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Application of the integrated glucose-insulin model for cross-study characterization of T2DM patients on metformin background treatment
AstraZeneca, Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
AstraZeneca, Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.ORCID iD: 0000-0003-3531-9452
AstraZeneca, Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, S-43183 Molndal, Sweden.;Univ Gothenburg, Dept Endocrinol, Sahlgrenska Univ Hosp, Gothenburg, Sweden.;Univ Gothenburg, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden..
2016 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 82, no 6, 1613-1624 p.Article in journal (Refereed) Published
Abstract [en]

AimThe integrated glucose-insulin (IGI) model is a semi-mechanistic physiological model which can describe the glucose-insulin homeostasis system following various glucose challenge settings. The aim of the present work was to apply the model to a large and diverse population of metformin-only-treated type 2 diabetes mellitus (T2DM) patients and identify patient-specific covariates. MethodsData from four clinical studies were pooled, including glucose and insulin concentration-time profiles from T2DM patients on stable treatment with metformin alone following mixed-meal tolerance tests. The data were collected from a wide range of patients with respect to the duration of diabetes and level of glycaemic control. ResultsThe IGI model was expanded by four patient-specific covariates. The level of glycaemic control, represented by baseline glycosylated haemoglobin was identified as a significant covariate for steady-state glucose, insulin-dependent glucose clearance and the magnitude of the incretin effect, while baseline body mass index was a significant covariate for steady-state insulin levels. In addition, glucose dose was found to have an impact on glucose absorption rate. The developed model was used to simulate glucose and insulin profiles in different groups of T2DM patients, across a range of glycaemic control, and it was found accurately to characterize their response to the standard oral glucose challenge. ConclusionsThe IGI model was successfully applied to characterize differences between T2DM patients across a wide range of glycaemic control. The addition of patient-specific covariates in the IGI model might be valuable for the future development of antidiabetic treatment and for the design and simulation of clinical studies.

Place, publisher, year, edition, pages
2016. Vol. 82, no 6, 1613-1624 p.
Keyword [en]
glucose, glycaemic control, insulin, integrated glucose-insulin model, NONMEM, type 2 diabetes mellitus
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-310735DOI: 10.1111/bcp.13069ISI: 000387504500019PubMedID: 27450071OAI: oai:DiVA.org:uu-310735DiVA: diva2:1058203
Funder
AstraZeneca
Available from: 2016-12-20 Created: 2016-12-19 Last updated: 2016-12-20Bibliographically approved

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