Objective: The ingestion of glucose is an extensively studies process. However, few publications describe this process using a population approach and none have investigated this process over a wider 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 testing (OGTT) with several glucose loads (25, 75, 125 g) was used in a population analysis. A previously published study [1] was conducted in eight patients with type 2 diabetes mellitus and eight gender, age and body mass index (BMI)-matched healthy control subjects. In addition to glucose, the subjects ingested 1.5 g of acetaminophen dissolved in the glucose solution to monitor the rate of gastric emptying. The glucose homeostasis was accounted for by use of the IGI model with observed insulin to drive glucose elimination; all parameters unrelated to absorption were fixed to reported values [2]. Linear and saturable absorption over the intestinal membrane was investigated as well as several 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 acetaminophen data. Acetaminophen data and glucose was modeled sequentially. Model development was guided by goodness of fit and objective function value. All modeling was performed using NONMEM 7.2.
Results and Conclusions: Of the investigated models it was clear that saturable absorption model 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 [3] and Kellet et al [4] who measured the rate of glucose absorption over a range of glucose concentrations in perfused intestine. These results will further improve the performance of the IGI model and facilitate investigations of drug effects on glucose absorption and incretin hormones.
References:
1. 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.
2. 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.
3. 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.
4. 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.