Modelling of glucose absorption
Oskar Alskär (1), Jonatan I. Bagger (2), Marie Berglund (1) Mats O. Karlsson (1), Filip K. Knop (2), Tina Vilsbøll (2), Maria C. Kjellsson (1)
(1) Pharmacometrics research group, Department of Pharmaceutical biosciences, Uppsala University, Sweden and (2) Diabetes Research Division, Department of Internal Medicine F, Gentofte Hospital, University of Copenhagen, Denmark
Objectives: The ingestion of glucose is an extensively studied process. However, few publications describe this process using a population approach and none have investigated this process over a wide range of glucose doses including knowledge of physiology. Therefore, the objective of this work was to develop a semi-mechanistic population model describing intestinal absorption of different glucose doses to be used in conjugation with the integrated glucose insulin (IGI) model and compare that to the performance of more empirical models.
Methods: Data of plasma glucose and plasma insulin from three 4-h oral glucose tolerance test (OGTT) with different glucose loads (25, 75 and 125 g) was used in this population analysis. The previously published study  was conducted in eight patients with type 2 diabetes mellitus and eight gender, age and body mass index-matched healthy control subjects. In addition to glucose the subjects ingested 1.5 g of paracetamol dissolved in the glucose solution to monitor the rate of gastric emptying. The glucose homeostasis was accounted for by using the IGI model using observed insulin to drive glucose elimination; all parameters unrelated to absorption were kept fixed to the reported values . Linear and saturable absorption through the intestinal membrane was investigated as well as different models for absorption delay such as lag time, transit compartment and semi-mechanistic models which accounts for gastric emptying. The rate of gastric emptying in the subjects was described by a flexible input model using the paracetamol data. Paracetamol data and glucose was modelled sequentially. Model development was guided by goodness of fit and objective function value. All modelling was performed using NONMEM 7.2.
Results: Saturable absorption was superior to linear absorption regardless of the absorption model applied. The semi-mechanistic models were sensitive to the assumed small intestinal transit time and the benefit of the semi-mechanistic models was cancelled out by the increased run-times. The finding that glucose absorption is saturable at high concentrations is consistent with Pappenheimer et al and Kellet et al whom measured the rate of glucose absorption over a range of glucose concentrations in perfused intestine [3, 4].
Conclusions: These results will further improve the performance of the IGI model and allow for investigations of drug effects on glucose absorption.
Acknowledgement: This work was supported by the DDMoRe (www.ddmore.eu) project.
 Bagger, J. I., F. K. Knop, et al. Impaired regulation of the incretin effect in patients with type 2 diabetes. Journal of Clinical Endocrinology & Metabolism, 2011; 96(3): 737-745.
 Silber HE, Jauslin PM, Frey N, et al. An integrated model for glucose and insulin regulation in healthy volunteers and type 2 diabetic patients following intravenous glucose provocation. J Clin Pharmacol, 2007; 47: 1159-1171.
 Pappenheimer, J. and K. Reiss. Contribution of solvent drag through intercellular junctions to absorption of nutrients by the small intestine of the rat. Journal of Membrane Biology, 1987; 100(1): 123-136.
Kellett, G. L. and P. A. Helliwell. The diffusive component of intestinal glucose absorption is mediated by the glucose-induced recruitment of GLUT2 to the brush-border membrane. Biochemical Journal, 2000; 350(Pt 1): 155.