title: Mechanism-based population modelling for assessment of L-cell function based on total GLP-1 response following an oral glucose tolerance test.
abstract: GLP-1 is an insulinotropic hormone that synergistically with glucose gives rise to an increased insulin response. Its secretion is increased following a meal and it is thus of interest to describe the secretion of this hormone following an oral glucose tolerance test (OGTT). The aim of this study was to build a mechanism-based population model that describes the time course of total GLP-1 and provides indices for capability of secretion in each subject. The goal was thus to model the secretion of GLP-1, and not its effect on insulin production. Single 75 g doses of glucose were administered orally to a mixed group of subjects ranging from healthy volunteers to patients with type 2 diabetes (T2D). Glucose, insulin, and total GLP-1 concentrations were measured. Prior population data analysis on measurements of glucose and insulin were performed in order to estimate the glucose absorption rate. The individual estimates of absorption rate constants were used in the model for GLP-1 secretion. Estimation of parameters was performed using the FOCE method with interaction implemented in NONMEM VI. The final transit/indirect-response model obtained for GLP-1 production following an OGTT included two stimulation components (fast, slow) for the zero-order production rate. The fast stimulation was estimated to be faster than the glucose absorption rate, supporting the presence of a proximal-distal loop for fast secretion from L: -cells. The fast component (st₃) = 8.64·10⁻⁵ [mg⁻¹]) was estimated to peak around 25 min after glucose ingestion, whereas the slower component (st₄ = 26.2·10⁻⁵ [mg⁻¹]) was estimated to peak around 100 min. Elimination of total GLP-1 was characterised by a first-order loss. The individual values of the early phase GLP-1 secretion parameter (st₃) were correlated (r = 0.52) with the AUC(0-60 min.) for GLP-1. A mechanistic population model was successfully developed to describe total GLP-1 concentrations over time observed after an OGTT. The model provides indices related to different mechanisms of subject abilities to secrete GLP-1. The model provides a good basis to study influence of different demographic factors on these components, presented mainly by indices of the fast- and slow phases of GLP-1 response.
authors.affiliation: Quantitative Clinical Pharmacology, Novo Nordisk A/S, Søborg, Denmark. jbem@novonordisk.com
authors.forename: Jonas B
authors.initials: JB
authors.lastname: Møller
authors.forename: William J
authors.initials: WJ
authors.lastname: Jusko
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Jens J
authors.initials: JJ
authors.lastname: Holst
authors.forename: Rune V
authors.initials: RV
authors.lastname: Overgaard
authors.forename: Henrik
authors.initials: H
authors.lastname: Madsen
authors.forename: Steen H
authors.initials: SH
authors.lastname: Ingwersen
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D019858:Enteroendocrine Cells / Q000378:metabolism*; D005215:Fasting; D052216:Glucagon-Like Peptide 1 / Q000097:blood / Q000378:metabolism*; D005951:Glucose Tolerance Test / Q000706:statistics & numerical data*; D006801:Humans; D007328:Insulin / Q000097:blood; D008875:Middle Aged; D015233:Models, Statistical
chemical_list: D001786:Blood Glucose; D007328:Insulin; D052216:Glucagon-Like Peptide 1