Insulin secretion and hepatic extraction during euglycemic clamp study: modelling of insulin and C-peptide data
C. Dansirikul, M.O. Karlsson
Division of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden
Objectives: Insulin and C-peptide are co-secreted peptides from beta-cells on an equimolar basis. While 40-85% of insulin have been reported to be extracted by liver after secretion1-3, only a negligible amount of C-peptide is lost on a single pass through the liver. This analysis was performed to characterize the endogenous insulin secretion profile and its hepatic extraction when C-peptide data were utilized as a measure of pre-hepatic secretion.
Methods: Insulin and C-peptide concentration-time data were available from 15 healthy volunteers, who participated in a 24-hour euglycemic clamp study (without insulin injection). NONMEM VI with First Order Conditional Estimation (FOCE) method was used during the analyses. A flexible staircase of zero order input model4 was fitted to C-peptide concentration-time data whilst their disposition pharmacokinetics parameters (two-compartment model) were fixed to values from literature5. Different number of change-points was tested (2, 3, 4, and 5 change-points). Hepatic extraction of insulin was subsequently estimated using a sequential modelling approach. As such population parameters describing C-peptide secretion were fixed to their estimated values, and hepatic extraction of insulin was then estimated. During the estimation of hepatic insulin extraction, the Laplacian estimation method was used, in which it allowed the contribution of insulin concentration below the low limit of quantification (LLOQ) to the likelihood estimates.
Results: A zero order input model with 5 change-points was chosen to portray endogenous secretion profile of C-peptide. These change-points were at baseline, and 3, 6, 12, and 18 hours after study started. Secretion of C-peptide at baseline was 103 pmol/min. Its secretion then decreased over time up to 18 hours. Secretion was 90%, 77%, 63%, and 55% of the value at baseline, for the first four steps. After the last change-point (18 hours), secretion increased slightly to 61% of the value at baseline. Hepatic insulin extraction was estimated to be 56%. Inter-individual variability of hepatic extraction was not statistically significant to be included in the model (log-likelihood ratio test, at p-value of 0.05).
Conclusions: During a 24-hour euglycemic clamp, secretion of C-peptide and insulin changed over time. Hepatic insulin extraction was estimated to be similar to previous studies.
. C Cobelli et al. Diabetes 37: 223-31 (1988).
. A Tura, et al. Am J Physiol Endocrinol Metab 281: E966-74 (2001).
. JJ Meier, et al. Diabetes 54: 1649-56 (2005).
. A Lindberg-freijs et al. Biopharmaceutics & Drug Disposition 15: 75-86 (1994).
. E Van Cauter, et al. Diabetes 41: 368-77 (1992).