Introduction and Objective: Prohormone convertase enzymes within α-cells process proglucagon into several peptides. These include glicentin (GLY), major proglucagon fragment (MPGF), and oxyntomodulin (OXM). Assessing their in vivo secretion (SR) can provide insights on α-cell function in health and disease. However, estimating their SR from peripheral concentrations requires knowledge of their kinetics. Here we propose a method that enables quantification of proglucagon fragment kinetics.Methods: Plasma glucagon (GLN), GLY, MPGF and OXM were frequently measured over 1 hour during a somatostatin infusion (60 ng/kg/min 0 – 60 min), which inhibited endogenous hormone SR, while exogenous GLN (1.5 ng/kg/min 0 – 60 min) was infused to control circulating GLN levels. A single compartment model, characterized by the half-life (t1/2), was used to describe the decay of GLY, MPGF and OXM. The knowledge that MPGF and GLN are secreted in an equimolar fashion enabled the calculation of the MPGF volume of distribution (Vd).Results: The model fitted the data well (Fig 1). Proglucagon fragment kinetic parameters were (mean ± SE): t1/2(MPGF) = 44 ± 3 min, Vd(MPGF) = 15 ± 3 L, t1/2(GLY) = 29 ± 4 min, t1/2(OXM) = 76 ± 17 min.Conclusion: We describe a method to estimate GLY, MPGF and OXM kinetic parameters. This will enable calculation of fragment SR, possibly enabling the early detection of α-cell dysfunction.
F. Boscolo: None. H.E. Christie: None. S. Mohan: None. A. Egan: None. A. Vella: Advisory Panel; Ended; Boehringer Ingelheim International GmbH. Advisory Panel; Current; Rezolute. Research Support; Current; Dexcom, Inc. Advisory Panel; Current; Neurotronic, Amylx. C. Dalla Man: Other – Webinar provider; Ended; Sanofi. Other – Joint research project; Current; Sanofi-Aventis Deutschland GmbH.
DK 116231 DK 78646
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