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[10].
• 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)[11].
• 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[10].
• Most common when patients are exposed to beef or pork insulin, rather than only to human or analog insulins[9].
• 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[10].
• Standard immunoprecipitation and agglutination analytic methods cannot measure insulin antibodies since insulin antibody immune complexes do not precipitate[10].
• High sensitivity is required for evaluating autoantibodies, which are in much lower concentration than antibodies to exogenous insulin[13].
• Gel filtration chromatography can identify insulin immunocomplexes with addition of exogeneous insulin to diagnose insulin autoimmune syndrome without necessarily using radiolabelled reagants[1].

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[9].
• 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[11].

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[16].
• Circulating IgE antibodies to insulin may cause dermal and systemic allergic reactions to animal-source insulin[10].
• Allergy to protamine and zinc (which help slow insulin absorption) need to be distinguished from allergy to insulin[15].

• Autoimmune hypoglycemia can be due to endogenous antibodies to insulin or the insulin receptor[11].

INTERPRETATION

TREATMENT

• For severely insulin resistant patients, positive antibody testing can lead to consideration of the following treatments: switching insulin formulations, glucocorticoid therapy, or rarely plasmaphoresis[11][17].
• Insulin allergy can be treated with antihistamines to control symptoms, switching insulin preparations, or immunotherapy in the form of desensitization[9].

• Autoimmune hypoglycemia can be treated with tapering doses of corticosteroids to suppress endogenous insulin antibodies[12].
• Anti-CD20 antibody therapy (Rituximab) may achieve gradual disappearance of anti-insulin antibodies [8].

LIMITATIONS OR CONFOUNDERS

• No standardization of the insulin antibody assay is available for proper quantification[10].
• Diagnosis of insulin allergy is not established by presence of IgE alone as it can be found in patients with no apparent allergy[10].
• 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[10].

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. Church D, Cardoso L, Bradbury S, et al. Diagnosis of insulin autoimmune syndrome using polyethylene glycol precipitation and gel filtration chromatography with ex vivo insulin exchange. Clin Endocrinol (Oxf). 2016.  [PMID:27588366]

   Comment: This study on 3 patients without diabetes but with recurrent spontaneous hyperinsulinemic hypoglycemia found that caution must be used in using immunoprecipitation with polyethylene glycol, but gel filtration chromatography can identify insulin immunocomplexes with enhanced sensitivity.
   

2. Shigeno R, Horie I, Ando T, et al. Low-carbohydrate diet combined with SGLT2 inhibitor for refractory hyperglycemia caused by insulin antibodies. Diabetes Res Clin Pract. 2016;116:43-5.  [PMID:27321315]

   Comment: This case report found that treatment with an SGLT inhibitor and low carbohydrate diet was effective in a patient with type 2 diabetes patient complicated with a high insulin antibody titers.
   

3. Kato T, Iizuka K, Niwa H, et al. Liraglutide improved glycaemic instability in a patient with diabetes with insulin antibodies. BMJ Case Rep. 2016;2016.  [PMID:27440852]

   Comment: This case report suggests that liraglutide treatment in a 52-year-old man with type 2 diabetes with glycemic instability and high insulin antibody titers yielded improved glycemic stability.
   

4. Hirai H, Ogata E, Kikuchi N, et al. The effects of liraglutide on both hypereosinophilic insulin allergy and the characteristics of anti-insulin antibodies in type 2 diabetes mellitus: a case report. J Med Case Rep. 2016;10:202.  [PMID:27456688]

   Comment: This case report found that treatment with liraglutide in a 70-year-old man with type 2 diabetes who developed insulin allergy with hypereosinophilia yielded improvements in his insulin allergy and serum glycated hemoglobin.
   

5. Thalange N, Bereket A, Jensen LB, et al. Development of Insulin Detemir/Insulin Aspart Cross-Reacting Antibodies Following Treatment with Insulin Detemir: 104-week Study in Children and Adolescents with Type 1 Diabetes Aged 2-16 Years. Diabetes Ther. 2016;7(4):713-724.  [PMID:27600385]

   Comment: This recent randomized trial on 146 children with type 1 diabetes found no correlation between the level of specific or cross reacting antibodies and glycated hemogloblin or basal insulin dosing.
   

6. Hayashi A, Takano K, Kawai S, et al. SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies. Endocr J. 2016;63(2):187-91.  [PMID:26549210]

   Comment: This case report of a 47-year-old man with type 2 diabetes with poor glycemic control and recurring hypoglycemia due to insulin antibodies found improvement in his hyperglycemia and hypoglycemic events with SGLT2 inhibitor therapy.
   

7. Lanas A, Paredes A, Espinosa C, et al. [Insulin autoimmune syndrome: Report of two cases]. Rev Med Chil. 2015;143(7):938-42.  [PMID:26361032]

   Comment: This article presents 2 cases of patients without prior exposure to exogeneous insulin who developed hypoglycemia in context of anti-insulin antibodies who responded well to carbohydrate restriction, acarbose, and prednisone.
   

8. Jassam N, Amin N, Holland P, et al. Analytical and clinical challenges in a patient with concurrent type 1 diabetes, subcutaneous insulin resistance and insulin autoimmune syndrome. Endocrinol Diabetes Metab Case Rep. 2014;2014:130086.  [PMID:24711924]

   Comment: This article presents a case of a 15-year-old with type 1 diabetes with anti-insulin antibodies where interference with the pharmacological action of administered insulin contributed to insulin resistance and hypoglycemia. Treatment with rituximab was associated with a gradual disappearance of anti-insulin antibodies.
   

9. Heinzerling L, Raile K, Rochlitz H, et al. Insulin allergy: clinical manifestations and management strategies. Allergy. 2008;63(2):148-55.  [PMID:18186805]

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

10. Fineberg SE, Kawabata TT, Finco-Kent D, et al. Immunological responses to exogenous insulin. Endocr Rev. 2007;28(6):625-52.  [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.
    

11. Koyama R, Nakanishi K, Kato M, et al. Hypoglycemia and hyperglycemia due to insulin antibodies against therapeutic human insulin: treatment with double filtration plasmapheresis and prednisolone. Am J Med Sci. 2005;329(5):259-64.  [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.
    

12. Redmon JB, Nuttall FQ. Autoimmune hypoglycemia. Endocrinol Metab Clin North Am. 1999;28(3):603-18, vii.  [PMID:10500933]

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

13. Greenbaum CJ, Palmer JP, Kuglin B, 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. 1992;74(5):1040-4.  [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.
    

14. 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. 1985;105(1):108-13.  [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.
    

15. Feinglos MN, Jegasothy BV. "Insulin" allergy due to zinc. Lancet. 1979;1(8108):122-4.  [PMID:84149]

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

16. Chance RE, Root MA, Galloway JA. The immunogenicity of insulin preparations. Acta Endocrinol Suppl (Copenh). 1976;205:185-98.  [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.
    

17. Kahn CR, Rosenthal AS. Immunologic reactions to insulin: insulin allergy, insulin resistance, and the autoimmune insulin syndrome. Diabetes Care. 1979;2(3):283-95.  [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.