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Weight-HbA1c-Insulin-Glucose Model for Describing Disease Progression of Type 2 Diabetes
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 Group)
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.
2016 (English)In: CPT: Pharmacometrics & Systems Pharmacology, ISSN 2163-8306, Vol. 5, no 1, 11-19 p.Article in journal (Refereed) Published
Abstract [en]

A previous semi-mechanistic model described changes in fasting serum insulin (FSI), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) in patients with type 2 diabetic mellitus (T2DM) by modeling insulin sensitivity and β-cell function. It was later suggested that change in body weight could affect insulin sensitivity, which this study evaluated in a population model to describe the disease progression of T2DM. Nonlinear mixed effects modeling was performed on data from 181 obese patients with newly diagnosed T2DM managed with diet and exercise for 67 weeks. Baseline β-cell function and insulin sensitivity were 61% and 25% of normal, respectively. Management with diet and exercise (mean change in body weight = -4.1 kg) was associated with an increase of insulin sensitivity (30.1%) at the end of the study. Changes in insulin sensitivity were associated with a decrease of FPG (range, 7.8–7.3 mmol/L) and HbA1c (6.7–6.4%). Weight change as an effector on insulin sensitivity was successfully evaluated in a semi-mechanistic population model.

Place, publisher, year, edition, pages
2016. Vol. 5, no 1, 11-19 p.
Keyword [en]
diabetes, disease progression, semi-mechanistic, population model, weight, glucose, insulin
National Category
Endocrinology and Diabetes
Research subject
Pharmaceutical Science
Identifiers
URN: urn:nbn:se:uu:diva-272228DOI: 10.1002/psp4.12051ISI: 000381560300002PubMedID: 26844011OAI: oai:DiVA.org:uu-272228DiVA: diva2:893556
Available from: 2016-01-12 Created: 2016-01-12 Last updated: 2016-10-06Bibliographically approved
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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Choy, SteveKjellsson, MariaKarlsson, Mats

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