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

Research output: Contribution to journal › Article (Academic Journal) › peer-review

4 Citations (Scopus)

278 Downloads (Pure)

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 language	English
Pages (from-to)	3845-3855
Number of pages	11
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	103
Issue number	10
Early online date	31 Jul 2018
DOIs	https://doi.org/10.1210/jc.2018-00972
Publication status	Published - Oct 2018

Access to Document

10.1210/jc.2018-00972

Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Oxford University Press at https://academic.oup.com/jcem/article/103/10/3845/5061434 . Please refer to any applicable terms of use of the publisher.
Final published version, 714 KBLicence: CC BY

Fingerprint Dive into the research topics of 'Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome'. Together they form a unique fingerprint.

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

Church, David ; Cardoso, Luís ; Kay, Richard G ; Williams, Claire L ; Freudenthal, Bernard ; Clarke, Catriona ; Harris, Julie ; Moorthy, Myuri ; Karra, Efthmia ; Gribble, Fiona M ; Reimann, Frank ; Burling, Keith ; Williams, Alistair J K ; Munir, Alia ; Jones, T Hugh ; Führer, Dagmar ; Moeller, Lars C ; Cohen, Mark ; Khoo, Bernard ; Halsall, David ; Semple, Robert. / Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome. In: Journal of Clinical Endocrinology and Metabolism. 2018 ; Vol. 103, No. 10. pp. 3845-3855.

@article{3181db2472984d9abccf9fd100d4bc7d,

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 = oct,

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

language = "English",

volume = "103",

pages = "3845--3855",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Oxford University Press",

number = "10",

}

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', Journal of Clinical Endocrinology and Metabolism, vol. 103, no. 10, pp. 3845-3855. https://doi.org/10.1210/jc.2018-00972

Assessment and Management of Anti-insulin Autoantibodies in Varying Presentations of Insulin Autoimmune Syndrome. / Church, David; Cardoso, Luís; Kay, Richard G; Williams, Claire L; Freudenthal, Bernard; Clarke, Catriona; Harris, Julie; Moorthy, Myuri; Karra, Efthmia; Gribble, Fiona M; Reimann, Frank; Burling, Keith; Williams, Alistair J K; Munir, Alia; Jones, T Hugh; Führer, Dagmar; Moeller, Lars C; Cohen, Mark; Khoo, Bernard; Halsall, David; Semple, Robert.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 103, No. 10, 10.2018, p. 3845-3855.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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 - 2018/10

Y1 - 2018/10

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 (Academic Journal)

C2 - 30085133

VL - 103

SP - 3845

EP - 3855

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 10

ER -