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The Effects of a GLP-1 Analog on Glucose Homeostasis in Type 2 Diabetes Mellitus Quantified by an Integrated Glucose Insulin Model
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Ph)ORCID iD: 0000-0003-3531-9452
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2015 (English)In: CPT: Pharmacometrics & Systems Pharmacology, ISSN 2163-8306, Vol. 4, no 1, 1-9 p.Article in journal (Refereed) Published
Abstract [en]

In recent years, several glucagon-like peptide-1 (GLP-1)-based therapies for the treatment of type 2 diabetes mellitus (T2DM) have been developed. The aim of this work was to extend the semimechanistic integrated glucose-insulin model to include the effects of a GLP-1 analog on glucose homeostasis in T2DM patients. Data from two trials comparing the effect of steady-state liraglutide vs. placebo on the responses of postprandial glucose and insulin in T2DM patients were used for model development. The effect of liraglutide was incorporated in the model by including a stimulatory effect on insulin secretion. Furthermore, for one of the trials an inhibitory effect on glucose absorption was included to account for a delay in gastric emptying. As other GLP-1 receptor agonists have similar modes of action, it is believed that the model can also be used to describe the effect of other receptor agonists on glucose homeostasis.

Place, publisher, year, edition, pages
2015. Vol. 4, no 1, 1-9 p.
National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
URN: urn:nbn:se:uu:diva-244286DOI: 10.1002/psp4.11OAI: oai:DiVA.org:uu-244286DiVA: diva2:788377
Available from: 2015-02-13 Created: 2015-02-13 Last updated: 2016-04-12Bibliographically approved
In thesis
1. Pharmacometric Models of Glucose Homeostasis in Healthy Subjects and Diabetes Patients
Open this publication in new window or tab >>Pharmacometric Models of Glucose Homeostasis in Healthy Subjects and Diabetes Patients
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. Several models have been developed for describing the glucose-insulin system. Silber and Jauslin developed a semi-mechanistic integrated glucose insulin (IGI) model which simultaneously describe glucose and insulin profiles in either healthy subjects or type 2 diabetis mellitus (T2DM) patients. The model was developed for describing the basal system, i.e. when no drugs are present in the body. In this thesis the IGI model was extended to also include the effects of anti-diabetic drugs on glucose homeostasis. The model was extended to describe postprandial glucose and insulin excursions in T2DM patients treated with either biphasic insulin aspart or the GLP-1 receptor agonist liraglutide. These extensions make the model a useful tool in drug development as it can be used for elucidating the effects of new products as well as for clinical trial simulation. In this thesis several modelling tasks were also performed to get a more mechanistic description of the glucose-insulin system. A model was developed which describes the release of the incretin hormones glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 following the ingestion of various glucose doses. The effects of these hormones on the beta cell function were incorporated in a model describing both the C-peptide and insulin concentrations in healthy subjects and T2DM patients during either an oral glucose tolerance test or an isoglycaemic intravenous glucose infusion. By including measurements of both C-peptide and insulin concentrations in the model it could also be used to characterize the hepatic extraction of insulin.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 77 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 212
Glucose homeostasis, Type 2 diabetes, IGI model, Mechanismbased, NONMEM, pharmacometrics
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-274239 (URN)978-91-554-9499-5 (ISBN)
Public defence
2016-04-25, Room B42 in A4, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2016-04-04 Created: 2016-01-20 Last updated: 2016-04-12

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Røge, Rikke MKjellsson, Maria C
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