Semi-mechanistic models of glucose homeostasis and disease progression in type 2 diabetes

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Choy, Steve,1987-Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Pharmacometrics Group (författare)

Semi-mechanistic models of glucose homeostasis and disease progression in type 2 diabetes

BokEngelska2016

Förlag, utgivningsår, omfång ...

Uppsala :Acta Universitatis Upsaliensis,2016
78 s.
electronicrdacarrier

Nummerbeteckningar

LIBRIS-ID:oai:DiVA.org:uu-273709
ISBN:9789155494568
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-273709URI

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Språk:engelska
Sammanfattning på:engelska

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Ämneskategori:vet swepub-contenttype
Ämneskategori:dok swepub-publicationtype

Serie

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy,1651-6192 ;210

Anmärkningar

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.

Ämnesord och genrebeteckningar

MEDICIN OCH HÄLSOVETENSKAP Klinisk medicin Endokrinologi och diabetes hsv//swe
MEDICAL AND HEALTH SCIENCES Clinical Medicine Endocrinology and Diabetes hsv//eng
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

Biuppslag (personer, institutioner, konferenser, titlar ...)

Kjellsson, Maria,DocentUppsala universitet,Institutionen för farmaceutisk biovetenskap (preses)
Karlsson, Mats,ProfessorUppsala universitet,Institutionen för farmaceutisk biovetenskap (preses)
de Winter, Willem,DrJanssen Prevention Center, Janssen Research & Development, Leiden, The Netherlands (preses)
Mari, Andrea,DrNeuroscience Institute, CNR (National Research Council), Padova, Italy (opponent)
Uppsala universitetInstitutionen för farmaceutisk biovetenskap (creator_code:org_t)

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Av författaren/redakt...: Choy, Steve, 198 ...; Kjellsson, Maria ...; Karlsson, Mats, ...; de Winter, Wille ...; Mari, Andrea, Dr

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