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

Research output: Contribution to journalArticle

  • 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 Halsall
  • Robert Semple
Original languageEnglish
Pages (from-to)3845-3855
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Issue number10
Early online date31 Jul 2018
DateAccepted/In press - 26 Jul 2018
DateE-pub ahead of print - 31 Jul 2018
DatePublished (current) - Oct 2018


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.

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