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Modeling of 24-Hour Glucose and Insulin Profiles in Patients With Type 2 Diabetes Mellitus Treated With Biphasic Insulin Aspart
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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2014 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 54, no 7, 809-817 p.Article in journal (Refereed) Published
Abstract [en]

Insulin therapy for diabetes patients is designed to mimic the endogenous insulin response of healthy subjects and thereby generate normal blood glucose levels. In order to control the blood glucose in insulin-treated diabetes patients, it is important to be able to predict the effect of exogenous insulin on blood glucose. A pharmacokinetic/pharmacodynamic model for glucose homoeostasis describing the effect of exogenous insulin would facilitate such prediction. Thus the aim of this work was to extend the previously developed integrated glucose-insulin (IGI) model to predict 24-hour glucose profiles for patients with Type 2 diabetes following exogenous insulin administration. Clinical data from two trials were included in the analysis. In both trials, 24-hour meal tolerance tests were used as the experimental setup, where exogenous insulin (biphasic insulin aspart) was administered in relation to meals. The IGI model was successfully extended to include the effect of exogenous insulin. Circadian variations in glucose homeostasis were assessed on relevant parameters, and a significant improvement was achieved by including a circadian rhythm on the endogenous glucose production in the model. The extended model is a useful tool for clinical trial simulation and for elucidating the effect profile of new insulin products.

Place, publisher, year, edition, pages
2014. Vol. 54, no 7, 809-817 p.
National Category
Endocrinology and Diabetes
URN: urn:nbn:se:uu:diva-219250DOI: 10.1002/jcph.270ISI: 000337627100010PubMedID: 24446385OAI: oai:DiVA.org:uu-219250DiVA: diva2:698753
Available from: 2014-02-25 Created: 2014-02-25 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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Kjellsson, Maria C
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