancet 1:122, 1979  [PMID:84149]

    Comment: This 1979 paper describes the phenomenon of allergy to zinc in commercially prepared insulins.

  7. Grammer LC, Roberts M, Patterson R: IgE and IgG antibody against human (recombinant DNA) insulin in patients with systemic insulin allergy. J Lab Clin Med 105:108, 1985  [PMID:3881543]

    Comment: This paper notes the presence of IgE and IgG antibodies to human insulin as well as bovine and porcine insulin in patients found to have systemic insulin allergy.

  8. Kahn CR, Rosenthal AS: Immunologic reactions to insulin: insulin allergy, insulin resistance, and the autoimmune insulin syndrome. Diabetes Care 2:283, 1979 May-Jun  [PMID:510122]

    Comment: This is a review from 1979 (one of the original papers) that provides a summary of insulin allergy and insulin resistance and what was known about the mechanisms at that time.

  9. Redmon JB, Nuttall FQ: Autoimmune hypoglycemia. Endocrinol Metab Clin North Am 28:603, 1999  [PMID:10500933]

    Comment: This excellent review describes the clinical significance, pathogenesis, evaluation, and management of autoimmune hypoglycemia.

  10. Radermecker RP, Renard E, Scheen AJ: Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion, and impact on glucose control. Diabetes Metab Res Rev 25:491, 2009  [PMID:19496088]

    Comment: This 2009 reference discusses the significance of different modalities of insulin administration toward development of insulin antibodies and its potential implications toward management.

  11. Schlichtkrull J et al: Clinical aspects of insulin--antigenicity. Diabetes 21:649, 1972  [PMID:5066240]

    Comment: This is one of the original papers that describes the antigenicity of insulin.

  12. Sutton M et al: Insulin autoantibodies at diagnosis of insulin-dependent diabetes: effect on the antibody response to insulin treatment. Metabolism 37:1005, 1988  [PMID:3185283]

    Comment: This study assessed whether insulin antibody response over the first year of treatment with insulin was different in individuals with or without insulin autoantibodies. They noted that patients with insulin autoantibodies at diagnosis develop higher insulin antibody measurements when subsequently treated with exogenous insulin.

  13. Salardi S et al: An 8-year follow-up of anti-insulin antibodies in diabetic children: relation to insulin autoantibodies, HLA type, beta-cell function, clinical course and type of insulin therapy. Acta Paediatr 84:639, 1995  [PMID:7670246]

    Comment: This trial studied 105 children and adolescents with insulin dependent diabetes and noted an inverse relationship between insulin autoantibodies and age at diagnosis; they compared levels of antibodies to A1c values, insulin requirement, HLA, and presence of early complications and concluded that antibodies did not have significant effects on the clinical course of the disease.

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