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dc.contributor.authorKay, Richard
dc.contributor.authorBarker, Peter
dc.contributor.authorBurling, Keith
dc.contributor.authorCohen, Mark
dc.contributor.authorHalsall, David
dc.contributor.authorReimann, Frank
dc.contributor.authorGribble, Fiona
dc.contributor.authorSemple, Robert K
dc.contributor.authorChurch, David
dc.date.accessioned2021-04-20T23:30:22Z
dc.date.available2021-04-20T23:30:22Z
dc.date.issued2021-06-01
dc.identifier.issn0009-9147
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/321363
dc.description.abstractBACKGROUND: Determination of C-peptide is important in the investigation of unexplained hyperinsulinemic hypoglycemia because a high C-peptide concentration usually indicates endogenous insulin hypersecretion. Insulin autoimmune syndrome (IAS) denotes hyperinsulinemic hypoglycemia due to insulin-binding antibodies that prolong insulin half-life. C-peptide clearance is considered to be unaffected, and although a marked C-peptide immunoreactivity in hypoglycemic samples has been reported, it has been suspected to be artifactual. High-resolution mass spectrometry enables examination of the basis of C-peptide-immunoreactivity in IAS. METHODS: Precipitation of plasma with polyethylene glycol was followed by C-peptide immunoassay. Plasma peptides extracted by solvent precipitation were characterized by nano-LC-MS/MS and analyzed using an untargeted data-dependent method. Peptides related to proinsulin, in amino acid sequence, were identified using proprietary bioinformatics software and confirmed by repeat LC-MS/MS analysis. Gel filtration chromatography coupled to LC-MS/MS was used to identify proinsulin-related peptides present in IAS immunocomplexes. Results were compared with those from C-peptide immunoassay. RESULTS: Polyethylene glycol precipitation of IAS plasma, but not control plasma, depleted C-peptide immunoreactivity consistent with immunoglobulin-bound C-peptide immunoreactivity. LC-MS/MS detected proinsulin and des 31,32 proinsulin at higher abundance in IAS plasma compared with control plasma. Analysis by gel filtration chromatography coupled to LC-MS/MS demonstrated proinsulin and des 31,32 proinsulin, but no C-peptide, in plasma immunocomplexes. CONCLUSIONS: Antibody binding can enrich proinsulin and des 31,32 proinsulin in IAS immunocomplexes. Proinsulin cross-reactivity in some C-peptide immunoassays can lead to artifactually increased C-peptide results.
dc.description.sponsorshipDiabetes Research & Wellness Foundation (Sutherland–Earl Clinical Fellowship), Medical Research Council
dc.format.mediumPrint
dc.languageeng
dc.publisherOxford University Press (OUP)
dc.rightsAll rights reserved
dc.titleIncreased C-Peptide Immunoreactivity in Insulin Autoimmune Syndrome (Hirata Disease) Due to High Molecular Weight Proinsulin.
dc.typeArticle
prism.endingPage862
prism.issueIdentifier6
prism.publicationDate2021
prism.publicationNameClin Chem
prism.startingPage854
prism.volume67
dc.identifier.doi10.17863/CAM.68484
dcterms.dateAccepted2021-02-24
rioxxterms.versionofrecord10.1093/clinchem/hvab043
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-06
dc.contributor.orcidKay, Richard [0000-0002-3827-8687]
dc.contributor.orcidReimann, Frank [0000-0001-9399-6377]
dc.contributor.orcidGribble, Fiona [0000-0002-4232-2898]
dc.identifier.eissn1530-8561
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UU_12012/1)
pubs.funder-project-idMedical Research Council (MR/M009041/1)
cam.issuedOnline2021-05-24
cam.orpheus.counter6
rioxxterms.freetoread.startdate2024-04-20


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