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An Integrated Glucose-Insulin Model to Describe Oral Glucose Tolerance Test Data in Type 2 Diabetics

From the Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, University of Uppsala, Sweden (Ms Jauslin, Ms Silber, Dr Simonsson, Dr Karlsson); Clinical Pharmacology, Modeling and Simulation Group, F. Hoffmann-La Roche Inc, Basel, Switzerland (Ms Jauslin, Dr Frey, Dr Gieschke, Dr Jorga).

An integrated model for the glucose-insulin system describing oral glucose tolerance test data was developed, extending on a previously introduced model for intravenous glucose provocations. Model extensions comprised the description of glucose absorption by a chain of transit compartments with a mean transit time of 35 minutes, a bioavailability of 80%, and a representation of the incretin effect, expressed as a direct effect of the glucose absorption rate on insulin secretion. The ability of the model to predict the incretin effect was assessed by simulating the observed difference in insulin response following an oral glucose tolerance test compared with an isoglycemic glucose infusion mimicking an oral glucose tolerance test profile. The extension of the integrated glucose-insulin model to gain information from oral glucose tolerance test data considerably expands its range of applications because the oral glucose tolerance test is one of the most common glucose challenge experiments for assessing the efficacy of hypoglycemic agents in clinical drug development.

Key Words: NONMEM • glucose homeostasis • incretin effect • glucagon-like peptide-1

Address for correspondence: Petra M. Jauslin, MSc Pharm, F. Hoffmann-La Roche Inc, Clinical Pharmacology (M&S), PDMP, B 15/1.030, Grenzacherstr 124, CH-4070 Basel, Switzerland.

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