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An integrated glucose-insulin model to describe oral glucose tolerance test data in type 2 diabetics
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
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2007 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 47, no 10, 1244-1255 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2007. Vol. 47, no 10, 1244-1255 p.
Keyword [en]
NONMEM, glucose homeostasis, incretin effect, glucagon-like peptide-1
National Category
Pharmaceutical Sciences Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-13502DOI: 10.1177/0091270007302168ISI: 000249872700003PubMedID: 17906159OAI: oai:DiVA.org:uu-13502DiVA: diva2:41272
Available from: 2008-01-23 Created: 2008-01-23 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Integrated Modeling of Glucose and Insulin Regulation Following Provocation Experiments
Open this publication in new window or tab >>Integrated Modeling of Glucose and Insulin Regulation Following Provocation Experiments
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Blood glucose is controlled by a complex system of insulin and other hormones to assure a constant supply of glucose to the tissues. Type 2 diabetes is a metabolic disorder which is characterized by progressively worsening glycemic control due to a relative deficiency of insulin secretion and a decreased response to insulin. Numerous mathematical models have been developed with the aim of describing glucose and insulin regulation. A drawback with most previously presented models is that they use an open-loop approach which simplifies the model development but at the same time limits the possible use for predictive purposes.

The integrated glucose-insulin model presented in this thesis is a semi-mechanistic model which describes glucose and insulin simultaneously. The model has been used to analyze both intravenous and oral provocations and has been shown to describe and predict healthy and diabetic individuals well. Important differences between healthy and diabetic individuals were identified in insulin secretion and sensitivity. The model was used for design optimization of the intravenous glucose tolerance test and it was shown that the design could be improved and simplified by reduction of the number of samples and by change of glucose and insulin dose. Two methodological aspects which were of importance for model development were evaluated. These were (i) comparison of methods for incorporation of baseline data, and (ii) evaluation of the effects of model misspecification on hypothesis testing for covariate inclusion. Baseline information should be included in the model using either of three presented methods and normalization or subtraction of baseline should be avoided. The likelihood ratio test performed well in most cases except when serial correlation was present.

In conclusion, a new model for glucose and insulin regulation has been proposed which is expected to play an important role in clinical development of anti-diabetic drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 92
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-99195 (URN)978-91-554-7463-8 (ISBN)
Public defence
2009-04-24, B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2009-04-03 Created: 2009-03-10 Last updated: 2011-05-11Bibliographically approved
2. Mechanism-Based Modeling of the Glucose-Insulin Regulation during Clinical Provocation Experiments
Open this publication in new window or tab >>Mechanism-Based Modeling of the Glucose-Insulin Regulation during Clinical Provocation Experiments
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 2 diabetes is a complex chronic metabolic disorder characterized by hyperglycemia associated with a relative deficiency of insulin secretion and a reduced response of target tissues to insulin. Considerable efforts have been put into the development of models describing the glucose-insulin system. The best known is Bergman’s “minimal” model for glucose, which is estimating glucose concentrations using fixed insulin concentrations as input. However, due to the involved feedback mechanisms, simultaneous modeling of both entities would be advantageous. This is particularly relevant if the model is intended to be used as a predictive tool. The mechanism-based glucose-insulin model presented in this thesis is able to simultaneously describe glucose and insulin profiles following a wide variety of clinical provocation experiments, such as intravenous and oral glucose tolerance tests, clamp studies and sequential meal tests over 24 hours. It consists of sub-models for glucose, labeled glucose and insulin kinetics. It also incorporates control mechanisms for the regulation of glucose production, insulin secretion, and glucose uptake. Simultaneous analysis of all data by nonlinear mixed effect modeling was performed in NONMEM.

Even if this model is a crude representation of a complex physiological system, its ability to represent the main processes of this system was established by identifying: 1) the difference in insulin secretion and insulin sensitivity between healthy volunteers and type 2 diabetics, 2) the action of incretin hormones after oral administration of glucose, 3) the circadian variation of insulin secretion and 4) the correct mechanism of action of a glucokinase activator, a new oral antidiabetic compound acting on both the pancreas and the liver.

These promising results represent a proof of concept of a mechanistic drug-disease model that could play an important role in the clinical development of anti-diabetic drugs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 73
Keyword
Pharmacokinetics/Pharmacotherapy, Glucose homeostasis, Type 2 diabetes, IVGTT, OGTT, Meal test, Circadian variation, Mechanism-based, NONMEM, Farmakokinetik/Farmakoterapi
Identifiers
urn:nbn:se:uu:diva-8719 (URN)978-91-554-7195-8 (ISBN)
Public defence
2008-05-23, B21, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2008-04-28 Created: 2008-04-28 Last updated: 2011-03-21Bibliographically approved

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Silber, Hanna ESimonsson, Ulrika S HKarlsson, Mats O

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