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

J Clin Endocrinol Metab. 2018 Oct 1;103(10):3845-3855. doi: 10.1210/jc.2018-00972.


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: Six 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 ELISA and RIA, and IA were further characterized using radioligand binding studies.

Results: All patients were diagnosed with IAS (five IgG, one IgA) based on a 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. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four 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.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Autoimmune Diseases / diagnosis*
  • Autoimmune Diseases / drug therapy
  • Autoimmune Diseases / immunology
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Chromatography, Gel
  • Congenital Hyperinsulinism / diagnosis*
  • Congenital Hyperinsulinism / drug therapy
  • Congenital Hyperinsulinism / immunology
  • Diazoxide / therapeutic use
  • Female
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Insulin / blood
  • Insulin Antibodies / blood*
  • Insulin Resistance / physiology
  • Male
  • Middle Aged
  • Syndrome


  • Biomarkers
  • Blood Glucose
  • C-Peptide
  • Immunosuppressive Agents
  • Insulin
  • Insulin Antibodies
  • Diazoxide