Commentary: Reduction in C-Peptide Levels and Influence on Pharmacokinetics and Pharmacodynamics of Insulin Preparations: How to Conduct a High-Quality Euglycemic Clamp Study

In a recent issue of this journal, Yi Tao and coworkers published a comprehensive article (Tao et al., 2021) focusing on the effect of C-peptide in a euglycemic clamp on the evaluation of the pharmacokinetics (PK) and pharmacodynamics (PD) of insulin preparations, therefore elucidating the method to perform a high-quality euglycemic clamp.We completely agree that suppression of endogenous insulin is of paramount importance in euglycemic clamp in healthy volunteers (European Medicines Agency, 2015;Heise et al., 2016).The topic of evaluating the reduction of postdose C-peptide and its influence on the PK/PD of the study preparations is interesting and deserves research.The work by Tao et al. (2021) included a total of 39 euglycemic clamps lasting for up to 24 h evaluating the PK/PD of insulin glargine in healthy volunteers.These volunteers were divided into three groups according to the reduction of C-peptide levels: group A (ratio of C-peptide reduction <30%, n = 13), group B (ratio of C-peptide reduction between ≥30% and <50%, n = 15), and group C (ratio of C-peptide reduction ≥50%, n = 11).The PK/PD of insulin glargine and the clamp quality index were compared among the three groups.This article is of significance considering improving the quality of the clamp study.In this letter, based on the reported studies and our experiences (Heise et al., 2016;Li et al., 2012;Liu et al., 2021;Li et al., 2021), we intend to provide different opinions on the method and some results of this article.First, the EMA guideline recommends using specific assays that are capable of distinguishing between exogenous and endogenous insulin to determine the concentration of insulin analogs (European Medicines Agency, 2015).In the published work by Yi Tao and colleagues, the insulin glargine level was determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS) method which is known for its specificity and has been used in the bioanalysis of peptides, including insulin and insulin analogs (Xu et al., 2017;Xu et al., 2014;Thomas et al., 2014).In the previous report, Xu et al. (2014) conducted selectivity experiments for the LC-MS/MS assay, demonstrating no cross-talk

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