Model-based Analysis of the GLP-1 Response Following an Oral Glucose Tolerance Test (OGTT)
Jonas Bech Møller
QCP, Novo Nordisk A/S
Objectives: GLP-1 is an insulinotropic hormone giving rise to an increased insulin response in synergy with glucose [1]. In order to investigate how the secretion of this hormone is affected by demographic factors and by the progression of diabetes, a mechanistic model was built for characterising the secretion of GLP-1 following an oral glucose tolerance test (OGTT). Indices based on such a model can in subsequent studies provide further pathophysiological insight compared to a standard non-compartmental approach (NCA).
Methods: Single 75 g dose of glucose was administered orally to subjects ranging from healthy volunteers to patients with type 2 diabetes. Glucose, insulin, and total GLP-1 concentrations were measured sequentially [2]. Prior population data analysis of glucose and insulin were performed in order to estimate the glucose absorption rate. The values of absorption rates were used in the model for GLP-1 secretion. Estimation of parameters was performed using the FOCE method with interaction implemented in NONMEM VI.
Results: The final indirect-response model for GLP-1 production following an OGTT included two components on the stimulation of the zero-order production rate of GLP-1[3]. One component related to the ingestion of glucose (fast), and a component related to the absorption rate of the glucose (slow). The identification of the fast component (with a peak prior to the glucose absorption peak) could indicate the presence of a proximal-distal loop for fast secretion from L-cells. This component was estimated to peak around 25 min. after glucose ingestion, whereas the slower component peaked around 100 min after ingestion. Elimination of total GLP-1 was characterised by first-order elimination. The individual parameter values of the early phase GLP-1 secretion were correlated (r~0.64) with the AUC (0-60 min.) for GLP-1.
Conclusions: A mechanistic population model was successfully developed to describe total GLP-1 concentrations over time observed in an OGTT. The model indicates two different mechanisms for stimulating GLP-1 secretion and may serve as a tool for studying the influence of factors (demographics etc.), on these components.
References:
[1] Holst JJ 2007. The Physiology of Glucagon-like Peptide 1. Physiol Rev 87(4):1409-1439.
[2] Hansen T, Drivsholm T, Urhammer SA, Palacios RT, Vølund A, Borch-Johnsen K, Pedersen O 2007. The BIGTT Test. Diabetes Care 30(2):257-262.
[3] Jonas B. Møller, William J. Jusko, Wei Gao, Torben Hansen, Oluf Pedersen, Jens J. Holst, Rune V. Overgaard, Henrik Madsen, Steen H. Ingwersen. Mechanism-based population modelling for assessment of L-cell function based on total GLP-1 response following an oral glucose tolerance test. Submitted to J.PK.PD
