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Model-based quantification of the natural diabetes disease progression and lifestyle intervention effects on weight, beta cell function and insulin sensitivity for subjects with impaired glucose tolerance
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. School of Pharmaceutical Sciences, Universiti Sains Malaysia, Malaysia. (Pharmacometrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Pharmacometrics)
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio Campus, Kuopio, Finland.
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
Model-based, impaired glucose tolerance, diabetes disease progression model, lifestyle intervention, insulin sensitivity, beta cell function, postprandial glucose, weight, fasting plasma glucose, fasting serum insulin, HbA1c
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-316834OAI: oai:DiVA.org:uu-316834DiVA: diva2:1080146
Available from: 2017-03-09 Created: 2017-03-09 Last updated: 2017-03-10
In thesis
1. Pharmacometrics Modelling in Type 2 Diabetes Mellitus: Implications on Study Design and Diabetes Disease Progression
Open this publication in new window or tab >>Pharmacometrics Modelling in Type 2 Diabetes Mellitus: Implications on Study Design and Diabetes Disease Progression
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacometric modelling is widely used in many aspects related to type 2 diabetes mellitus (T2DM), for instance in the anti-diabetes drug development, and in quantifying the disease progression of T2DM.

The aim of this thesis were to improve the design of early phase anti-diabetes drug development studies with the focus on the power to identify mechanism of drug action (MoA), and to characterize and quantify the progression from prediabetes to overt diabetes, both the natural progression and the progression with diet and exercise interventions, using pharmacometrics modelling.

The appropriateness of a study design depends on the MoAs of the anti-hyperglycaemic drug. Depending on if the focus is power to identify drug effect or accuracy and precision of drug effect, the best design will be different. Using insulin measurements on top of glucose has increase the power to identify a correct drug effect, distinguish a correct MoA from the incorrect, and to identify a secondary MoA in most cases. The accuracy and precision of drug parameter estimates, however, was not affected by insulin. A natural diabetes disease progression model was successfully added in a previously developed model to describe parameter changes of glucose and insulin regulation among impaired glucose tolerance (IGT) subjects, with the quantification of the lifestyle intervention. In this model, the assessment of multiple short-term provocations was combined to predict the long-term disease progression, and offers apart from the assessment of the onset of T2DM also the framework for how to perform similar analysis. Another previously published model was further developed to characterize the weight change in driving the changes in glucose homeostasis in subjects with IGT. This model includes the complex relationship between dropout from study and weight and glucose changes.

This thesis has provided a first written guidance in designing a study for pharmacometrics analysis when characterizing drug effects, for early phase anti-diabetes drug development. The characterisation of the progression from prediabetes to overt diabetes using pharmacometrics modelling was successfully performed. Both the natural progression and the progression with diet and exercise interventions were quantified in this thesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 93 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 226
Keyword
Pharmacometric, type 2 diabetes mellitus, impaired glucose tolerance, prediabetes, anti-diabetes drug development, insulin, glucose, natural diabetes disease progression, lifestyle intervention, short-term provocation, long-term effect, glucose homeostasis, glucose and insulin regulation, weight, dropout
National Category
Pharmaceutical Sciences Endocrinology and Diabetes
Research subject
Pharmaceutical Science; Endocrinology and Diabetology
Identifiers
urn:nbn:se:uu:diva-317040 (URN)978-91-554-9844-3 (ISBN)
Public defence
2017-04-28, B42, Biomedical Center, Uppsala University, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2017-04-05 Created: 2017-03-10 Last updated: 2017-04-18

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