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Exp Clin Endocrinol Diabetes. 2023 Mar; 131(3): 173–178.
Published online 2023 Jan 11. doi:10.1055/a-1998-6889
PMCID: PMC9998184
PMID: 36630986
Sebastian Hörber,1,2,3 Matthias Orth,4 Andreas Fritsche,2,3,5 and Andreas Peter1,2,3
Author information Article notes Copyright and License information PMC Disclaimer
Abstract
C-peptide is an increasingly used and established marker for beta cell functionby assessing endogenous insulin secretion. Accurate and comparable C-peptidemeasurements are needed in clinical practice and research studies. For example,to calculate HOMA-indices, the C-peptide/glucose ratio, and theclassification of recently published novel subgroups of diabetes and prediabeteshave used C-peptide measurements. Although the process for standardization ofC-peptide measurements is advanced, its full implementation is still missing;therefore, the current status of the comparability of C-peptide measurementsusing different immunoassays is unclear. Here we compared five widely usedC-peptide immunoassays on different analyzers (Abbott ALINITY i, DiaSorinLiaison XL, Roche Cobas e411, Siemens Healthineers ADVIA Centaur XPT, andImmulite 2000 XPi) using serum samples covering the clinically relevantC-peptide concentration range. Although all investigated immunoassays aretraceable to the international reference reagent for C-peptide (NIBSC code:84/510), results of C-peptide measurements showed significantdifferences between analyzers in the entire concentration range, especially withincreasing C-peptide concentrations. The mean bias was largest (36.6%)between results of the immunoassays by Roche and Siemens Healthineers (ADVIACentaur XPT), and both assays revealed large discrepancies compared toimmunoassays by Abbott, DiaSorin, and Siemens Healthineers (Immulite 2000 XPi).In contrast, the three latter assays showed similar C-peptide results (meanbias: 2.3% to 4.2%). Consequently, C-peptide discrepancies mightaffect clinical diagnosis and the interpretation of study results. Therefore,there is an urgent need to implement and finalize the standardization process ofC-peptide measurements to improve patient care and the comparability of researchstudies.
Key words: Diabetes, Prediabetes, Immunoassay, Standardization, Harmonization
Introduction
C-peptide is a 31 amino acids polypeptide secreted by pancreatic beta cells into thecirculation in equimolar amounts to insulin. In contrast to insulin, C-peptideexhibits a prolonged biological half-life; therefore, its plasma concentrations arehigher compared to insulin1. Inclinical routine, C-peptide measurements are used to assess endogenous insulinsecretion, to distinguish between type 1, type 2, and other specific types ofdiabetes, and for differential diagnosis of fasting hypoglycemia1234. C-peptide is also used for thecalculation of HOMA (homeostatic model assessment) indices (e. g., HOMA-2Bor HOMA-IR), i. e., for estimating insulin secretion and insulin resistance,especially in patients on insulin therapy. Using C-peptide measurements, theseindices are necessary for the classification of novel subgroups in diabetes andprediabetes56. C-peptide measurements are also usefulfor assessing the insulin secretion capacity and therapeutic consequences inpatients with diabetes, as proposed by the recently publishedC-peptide/glucose ratio7.Furthermore, preserved C-peptide concentrations are associated with lowercomplication rates in type 1 diabetes; the measurements of C-peptide is used as theprimary outcome for clinical trials of novel type 1 diabetes therapies8910.
To reliably evaluate circulating C-peptide concentrations in daily practice, clinicaltrials, and research studies, a prerequisite is that results of different C-peptideimmunoassay measurements should be comparable, i. e., C-peptide immunoassaysare standardized11. In general, thefollowing assumptions are needed to achieve standardization of a measurand: thebiomarker has a well-defined molecular composition, and measurement results aretraceable to a primary reference material using a reference management system12. Since the molecular composition ofC-peptide is well-defined and a traceability chain for the standardization processhas been proposed, standardization of C-peptide immunoassays can be achieved13. During the last decades, much effortswas made to standardize C-peptide immunoassays; more than three decades ago, thefirst international reference reagent (IRR) for human C-peptide (NIBSC code:84/510) was established, and reference methods for the reliable and accuratemeasurement of C-peptide concentrations were published1415161718.
Since to which extent this system has been implemented is not known, the aim of thestudy was to investigate the current status of the comparability of C-peptideimmunoassays by comparing the results of C-peptide measurements of the most widelyused immunoassays. Furthermore, the impact on clinical decisions and interpretationof clinical trials and research studies is elaborated here, and the current statusand efforts of the C-peptide standardization process are discussed.
