Abstract
SummaryContextInsulin‐binding antibodies may produce severe dysglycaemia in insulin‐naïve patients (‘insulin autoimmune syndrome’ (IAS) or Hirata disease), while rendering routine insulin assays unreliable.ObjectiveTo assess the performance of clinically used insulin assays and an optimal analytical approach in the context of IAS.DesignObservational biochemical study of selected patients with hyperinsulinaemic hypoglycaemia.PatientsThree patients without diabetes with recurrent spontaneous hyperinsulinaemic hypoglycaemia and ‘positive’ insulin antibodies.MeasurementsA panel of clinically used insulin assays (Siemens ADVIA ® Centaur, Siemens Immulite® 2000, DiaSorin LIAISON ® XL, PE AutoDELFIA ® and the Beckman Coulter Access® 2) were used before and after plasma dilution or polyethylene glycol (PEG) precipitation. Anti‐insulin IgG antibodies were measured by Isletest™‐IAA ELISA. Gel filtration chromatography (GFC) was undertaken with and without preincubation of plasma with exogenous insulin.ResultsDilution of IAS plasma with assay‐specific buffer increased insulin recovery, supporting negative immunoassay interference by antibodies. PEG precipitation of IAS plasma decreased insulin recovery using all assays except the Immulite® 2000. GFC discriminated high molecular weight and monomeric insulin, while ex vivo addition of exogenous insulin to plasma increased insulin bound to antibody, thereby improving the sensitivity of detection of insulin immunocomplexes.ConclusionsImmunoprecipitation with PEG must be used with caution in screening for insulin–antibody complexes as results are assay dependent. GFC with addition of exogenous insulin can identify significant insulin immunocomplexes with enhanced sensitivity, with attendant greater clinical utility and avoidance of radiolabelled reagents.
Highlights
The existence of hormone–immunoglobulin complexes is well known
The three patients studied were female, presented with recurrent spontaneous hyperinsulinaemic hypoglycaemia, ‘positive’ insulin antibodies and were not treated for diabetes mellitus at the time of blood sampling
We found polyethylene glycol (PEG) precipitation of plasma from a patient with insulin autoantibodies demonstrated decreased insulin recovery in PEG supernatant using all assays except the Immuliteâ 2000, which may relate to a matrix effect caused by the viscosity of PEG in this assay
Summary
The existence of hormone–immunoglobulin complexes (so called ‘macrohormones’) is well known. Demonstration of insulin-binding immunoglobulin was first reported in the circulation of patients treated with exogenous insulin in 1955,7 and such antibodies were the focus of many studies when animal-derived insulins were commonly used. Some such insulin-binding antibodies in plasma have been shown to alter insulin pharmacokinetics and/or pharmacodynamics, both in patients na€ıve to insulin therapy (‘insulin autoimmune syndrome’ (IAS) or ‘Hirata disease’)[8] and in patients with labile diabetes treated with modern genetically engineered insulin analogues.[9] In both situations, patients may present with insulin resistance and/
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