Clinical Tests> Immunology>

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 (Fineberg et al).
• 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) (Koyama et al).
• 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 (Fineberg et al)
• Most common when patients are exposed to beef or pork insulin, rather than only to human or analog insulins (Heinzerling et al).
• 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 (Fineberg et al).
• Standard immunoprecipitation and agglutination analytic methods cannot measure insulin antibodies since insulin antibody immune complexes do not precipitate (Fineberg et al).
• High sensitivity is required for evaluating autoantibodies which are in much lower concentration than antibodies to exogenous insulin (Greenbaum et al)

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 (Heinzerling et al).
• 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 (Koyama et al).

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 (Chance et al).
• Circulating IgE antibodies to insulin may cause dermal and systemic allergic reactions to animal-source insulin (Fineberg et al).
• Allergy to protamine and zinc (which help slow insulin absorption) need to be distinguished from allergy to insulin (Feinglos et al).
• Autoimmune hypoglycemia can be due to endogenous antibodies to insulin or the insulin receptor (Koyama et al).

INTERPRETATION

• Most studies show no relationship between the presence of insulin antibodies and complications such as nephropathy, retinopathy, and neuropathy (Fineberg et al).
• Rarely, antibodies bind differently to different insulins from different species; clinical improvement may result from switching insulin sources (Grammer et al).
• 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 (Fineberg et al).
• For severely insulin resistant patients, positive antibody testing can lead to consideration of the following treatments: switching insulin formulations, glucocorticoid therapy, or rarely plasmaphoresis (Kahn et al, Koyama et al).
• Insulin allergy can be treated with antihistamines to control symptoms, switching insulin preparations, or immunotherapy in the form of desensitization (Heinzerling et al).
• Autoimmune hypoglycemia can be treated with tapering doses of corticosteroids to suppress endogenous insulin antibodies (Redmon et al).

LIMITATIONS OR CONFOUNDERS

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

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