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Prediction of Impending Type 1 Diabetes through Automated Dual-Label Measurement of Proinsulin:C-Peptide Ratio

Journal Contribution - Journal Article

BACKGROUND: The hyperglycemic clamp test, the gold standard of beta cell function, predicts impending type 1 diabetes in islet autoantibody-positive individuals, but the latter may benefit from less invasive function tests such as the proinsulin:C-peptide ratio (PI:C). The present study aims to optimize precision of PI:C measurements by automating a dual-label trefoil-type time-resolved fluorescence immunoassay (TT-TRFIA), and to compare its diagnostic performance for predicting type 1 diabetes with that of clamp-derived C-peptide release.

METHODS: Between-day imprecision (n = 20) and split-sample analysis (n = 95) were used to compare TT-TRFIA (AutoDelfia, Perkin-Elmer) with separate methods for proinsulin (in-house TRFIA) and C-peptide (Elecsys, Roche). High-risk multiple autoantibody-positive first-degree relatives (n = 49; age 5-39) were tested for fasting PI:C, HOMA2-IR and hyperglycemic clamp and followed for 20-57 months (interquartile range).

RESULTS: TT-TRFIA values for proinsulin, C-peptide and PI:C correlated significantly (r2 = 0.96-0.99; P<0.001) with results obtained with separate methods. TT-TRFIA achieved better between-day %CV for PI:C at three different levels (4.5-7.1 vs 6.7-9.5 for separate methods). In high-risk relatives fasting PI:C was significantly and inversely correlated (rs = -0.596; P<0.001) with first-phase C-peptide release during clamp (also with second phase release, only available for age 12-39 years; n = 31), but only after normalization for HOMA2-IR. In ROC- and Cox regression analysis, HOMA2-IR-corrected PI:C predicted 2-year progression to diabetes equally well as clamp-derived C-peptide release.

CONCLUSIONS: The reproducibility of PI:C benefits from the automated simultaneous determination of both hormones. HOMA2-IR-corrected PI:C may serve as a minimally invasive alternative to the more tedious hyperglycemic clamp test.

Journal: PLOS ONE
ISSN: 1932-6203
Issue: 12
Volume: 11
Publication year:2016
  • ORCID: /0000-0003-4445-308X/work/156351563
  • PubMed Central Id: PMC5131964
  • ORCID: /0000-0002-6463-4585/work/110052909
  • ORCID: /0000-0001-7179-1717/work/83057859
  • ORCID: /0000-0003-2304-5298/work/61726065
  • ORCID: /0000-0002-6440-2485/work/61423523
  • ORCID: /0000-0002-8671-4527/work/61349412
  • ORCID: /0000-0002-9007-6177/work/60767578
  • ORCID: /0000-0002-9007-5203/work/58117045
  • DOI: https://doi.org/10.1371/journal.pone.0166702
  • WoS Id: 000389482700036
  • Scopus Id: 84999652767
CSS-citation score:1
Authors:Regional
Accessibility:Open