Materials and Methods
Study design and sample material
The study was conducted as part of a quality control measurement approach at theInstitute for Clinical Chemistry and Pathobiochemistry of the UniversityHospital Tübingen, Germany. Serum samples from clinical routine wererandomly selected, and each sample was divided into at least five identicalaliquots and immediately stored at –80°C. All aliquots werecompletely anonymized and labeled with ongoing codes. All procedures were inaccordance with the declaration of Helsinki and its later amendments and havebeen approved by the local ethics committee (project number113/2014BO1).
C-peptide immunoassays
For comparison of C-peptide immunoassays, five different immunoanalyzer platformswere used in the study (Table 1).C-peptide measurements were performed using the ADVIA Centaur XPT and theImmulite 2000 XPi (both from Siemens Healthineers, Eschborn, Germany) and theCobas e411 (Roche Diagnostics, Mannheim, Germany) in the central laboratory ofthe Institute for Clinical Chemistry and Pathobiochemistry of the UniversityHospital Tübingen. Measurements using the Liaison XL (Diasorin,Dietzenbach, Germany) and the ALINITY i (Abbott, Wiesbaden, Germany) wereperformed at the MVZ Labor Ludwigsburg, Germany and the Institute of LaboratoryMedicine at the Vinzenz von Paul Kliniken Stuttgart, Germany, respectively. Allmeasurements were performed between August 2021 and October 2021.
Table 1Analyzers and immunoassays used for C-peptidemeasurements in the study.
| Platform/Analyzer | ALINITY i | ADVIA Centaur XPT | Cobas e411 | Immulite 2000 XPi | Liaison XL |
|---|---|---|---|---|---|
| Manufacturer | Abbott | Siemens Healthineers | Roche Diagnostics | Siemens Healthineers | DiaSorin |
| Technology | CLIA | CLIA | ECLIA | CLIA | CLIA |
| Traceability of Calibrators | WHO IRR 84/510 | WHO IRR 84/510 | WHO IRR 84/510 | WHO IRR 84/510 | WHO IRR 84/510 |
| Limit of Quantification/Detection* (LoQ,nmol/L)# | 0.03 | 0.02 | 0.05 | 0.03* | 0.03 |
| Reference interval#,nmol/L | 0.26–1.73 | 0.27–1.27 | 0.37–1.47 | 0.30–2.35 | 0.26–1.39 |
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#according to the manufacturer. Abbreviations: CLIA:chemiluminescence immunoassay; ECLIA: electrochemiluminescenceimmunoassay; IRR: international reference reagent; WHO: World HealthOrganization
Statistical analysis
Results from C-peptide immunoassays were converted and reported in SI units(1 μg/L=0.331 nmol/L). Methodcomparison was conducted using Passing-Bablok regression analysis andBland-Altman plots. Mean biases obtained by Bland-Altman analysis were reportedas % difference as follows: (result of method B – result ofmethod A)/average vs. average. Analyses were performed, and figures werecreated using GraphPad Prism 9.1.2 software.
Results
A total of 50 serum samples were used for the comparison of five commerciallyavailable and widely used C-peptide immunoassays (Table 1). C-peptide measurement resultsranged from 0.16–6.23 nmol/L depending on the investigatedimmunoassay. According to the German external quality assessment survey (report05/2022 from INSTAND e.V.) the majority of all participating laboratories(94%) are using one of these assays. Among them, the Roche C-peptide assayis the most widely used method (n=101 of 191 participating laboratories).The C-peptide immunoassays from DiaSorin (n=29), Abbott (n=22),Siemens Healthineers ADVIA Centaur XPT/Atellica (n=13), and SiemensImmulite (n=14; former DPC Biermann) were used by a smaller number oflaboratories in the same period. At the time of the study, all immunoassays werecalibrated against the World Health Organization (WHO) international referencereagent (NIBSC code: 84/510).
Fig. 1shows the results of C-peptidemeasurements using the aforementioned immunoanalyzers separated by single specimens.Substantial differences between immunoassays were observed in the entireconcentration range, especially with increasing C-peptide concentrations. Since themajority of the participating laboratories in the external quality assessment usethe Roche C-peptide immunoassay, Passing-Bablok analyses were conducted using theRoche C-peptide assay in comparison to the other C-peptide immunoassays. Linearassociations were observed for all comparisons (R2>0.97; seeFig. 2). Using Bland-Altmananalysis to determine the mean bias between C-peptide immunoassays, the largestdifference (ADVIA Centaur XPT – Roche Cobas e411: mean bias–36.6%;Table 2) wasobserved between C-peptide assays from Siemens Healthineers (ADVIA Centaur XPT) andRoche. The Siemens Healthineers ADVIA Centaur XPT assay also revealed lowerC-peptide concentrations in comparison to the assays from Abbott (-20.3%),DiaSorin (19.1%), and Siemens Healthineers (Immulite;−24.4%). The Roche Cobas e411 assay showed higher C-peptideconcentrations compared to Abbott (16.3%), DiaSorin (18.6%), andSiemens Healthineers Immulite (13.3%). C-peptide assays by Abbott, DiaSorin,and Siemens (Immulite) exhibited a similar performance (meanbiases<5%).
