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Semi-mechanistic mo...
Semi-mechanistic models of glucose homeostasis and disease progression in type 2 diabetes
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- Choy, Steve, 1987- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Pharmacometrics Group
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- Kjellsson, Maria, Docent (thesis advisor)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- Karlsson, Mats, Professor (thesis advisor)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap
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- de Winter, Willem, Dr (thesis advisor)
- Janssen Prevention Center, Janssen Research & Development, Leiden, The Netherlands
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- Mari, Andrea, Dr (opponent)
- Neuroscience Institute, CNR (National Research Council), Padova, Italy
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(creator_code:org_t)
- ISBN 9789155494568
- Uppsala : Acta Universitatis Upsaliensis, 2016
- English 78 s.
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Series: Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 210
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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
- Farmaceutisk vetenskap
- Pharmaceutical Science
Publication and Content Type
- vet (subject category)
- dok (subject category)
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