Calculated Pattern of Intraportal Insulin Appearance Without Independent Assessment of C-Peptide Kinetics

Abstract

Prehepatic (β-cell insulin release can be calculated with C-peptide measurements, but this requires independent determination of kinetics of C-peptide disappearance from plasma. We introduce an approach by which a prehepatic insulin release pattern is calculated from plasma insulin and C-peptide, without separate C-peptide kihetic analysis. Human insulin and C-peptide were infused intraportally into conscious dogs (n = 11) at equimolar rates; endogenous insulin and C-peptide release were suppressed with somatostatin (0.8 μg · kg⁻¹ · min⁻¹). Insulin and C-peptide were infused at basal and equimolar rates (range 19–72 pmol/min in dogs), and the infusions were slowly increased, in stepwise fashion, to a maximum at 60 min (range 152—613 pmol/min) and subsequently renormalized at either 85 (n = 6) or 195 (n = 5) min. Plasma insulin and C-peptide measurements were described simultaneously by a composite model of insulin and C-peptide plasma kinetics, with the molar intraportal appearance rate due to the infusion R(t) as an unknown input for both insulin and C-peptide catabolism. The model assumes one-compartment disappearance kinetics for both peptides. Fitting the model to the measured insulin and C-peptide data, we were able to compute the insulin-appearance pattern accurately for every experiment; calculated and actual secretion rates were highly correlated (r = .93−.97) and had very similar temporal patterns. Also calculated were the fractional disappearance rates for human insulin (t_1/2 = 6.9 min) and C-peptide (t_1/2 = 14 min) in the dog, as well as the C-peptide distribution volume (12.3 ±0.5% body wt). Islet cell insulin secretion can be determined in vivo from insulin and C-peptide measurement without separate analysis of C-peptide kinetics. This method will be applicable for quantification of β-cell secretion for diagnostic and experimental purposes.