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Modelling the disease progression from healthy to overt diabetes in ZDSD rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Group)
Janssen Prevention Center, Janssen Pharmaceutical Companies of Johnson & Johnson, Leiden, The Netherlands.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Group)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics Research Group)
(English)In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416Article in journal (Other academic) Submitted
Abstract [en]

Introduction: Studying the critical transitional phase between healthy to overtly diabetic in type 2 diabetes mellitus (T2DM) is of interest, but acquiring such clinical data is impractical due to ethical concerns and the long study duration required. ZDSD rats are a strain of rats bred specifically to spontaneously develop T2DM, and a population model using ZDSD rats was developed to describe this transition through altering insulin sensitivity (IS) as a result of accumulating excess body weight and β-cell function (BCF) to affect glucose-insulin homeostasis.

Methods and Materials: Body weight, fasting plasma glucose (FPG), and fasting serum insulin (FSI) were collected over 24 weeks from ZDSD rats (n=23) at age 7 weeks. A semi-mechanistic model previously developed with clinical data was adapted to rat data with BCF and IS estimated relative to humans. Non-linear mixed-effect model estimation was performed using NONMEM 7.3 with first-order interaction.

Results and Discussion: Baseline IS and BCF were 41% compared to healthy humans. BCF was described with a non-linear rise which peaked at 14 weeks before gradually declining to a negligible level. A component for excess growth reflecting obesity was used to affect IS, and a FPG-dependent urine effect exerted a 2 to 6-fold increase on the elimination of FPG.

Conclusion:  A semi-mechanistic model to describe the dynamics of glucose and insulin was successfully developed for a rat population, transitioning from healthy to advanced diabetes. It is also shown that weight loss can be modeled to mimic the “starvation in the midst of plenty” phenomenon seen in advanced hyperglycemia.

Keyword [en]
diabetes, disease progression, population model, rats, glucose, insulin, weight, insulin, glucose, Beta-cell function
National Category
Endocrinology and Diabetes
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-272230OAI: oai:DiVA.org:uu-272230DiVA: diva2:893559
Available from: 2016-01-12 Created: 2016-01-12 Last updated: 2017-11-30
In thesis
1. Semi-mechanistic models of glucose homeostasis and disease progression in type 2 diabetes
Open this publication in new window or tab >>Semi-mechanistic models of glucose homeostasis and disease progression in type 2 diabetes
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by consistently high blood glucose, resulting from a combination of insulin resistance and reduced capacity of β-cells to secret insulin. While the exact causes of T2DM is yet unknown, obesity is known to be a major risk factor as well as co-morbidity for T2DM. As the global prevalence of obesity continues to increase, the association between obesity and T2DM warrants further study. Traditionally, mathematical models to study T2DM were mostly empirical and thus fail to capture the dynamic relationship between glucose and insulin. More recently, mechanism-based population models to describe glucose-insulin homeostasis with a physiological basis were proposed and offered a substantial improvement over existing empirical models in terms of predictive ability.

The primary objectives of this thesis are (i) examining the predictive usefulness of semi-mechanistic models in T2DM by applying an existing population model to clinical data, and (ii) exploring the relationship between obesity and T2DM and describe it mathematically in a novel semi-mechanistic model to explain changes to the glucose-insulin homeostasis and disease progression of T2DM.

Through the use of non-linear mixed effects modelling, the primary mechanism of action of an antidiabetic drug has been correctly identified using the integrated glucose-insulin model, reinforcing the predictive potential of semi-mechanistic models in T2DM. A novel semi-mechanistic model has been developed that incorporated a relationship between weight change and insulin sensitivity to describe glucose, insulin and glycated hemoglobin simultaneously in a clinical setting. This model was also successfully adapted in a pre-clinical setting and was able to describe the pathogenesis of T2DM in rats, transitioning from healthy to severely diabetic.

This work has shown that a previously unutilized biomarker was found to be significant in affecting glucose homeostasis and disease progression in T2DM, and that pharmacometric models accounting for the effects of obesity in T2DM would offer a more complete physiological understanding of the disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 210
Keyword
pharmacokinetics, pharmacodynamics, pharmacometrics, glucose homeostasis, insulin, type 2 diabetes, obesity, weight, visceral adipose tissue, HbA1c, non-linear mixed effects, modelling, disease progression, ZDSD rats
National Category
Endocrinology and Diabetes
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-273709 (URN)978-91-554-9456-8 (ISBN)
Public defence
2016-03-04, B41, Biomedicinskt Centrum (BMC), Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-02-05 Created: 2016-01-17 Last updated: 2016-02-12

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