Fig. 1
Comparison of C-peptide measurements. Shown are results ofC-peptide measurements (in nmol/L) separated by specimens using five widelyused immunoassays.
Fig. 2
Regression analysis of C-peptide immunoassays. Passing-Bablokregression analyses were conducted using the measurement results of theRoche C-peptide immunoassay in comparison to the C-peptide measurementresults by Abbott, DiaSorin and Siemens Healthineers.
Table 2Comparison of C-peptide immunoassays. Shown are themean biases obtained by Bland-Altman analysis. Results are expressed inpercentage and read as follows (example): C-peptide concentrationsobtained using the Abbott ALINITY i immunoassay are higher (mean bias:+20.3%) compared to the average concentrations of theSiemens ADVIA Centaur XPT and the Abbott ALINITY i C-peptideimmunoassays.
| Abbott ALINITY I vs. | Siemens ADVIA Centaur XPT vs. | Roche Cobas e411 vs. | Siemens Immulite 2000 XPi vs. | DiaSorin Liaison XL vs. | |
|---|---|---|---|---|---|
| Abbott ALINITY i | – | −20.3% | +16.3% | +3.8% | −2.3% |
| Siemens ADVIA Centaur XPT | +20.3% | – | +36.6% | +24.4% | +19.1% |
| Roche Cobas e411 | −16.3% | −36.6% | – | −13.3 | −18.6% |
| Siemens Immulite 2000 XPi | −3.8% | −24.4% | +13.3% | - | −4.2% |
| DiaSorin Liaison XL | +2.3% | – 19.1% | +18.6% | +4.2% | - |
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Discussion
In the present study, the current status of the comparability of the most widely usedC-peptide immunoassays was compared. Substantial differences were found betweendifferent C-peptide immunoassays suggesting that the results of C-peptidemeasurements cannot be used interchangeably. Of note, assay discrepancies mightdirectly affect the interpretation of C-peptide results and, therefore, impactclinical diagnosis and the evaluation of clinical trials and research studies.
The study investigated five widely used and commercially available C-peptideimmunoassays using clinical samples covering the clinically relevant concentrationrange. Method comparison showed a linear association among C-peptide immunoassays ofall manufacturers. However, focusing on the agreement of different immunoassays,C-peptide results measured by immunoassays from Siemens Healthineers (ADVIA CentaurXPT) and Roche (Cobas e411) showed large discrepancies in the low as well as highconcentration range. Results obtained by C-peptide immunoassays from Abbott (ALINITYi), DiaSorin (Liason XL), and Siemens Healthineers (Immulite 2000 XPi) were similar.There are only a few reports of studies comparing the results of different C-peptideimmunoassays. In line with the presented results, a study by Wiedmeyer showedsubstantial between-laboratory variabilities for C-peptide measurements19. This study was performed about fifteenyears ago and demonstrated that normalization of C-peptide results using commutablesample calibrators modestly reduces assay discrepancies. However, this approach isineffective for comparison of clinical trials, indicating the need for timelystandardization of C-peptide measurements. In a recent study by Zhou et al.,C-peptide immunoassays from Abbott, Roche, and Siemens Healthineers showed similardiscrepancies20. They used pooled serumsamples and compared C-peptide results between 94 laboratories in China. Theanalytical performance of the investigated assays was satisfactory, but they alsofound substantial differences between immunoassays and concluded, in line with thepresent results, that still much effort has to be done to standardize C-peptidemeasurements.
