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Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Novo Nordisk AS, Soborg, Denmark.
Univ Copenhagen, Ctr Diabet Res, Gentofte Hosp, Hellerup, Denmark.; Univ Copenhagen, NNF Ctr Basic Metab Res, Copenhagen, Denmark.; Univ Copenhagen, Dept Biomed Sci, Panum Inst, Copenhagen, Denmark..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Novo Nordisk AS, Soborg, Denmark.
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2017 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 121, no 4, p. 290-297Article in journal (Refereed) Published
Abstract [en]

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), play an important role in glucose homeostasis by potentiating glucose-induced insulin secretion. Furthermore, GLP-1 has been reported to play a role in glucose homeostasis by inhibiting glucagon secretion and delaying gastric emptying. As the insulinotropic effect of GLP-1 is preserved in patients with type 2 diabetes (T2D), therapies based on GLP-1 have been developed in recent years, and these have proven to be efficient in the treatment of T2D. The endogenous secretion of both GIP and GLP-1 is stimulated by glucose in the small intestine, and the release is dependent on the amount. In this work, we developed a semimechanistic model describing the release of GIP and GLP-1 after ingestion of various glucose doses in healthy volunteers and patients with T2D. In the model, the release of both hormones is stimulated by glucose in the proximal small intestine, and no differences in the secretion dynamics between healthy individuals and patients with T2D were identified after taking differences in glucose profiles into account.

Place, publisher, year, edition, pages
2017. Vol. 121, no 4, p. 290-297
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-279065DOI: 10.1111/bcpt.12792ISI: 000409507900013PubMedID: 28374974OAI: oai:DiVA.org:uu-279065DiVA, id: diva2:907490
Funder
EU, FP7, Seventh Framework Programme, 115156Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-02-26Bibliographically approved
In thesis
1. Pharmacometric Models of Glucose Homeostasis in Healthy Subjects and Diabetes Patients
Open this publication in new window or tab >>Pharmacometric Models of Glucose Homeostasis in Healthy Subjects and Diabetes Patients
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from defects in insulin secretion, insulin action, or both. Several models have been developed for describing the glucose-insulin system. Silber and Jauslin developed a semi-mechanistic integrated glucose insulin (IGI) model which simultaneously describe glucose and insulin profiles in either healthy subjects or type 2 diabetis mellitus (T2DM) patients. The model was developed for describing the basal system, i.e. when no drugs are present in the body. In this thesis the IGI model was extended to also include the effects of anti-diabetic drugs on glucose homeostasis. The model was extended to describe postprandial glucose and insulin excursions in T2DM patients treated with either biphasic insulin aspart or the GLP-1 receptor agonist liraglutide. These extensions make the model a useful tool in drug development as it can be used for elucidating the effects of new products as well as for clinical trial simulation. In this thesis several modelling tasks were also performed to get a more mechanistic description of the glucose-insulin system. A model was developed which describes the release of the incretin hormones glucosedependent insulinotropic polypeptide and glucagon-like peptide-1 following the ingestion of various glucose doses. The effects of these hormones on the beta cell function were incorporated in a model describing both the C-peptide and insulin concentrations in healthy subjects and T2DM patients during either an oral glucose tolerance test or an isoglycaemic intravenous glucose infusion. By including measurements of both C-peptide and insulin concentrations in the model it could also be used to characterize the hepatic extraction of insulin.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 77
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 212
Keywords
Glucose homeostasis, Type 2 diabetes, IGI model, Mechanismbased, NONMEM, pharmacometrics
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-274239 (URN)978-91-554-9499-5 (ISBN)
Public defence
2016-04-25, Room B42 in A4, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-04-04 Created: 2016-01-20 Last updated: 2018-01-10
2. Mechanism-Based Modelling of Clinical and Preclinical Studies of Glucose Homeostasis
Open this publication in new window or tab >>Mechanism-Based Modelling of Clinical and Preclinical Studies of Glucose Homeostasis
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glucose is an important nutrient and energy source in the body. However, too high concentration in the blood is harmful and may lead to several complications developing over time. It was estimated that 5 million people in the world died from complications related to diabetes during 2015. Several hormones and physiological factors are involved in the regulation of glucose homeostasis. To evaluate different aspects of glucose homeostasis and the effect of interventions, such as pharmacological treatment, glucose tolerance tests can be performed. In a glucose tolerance test glucose is administered either orally or intravenously, blood is sampled frequently and analyzed for different biomarkers. Mechanism-based pharmacometric models is a valuable tool in drug development, which can be applied to increase the knowledge about complex systems such as glucose homeostasis, quantify the effects of drugs, generate more information from clinical trials and contribute to more efficient study design. In this thesis, a new comprehensive mechanism-based pharmacometric model was developed. The model is capable of describing the most important aspects of glucose homeostasis during glucose tolerance test in healthy individuals and patients with type 2 diabetes, over a wide range of oral and intravenous glucose doses. Moreover, it can simultaneously describe regulation of gastric emptying and glucose absorption, regulation of the incretin hormones GLP-1 and GIP, hepatic extraction of insulin and the incretin effect, regulation of glucagon synthesis and regulation of endogenous glucose production. In addition, an interspecies scaling approach was developed by scaling a previously developed clinical glucose insulin model to describe intravenous glucose tolerance tests performed in mice, rats, dogs, pigs and monkeys. In conclusion, the developed mechanism-based models in this thesis increases the knowledge about short term regulation of glucose homeostasis and can be used to investigate combination treatments, drugs with multiple effects, and translation of drug effects between species, leading to improved drug development of new antidiabetic compounds.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 248
Keywords
glucose homeostasis, pharmacometrics
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-343116 (URN)978-91-513-0247-8 (ISBN)
Public defence
2018-04-13, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-03-22 Created: 2018-02-26 Last updated: 2018-04-24

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Røge, Rikke MeldgaardAlskär, OskarKarlsson, Mats O

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