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

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

Author information

University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, United Kingdom.
National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge, United Kingdom.
Department of Clinical Biochemistry and Immunology, Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom.
Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.
Academic Endocrine Unity, Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Diabetes & Metabolism, Translational Health Sciences, University of Bristol, Southmead Hospital, Bristol, United Kingdom.
Department of Diabetes & Endocrinology, Royal Free Hospital, London, NHS Foundation Trust, London, United Kingdom.
Department of Clinical Biochemistry, Western General Hospital, NHS Lothian, Edinburgh, United Kingdom.
Core Biochemical Assay Laboratory, Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom.
Department of Endocrinology, Royal Hallamshire Hospital, Sheffield, United Kingdom.
Robert Hague Centre for Diabetes and Endocrinology, Barnsley Hospital, NHS Foundation Trust, Barnsley, United Kingdom.
Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
University of Edinburgh Centre for Cardiovascular Science, Queen's Medical Research Institute, Edinburgh, United Kingdom.



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.


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

Design and Setting:

Observational study in the UK Severe Insulin Resistance Service.


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.


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.


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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