All C-peptide immunoassays investigated in the present study were calibrated againstthe first international reference reagent (IRR, NIBSC code: 84/510) at thetime of the study. This standard was established more than 30 years ago and has beenused by the manufacturers for direct calibration of their immunoassays. Since 2017,the first international WHO C-peptide standard (NIBSC code 13/146) isavailable; it was established using more accurate methods compared to thepreparation of the IRR21. The IRR84/510, as well as the WHO standard 13/146 contain purified humanC-peptide. In an international comparison study, both standards showed reasonableagreement between laboratories21. Thestocks of the IRR 84/510 are exhausted; thus, the WHO standard13/146 will replace the IRR. However, the reference management system forthe international WHO standard 13/146 using the primary reference materialdirectly for calibration of the immunoassay is the same as for the IRR84/510, which was demonstrated to be ineffective in improving comparabilitybetween C-peptide immunoassays19. Inparallel to these efforts, another primary reference material has been establishedby the National Metrology Institute of Japan (NMIJ; CRM 6901-b) recommended by theinternational C-peptide standardization committee as primary reference material fora recently proposed and modified reference management system1322. This reference management system uses commutable matrix-basedreference materials for the calibration of immunoassays by manufacturers. The use ofmatrix-appropriate secondary reference materials (frozen serum samples) wasdemonstrated to substantially improve measurement results among methods13. However, these ongoing parallelefforts lead to confusion among the manufacturers and clinical laboratories.Furthermore, from the perspective of a manufacturer, regulatory issues regarding there-calibration of C-peptide immunoassays have to be considered that can varysignificantly among countries23. Toimprove efforts by the manufacturers and clinical laboratories for thestandardization process, the incorporation of standardization requirements forC-peptide immunoassays in clinical guidelines may be of great importance.
Recognizing the increasing importance of C-peptide measurements, the presenteddiscrepancies among C-peptide immunoassays impact clinical diagnosis andcomparability of study results. The recently proposed C-peptide/glucoseratio (CGR; both in the fasting state) as a marker for the insulin secretorycapacity was established from a large cohort of patients with newly diagnosed orknown type 2 diabetes7. In contrast tothe complex determination of HOMA indices, the CGR can be easily obtained and is,therefore, a useful parameter in clinical practice. The ratio is suggested to guidetreatment decisions for patients with type 2 diabetes, especially to evaluate ifthere is a need for insulin treatment. For the calculation of these cut-offs, theC-peptide immunoassay from Siemens Healthineers (ADVIA Centaur XPT) was used.Considering the present study results, it can be assumed that there will not beentirely negligible differences in the calculated CGR when using different C-peptideimmunoassays. The largest difference was found between the Roche Cobas immunoassayand the ADVIA Centaur XPT, potentially affecting therapy decisions based on the CGRcut-offs. Whether these differences actually affect the outcome of diabetes patientshave to be investigated in further studies. Moreover, the proposed novel diabetessubgroups by Ahlqvist et al. and also the prediabetes subphenotypes proposed byWagner et al. use HOMA-indices for the subgroup stratification56. Since C-peptide measurements were used for HOMA calculations, thepresent results indicate that the choice of the C-peptide immunoassay might affectthe subgroup stratification. There are several variables included in thestratification of the subgroups and, therefore, the impact of C-peptide differencesfor a single patient is unclear. However, the use of different C-peptideimmunoassays at different study sites clearly affects the comparability of studyresults. Furthermore, C-peptide is also an important parameter in type 1 diabetes.It is used in clinical trials as endpoint in the immunomodulatory therapies for type1 diabetes and also as a prognostic marker for type 1 diabetes-related complications8910. For example, the response to teplizumab, an anti-CD3 antibody thatcan delay progression to type 1 diabetes in high-risk subjects, is greater insubjects with lower C-peptide concentrations during an oral glucose tolerance testcompared to subjects with higher concentrations8. In the Scottish Diabetes Research Network Type 1 Bioresource(SDRNT1BIO), cohort it was demonstrated that residual C-peptide concentrations couldimprove clinical outcomes in type 1 diabetes, and also in the Diabetes Control andComplications Trial (DCCT), measurable C-peptide concentration was associated withbeneficial clinical outcomes910. Therefore, reliable and comparableC-peptide concentrations, especially in the low concentration range in this context,are a prerequisite.
In light of this variety of important indications for C-peptide measurements, theC-peptide standardization process needs to be implemented and finalized in the nearfuture. Until this approach is reached, it is important that C-peptide measurementsare conducted using the same immunoassay. In multi-center studies, C-peptidemeasurements should be performed at one study site using the same immunoassay. Inclinical practice, physicians should be aware of assay discrepancies when comparingC-peptide results of the patients, measured at different laboratories. To monitorthe next steps of the standardization process and verify the current status of thecomparability participation in external quality assessment programs is recommendedfor laboratories1324.
In conclusion, this study demonstrates that results of different C-peptideimmunoassays do not always agree, and assay discrepancies should be considered wheninterpreting C-peptide concentrations in the context of clinical decisions andclinical trials. To overcome these discrepancies, the proposed standardizationprocess should be urgently implemented to improve patient care and the comparabilityof research studies.
Acknowledgements
We thank M. Siegle (MVZ Labor Ludwigsburg) for performing the C-peptide measurementsusing the DiaSorin Liaison XL. Reagents for C-peptide measurements using the LiaisonXL were kindly provided by DiaSorin.
Footnotes
Conflict of Interest The authors declare that they have no conflict of interest.
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