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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Abstract

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
Volume103
Issue number10
Early online date31 Jul 2018
DOIs
Publication statusPublished - Oct 2018

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  • Cite this

    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. https://doi.org/10.1210/jc.2018-00972