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

Abstract Background: C-peptide, a marker of endogenous insulin, should be consistently inhibited during euglycemic clamping, while an elevated postdosing C-peptide (CPpostdosing) 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 [(CPpostdosing)max＞CPbaseline], group B [(CPpostdosing)max≤CPbaseline]. The endogenous insulin was approximately equal to the measured value of human insulin or calculated from the C-peptide. Results: The basal glucose, CPbaseline, 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, AUCGIR,0-8h was higher in group A (P＜0.05) under comparable IAsp exposure. AUCendogenous 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.