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The Predictive Ability of C-Peptide in Distinguishing Type 1 Diabetes ...

Abstract Objective This systematic review and meta-analysis aimed to investigate the predictive ability of plasma connecting peptide (C-peptide) levels in discriminating type 1 diabetes (T1D) from type 2 diabetes (T2D) and to inform evidence-based guidelines i

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Abstract

Objective

This systematic review and meta-analysis aimed to investigate the predictive ability of plasma connecting peptide (C-peptide) levels in discriminating type 1 diabetes (T1D) from type 2 diabetes (T2D) and to inform evidence-based guidelines in diabetes classification.

Methods

We conducted a holistic review and meta-analysis using PubMed, MEDLINE, EMBASE, and Scopus. The citations were screened from 1942 to 2021. The quality criteria and the preferred reporting items for systematic reviews and meta-analysis checklist were applied. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42022355088).

Results

A total of 23,658 abstracts were screened and 46 full texts reviewed. Of the 46 articles screened, 12 articles were included for the meta-analysis. Included studies varied by race, age, time, and proportion of individuals. The main outcome measure in all studies was C-peptide levels. A significant association was reported between C-peptide levels and the classification and diagnosis of diabetes. Furthermore, lower concentrations and the cutoff of <0.20 nmol/L for fasting or random plasma C-peptide was indicative of T1D. In addition, this meta-analysis revealed the predictive ability of C-peptide levels in discriminating T1D from T2D. Results were consistent using both fixed- and random-effect models. The I2 value (98.8%) affirmed the variability in effect estimates was due to heterogeneity rather than sampling error among all selected studies.

Conclusion

Plasma C-peptide levels are highly associated and predictive of the accurate classification and diagnosis of diabetes types. A plasma C-peptide cutoff of ≤0.20 mmol/L is indicative of T1D and of ≥0.30 mmol/L in the fasting or random state is indicative of T2D.

Introduction

Nowadays, diabetes mellitus (DM) is one of the greatest threats to community health in developed and developing countries.1 It is progressively becoming a global health challenge owing to its increasing prevalence worldwide.2, 3, 4, 5 As of the recent International Diabetes Federation data published in 2021, 537 million people are living with DM, which is expected to increase to 634 million by 2030.6 The accurate classification of the 2 main types of diabetes is crucial because it will help in a better understanding of the etiology, management, and treatment strategy of the patients with diabetes. Importantly, ensuring the appropriate treatment and its management is highly needed.7, 8, 9, 10, 11 Available guidelines are specific in treating type 1 diabetes (T1D) and type 2 diabetes (T2D) and thus exhibit distinct disparities.12, 13, 14, 15, 16 Moreover, the guidelines reflect marked difference in production of endogenous insulin among the 2 leading subtypes. Often, a severe insulin deficiency developed or reported in patients with T1D, which results in excessive glycemic instability; therefore, an accurate insulin replacement such as multiple injections is obligatory. In such circumstances, patients poorly respond to all noninsulin therapies if prescribed.17, 18, 19 On the contrary, patients with T2D secreted increased levels of insulin and responded well to all noninsulin medicines.20 Hence, a stable glycemia was often observed in patients with T2D. Moreover, these patients may attain reasonable control with nonphysiologic insulin regimes.21,22

The care management in a patient with diabetes is important and somehow not straightforward. Unfortunately, no published evidence-based criteria evolved yet to assist the available guidelines that classify diabetes accurately. In addition, there is limited guidance provisioned by the world’s leading health organizations as these entities are focusing more on the etiology of diabetes only.17,23 An informed treatment decision is always based on the insulin production in the body. An alternate or more appropriate way to measure insulin production is by measuring connecting peptide (C-peptide) levels in either blood or urine.24 C-peptide is a polypeptide secreted with insulin by the beta cells of the pancreas, produced by the enzymatic cleavage of proinsulin. Insulin and C-peptide are secreted in equimolar amounts. However, the half-life of C-peptide is longer than that of insulin, which provides a more stable measurement window.24, 25, 26, 27 In routine clinical practices, the measurement of C-peptide levels is seldom in patients with T2D and is not recommended by the current diabetes management guidelines for use unless T1D is suspected.12,28, 29, 30, 31 Consequently, the prime classification is often based on clinical judgments, such as patients of younger age and with slimmer bodies tend to be classified as T1D, whereas most patients of older age and with obesity tend to be classified as T2D.17 However, the increasing obesity rates result in an increased number of T2D cases in the younger population, which makes this outmoded division difficult and unclear.32, 33, 34

