Methods for measuring insulin secretion and hepatic insulin extraction in vivo, e.g., hepatic vein catheterization, are invasive, and can be applied during steady state only. We introduce a noninvasive method for measuring in vivo insulin secretion and its extraction by the liver during an intravenous glucose tolerance test (IVGTT). This method is based on a minimal model of C-peptide secretion and kinetics that is used for interpreting plasma C-peptide concentration data during an IVGTT in normal humans. The model allows the reconstruction of the time course of insulin secretion and, used in conjunction with a minimal model of insulin delivery and kinetics (described in a previous study), provides a noninvasive measure of the time course of hepatic insulin extraction [H(t)]. The C-peptide model also provides a direct prehepatic measure of β-cell sensitivity to glucose, expressed by two parameters related to first (ϕIC)- and second (ϕIIC)-phase insulin secretion. In the 11 healthy volunteers we studied, these parameters were 61 ± 11 pM · min−1 · mg−1 · dl and 0.0154 ± 0.0034 pM · min−2 · mg−1 · dl, respectively. H(t) showed an initial decrement for ∼30–50 min (from a fasting value of 63 ± 8% to a nadir of 53 ± 9%) after the glucose stimulus, then a steady value of ∼62% was reestablished and maintained throughout the experiment. The validity of the C-peptide model was further assessed by comparing its estimate of the fractional plasma clearance rate (k01) with that obtained in experiments in which biosynthetic human C-peptide was administered. The k01 averaged 0.063 ± 0.007 min−1, virtually identical to 0.060 ± 0.002 min−1 found in other studies. Because of its noninvasiveness, this modeling-based method should prove useful in the clinical investigation of many pathophysiological states

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