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 Halsall; Robert Semple

doi:10.1210/jc.2018-00972

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 / Description of output

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 language	English
Journal	The Journal of Clinical Endocrinology & Metabolism (JCEM)
Early online date	31 Jul 2018
DOIs	https://doi.org/10.1210/jc.2018-00972
Publication status	E-pub ahead of print - 31 Jul 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. The Journal of Clinical Endocrinology & Metabolism (JCEM). Advance online publication. https://doi.org/10.1210/jc.2018-00972

@article{bd45129d36a645bbb3e22a57a7ecaa9f,

title = "Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome",

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.",

author = "David Church and Lu{\'i}s Cardoso and Kay, {Richard G} and Williams, {Claire L} and Bernard Freudenthal and Catriona Clarke and Julie Harris and Myuri Moorthy and Efthmia Karra and Gribble, {Fiona M} and Frank Reimann and Keith Burling and Williams, {Alistair J K} and Alia Munir and Jones, {T Hugh} and Dagmar F{\"u}hrer and Moeller, {Lars C} and Mark Cohen and Bernard Khoo and David Halsall and Robert Semple",

year = "2018",

month = jul,

day = "31",

doi = "10.1210/jc.2018-00972",

language = "English",

journal = "The Journal of Clinical Endocrinology & Metabolism (JCEM)",

issn = "0021-972X",

publisher = "Oxford University Press",

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Church, D, Cardoso, L, Kay, RG, Williams, CL, Freudenthal, B, Clarke, C, Harris, J, Moorthy, M, Karra, E, Gribble, FM, Reimann, F, Burling, K, Williams, AJK, Munir, A, Jones, TH, Führer, D, Moeller, LC, Cohen, M, Khoo, B, Halsall, D & Semple, R 2018, 'Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome', The Journal of Clinical Endocrinology & Metabolism (JCEM). https://doi.org/10.1210/jc.2018-00972

TY - JOUR

T1 - Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome

AU - Church, David

AU - Cardoso, Luís

AU - Kay, Richard G

AU - Williams, Claire L

AU - Freudenthal, Bernard

AU - Clarke, Catriona

AU - Harris, Julie

AU - Moorthy, Myuri

AU - Karra, Efthmia

AU - Gribble, Fiona M

AU - Reimann, Frank

AU - Burling, Keith

AU - Williams, Alistair J K

AU - Munir, Alia

AU - Jones, T Hugh

AU - Führer, Dagmar

AU - Moeller, Lars C

AU - Cohen, Mark

AU - Khoo, Bernard

AU - Halsall, David

AU - Semple, Robert

PY - 2018/7/31

Y1 - 2018/7/31

N2 - 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.

AB - 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.

U2 - 10.1210/jc.2018-00972

DO - 10.1210/jc.2018-00972

M3 - Article

C2 - 30085133

SN - 0021-972X

JO - The Journal of Clinical Endocrinology & Metabolism (JCEM)

JF - The Journal of Clinical Endocrinology & Metabolism (JCEM)

ER -

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

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