Diabetes misclassification is seen in up to 15% of the cases, an often underestimated rate owing to the use of clinical judgments as a reference orthodox.35 Therefore, the current clinical practices are deficient because these are based on etiologic guidelines and arbitrations. Evidence-based criteria should be opted in accurately classifying the subtypes to ensure better diabetes management. In this regard, the difference in endogenous insulin production between the 2 diabetes types is vital.27,32,35 An individual’s C-peptide levels could play an important role in measuring these differences and, therefore, could predict and discriminate the T1D from T2D. Therefore, we aimed in this systematic review and meta-analysis of the available literature to identify the clinical criteria, particularly the predictive ability of C-peptide levels in discriminating T1D from T2D, and to inform evidence-based guidelines in diabetes classification. The current study protocol is registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD42022355088). No edits were made to the protocol.

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Section snippets

Material and Methods

We followed partly the PICO framework36 to conduct this systematic literature review, which included the population (individuals with DM, T1D/T2D), intervention (C-peptide levels), and outcomes (predict/distinguish T1D from T2D). Therefore, the formulated research question was “Do C-peptide levels distinguish individuals with T1D from T2D?”

Search Results

In total, 12 studies were selected for the systematic review and meta-analysis (ie, Forest plot). Figure 1 shows the PRISMA flowchart of all citations that were extracted/found.

Characteristics of Studies

The collective sample size of all included studies was 8929. Six studies followed an observational prospective study design, 5 observational retrospective design, and 1 a mixed study design. Of the 12 studies included, 3 were conducted in the United States, 4 in Sweden, and 1 each in Finland, Germany, Korea, Iran, and

Discussion

In this systematic review and meta-analysis of 12 studies reflective of almost 9000 participants, we found that the plasma C-peptide level is strongly associated with DM and accurately predicts the diagnosis and classification of the major subtypes of diabetes. Lower concentrations of plasma C-peptide or its lower cutoffs are highly discriminative in diagnosing T1D from T2D and are one of the major findings of this systematic review and meta-analysis.

The C-peptide level was the primary outcome

Strengths

We conducted this holistic and robust systematic review and meta-analysis by strictly following the PRISMA guidelines. A large number of the literature sources were screened. Two authors independently performed the reviewing and duplication process of the extracted data.

Limitations

This study has a few limitations. The main limitation of this systematic review and meta-analysis is the heterogeneity within the included studies that might persuade the C-peptide cutoff diagnostic performance. This high

Conclusions

This systematic review and meta-analysis suggest that plasma C-peptide level is highly associated with DM and accurately predicts the diagnosis and classification of T1D and T2D. A plasma C-peptide cutoff of ≤0.20 mmol/L is indicative of T1D and of ≥0.30 mmol/L in the fasting or random state is indicative of T2D. The use of C-peptide measures in clinical routine may potentially improve diabetes management.

Disclosure

The authors have no multiplicity of interest to disclose. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgment

This work was supported by the Rovira i Virgili University (URV), and there was no specific funding required. We thank Dr Mohammad Waqas Anjum for his contributions in facilitating the data extraction of this study.

Author Contributions

S.I., A.A.J., and S.R.-V. conceived and designed the study; S.I. and A.M.A. performed data collection; S.I., A.M.A., A.A.J., and S.R.-V. performed the analysis and interpretation of results; S.I., A.A.J., and S.R.-V. drafted the manuscript; and A.A.J. and S.R.-V. critically reviewed

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    • PROSPERO registry number: CRD42022355088.

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