Effects of Unsuppressed Endogenous Insulin On Pharmacokinetics And/Or Pharmacodynamics of Study Insulin In The Healthy: A Retrospective Cohort Study

Background: C-peptide, a marker of endogenous insulin, should be consistently inhibited during euglycemic clamping, while an elevated postdosing C-peptide (CP postdosing ) is not an occasional phenomenon. This study aimed to describe the effects of insufficient suppression of endogenous insulin on estimates of the pharmacokinetics and pharmacodynamics of subcutaneously injected insulin. Methods: : This was a retrospective cohort study that included 33 males who underwent a manual euglycemic clamp with a subcutaneous injection of insulin aspart (IAsp). Time-profiles of whole blood glucose, human insulin, glucose infusion rate (GIR), and C-peptide were recorded. The subjects were divided into two groups at a ratio of 2:1: group A [(CP postdosing ) max ＞CP baseline ], group B [(CP postdosing ) max ≤CP baseline ]. The endogenous insulin was approximately equal to the measured value of human insulin or calculated from the C-peptide. Results: : The basal glucose, CP baseline , basal human insulin, HOMA-IR, IAsp dose, and demographic statistics were all comparable between the two groups except the ‘clamped’ glucose. The ‘clamped’ glucose was 99.7±7.1% (group A) and 94.9±5.1% (group B) of baseline. After correction for ‘clamped’ glucose, AUC GIR,0-8h was higher in group A ( P ＜0.05) under comparable IAsp exposure. AUC endogenous insulin,0-8h calculated from C-peptide was different from that measured from human insulin in group A ( P ＜0.05), whereas no significant difference between these measures was observed in group B. Conclusions: : Blood glucose should be controlled below baseline to ensure the inhibition of endogenous insulin. Unsuppressed endogenous insulin may contribute to observed GIR, and the endogenous-insulin-corrected pharmacokinetics estimated by C-peptide may be inaccurate with insufficient endogenous insulin suppression.