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The Integrated Glucose Insulin Minimal Model: An improved version
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0002-2084-1531
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0003-1258-8297
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0003-3531-9452
2019 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 134, p. 7-19Article in journal (Refereed) Published
Abstract [en]

This paper describes the improved integrated minimal model for healthy subjects and patients with type 2 diabetes and the work leading up to this model. The original integrated minimal model characterizes simultaneously glucose and insulin following intravenous glucose tolerance test (IVGTT) in healthy subjects and provides apart from estimates of indices for insulin sensitivity (S-i) and glucose effectiveness (S-G), also full simulation capabilities. However, this model was developed using IVGTT data of total glucose and consequently, the model cannot separate hepatic glucose production from glucose disposal. By fitting the original integrated minimal model to IVGTT data of labelled and total glucose, we show that all parameter estimates of the glucose sub-model were significantly different between the fits, in particular, S-G, which was similar to 3 fold higher with total, compared to labelled glucose. In addition, the time profiles of hepatic glucose production, obtained from the model, were unphysiological in most subjects. To correct these flaws, we developed the improved integrated minimal model based on the non-integrated, two-compartment minimal model. The improved integrated minimal model showed physiologically plausible dynamic time profiles of hepatic glucose production and all parameter estimates were compatible with those reported in original publication of the non-integrated minimal model. The integrated minimal model offers the benefits of the original integrated minimal model with simulation capabilities, in presence of endogenous insulin, combined with the benefits of the non-integrated minimal model, which accurately estimates the clinical indices of insulin sensitivity and glucose effectiveness. In addition, the improved integrated minimal model describes, apart from healthy subjects, also patients with type 2 diabetes.

Place, publisher, year, edition, pages
2019. Vol. 134, p. 7-19
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-367052DOI: 10.1016/j.ejps.2019.04.010ISI: 000468081200002PubMedID: 30978382OAI: oai:DiVA.org:uu-367052DiVA, id: diva2:1266294
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2019-06-14Bibliographically approved
In thesis
1. Pharmacometric evaluation and improvement of models and study designs - applied in diabetes
Open this publication in new window or tab >>Pharmacometric evaluation and improvement of models and study designs - applied in diabetes
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pharmacometric models are increasingly used to improve the efficiency of the drug development process and increase our understanding of the studied underlying pathophysiological system. These models require assumptions for handling different types of data and the different model components, and the appropriateness of such assumptions must be carefully inspected for unbiased conclusions. The aim of this thesis was to develop new models, that by acknowledging the complexity of the data captures more information, and novel methodologies for model evaluation, as well as applying models to improve study designs, with practical illustrations in the therapeutic area of diabetes. Two new models were developed. An integrated minimal model was developed to enable clinical trial simulations in presence of endogenous insulin secretion while deriving the important physiological indices for clinical diagnosis. A multi-state model was developed for improved handling of survival data in presence of competing risks and interval-censored data. New methodologies for model evaluations were developed that include residual modeling and linearization for assessing possible improvements of the structural and statistical model components as well as using simulations to assess the captured information from the data between structurally different models. A mapping approach for parameters carrying similar information between different models was developed, allowing the derivation of physiological indices from the integrated glucose insulin model. Models were also successfully applied with the purpose of improving study designs, either based on anticipated drug effect or for assessment of physiological indices. In conclusion, new more informative models were developed by acknowledging the complexity of the data, novel methods were proposed and applied for model development/evaluation process, and models were used to improve study designs for clinical trials and clinical diagnosis. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 75
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 264
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-366715 (URN)978-91-513-0518-9 (ISBN)
Public defence
2019-01-18, B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2018-12-17 Created: 2018-11-27 Last updated: 2019-01-21

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Ibrahim, Moustafa M. A.Karlsson, MatsKjellsson, Maria C.

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