Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome

David Church, Luís Cardoso, Richard G Kay, Claire L Williams, Bernard Freudenthal, Catriona Clarke, Julie Harris, Myuri Moorthy, Efthmia Karra, Fiona M Gribble, Frank Reimann, Keith Burling, Alistair J K Williams, Alia Munir, T Hugh Jones, Dagmar Führer, Lars C Moeller, Mark Cohen, Bernard Khoo, David HalsallRobert Semple

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Context: Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia including surreptitious insulin administration. No standardized treatment regimen exists.

Objectives: To evaluate an analytic approach to IAS and responses to different treatments.

Design and Setting: Observational study in the UK Severe Insulin Resistance Service.

Patients: 6 patients with hyperinsulinemic hypoglycemia and detectable circulating anti-insulin antibody (IA).

Main outcome measures: Glycemia, plasma insulin and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), and IA were further characterized using radioligand binding studies.

Results: All patients were diagnosed with IAS (5 IgG, 1 IgA) based on high insulin:C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. 1 patient was managed conservatively, 4 were treated with diazoxide without sustained benefit, and 4 were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis.

Conclusions: IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin:C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.

Original languageEnglish
Pages (from-to)3845-3855
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Issue number10
Early online date31 Jul 2018
Publication statusPublished - Oct 2018

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    Church, D., Cardoso, L., Kay, R. G., Williams, C. L., Freudenthal, B., Clarke, C., Harris, J., Moorthy, M., Karra, E., Gribble, F. M., Reimann, F., Burling, K., Williams, A. J. K., Munir, A., Jones, T. H., Führer, D., Moeller, L. C., Cohen, M., Khoo, B., ... Semple, R. (2018). Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome. Journal of Clinical Endocrinology and Metabolism, 103(10), 3845-3855.