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Modeling of 24-Hour Glucose and Insulin Profiles of Patients With Type 2 Diabetes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
2011 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 51, no 2, 153-164 p.Article in journal (Refereed) Published
Abstract [en]

A model able to simultaneously characterize and simulate 24-hour glucose and insulin profiles following multiple meal tests was developed, extending an integrated glucose-insulin model for oral glucose tolerance tests that was previously published. The analysis was based on glucose and insulin measurements from 59 placebo-treated patients with type 2 diabetes. Circadian variations in glucose homeostasis were assessed on relevant parameters based on literature review. They were best described by a nighttime dip in insulin secretion between approximately 9 p.m. and 5 a.m. using a modulator function. The integrated glucose-insulin model has thus been shown to be applicable to real-life situations determined by multiple meals over the course of a day. This provides the basis for the analysis and simulation of long-term glucose and insulin data. The model may also prove useful for understanding antidiabetic drug actions and requirements in the context of circadian changes in glucose-insulin regulation.

Place, publisher, year, edition, pages
2011. Vol. 51, no 2, 153-164 p.
Keyword [en]
NONMEM, glucose homeostasis, type 2 diabetes, meal test, circadian rhythm
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97188DOI: 10.1177/0091270010362536ISI: 000286551600002PubMedID: 20220046OAI: oai:DiVA.org:uu-97188DiVA: diva2:172012
Available from: 2008-04-28 Created: 2008-04-28 Last updated: 2011-03-21Bibliographically approved
In thesis
1. 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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Karlsson, Mats

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