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

Abstract

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.

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References
1.
Saisho Y . Postprandial C-Peptide to Glucose Ratio as a Marker of β Cell Function: Implication for the Management of Type 2 Diabetes. Int J Mol Sci. 2016; 17(5). PMC: 4881566. DOI: 10.3390/ijms17050744. View

2.
Vittinghoff E, McCulloch C . Relaxing the rule of ten events per variable in logistic and Cox regression. Am J Epidemiol. 2006; 165(6):710-8. DOI: 10.1093/aje/kwk052. View

3.
Siljander H, Hermann R, Hekkala A, Lahde J, Tanner L, Keskinen P . Insulin secretion and sensitivity in the prediction of type 1 diabetes in children with advanced β-cell autoimmunity. Eur J Endocrinol. 2013; 169(4):479-85. DOI: 10.1530/EJE-13-0206. View

4.
Zethelius B, Hales C, Lithell H, Berne C . Insulin resistance, impaired early insulin response, and insulin propeptides as predictors of the development of type 2 diabetes: a population-based, 7-year follow-up study in 70-year-old men. Diabetes Care. 2004; 27(6):1433-8. DOI: 10.2337/diacare.27.6.1433. View

5.
De Pauw P, Vermeulen I, Ubani O, Truyen I, Vekens E, van Genderen F . Simultaneous measurement of plasma concentrations of proinsulin and C-peptide and their ratio with a trefoil-type time-resolved fluorescence immunoassay. Clin Chem. 2008; 54(12):1990-8. DOI: 10.1373/clinchem.2008.109710. View