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Mechanism-Based Modelling of Clinical and Preclinical Studies of Glucose Homeostasis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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 [en]
glucose homeostasis, pharmacometrics
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
URN: urn:nbn:se:uu:diva-343116ISBN: 978-91-513-0247-8 (print)OAI: oai:DiVA.org:uu-343116DiVA, id: diva2:1185518
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
List of papers
1. Model-Based Interspecies Scaling of Glucose Homeostasis
Open this publication in new window or tab >>Model-Based Interspecies Scaling of Glucose Homeostasis
2017 (English)In: CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY, ISSN 2163-8306, Vol. 6, no 11, p. 778-786Article in journal (Refereed) Published
Abstract [en]

Being able to scale preclinical pharmacodynamic response to clinical would be beneficial in drug development. In this work, the integrated glucose insulin (IGI) model, developed on clinical intravenous glucose tolerance test (IVGTT) data, describing dynamic glucose and insulin concentrations during glucose tolerance tests, was scaled to describe data from similar tests performed in healthy rats, mice, dogs, pigs, and humans. Several approaches to scaling the dynamic glucose and insulin were investigated. The theoretical allometric exponents of 0.75 and 1, for clearances and volumes, respectively, could describe the data well with some species-specific adaptations: dogs and pigs showed slower first phase insulin secretion than expected from the scaling, pigs also showed more rapid insulin dependent glucose elimination, and rodents showed differences in glucose effectiveness. The resulting scaled IGI model was shown to accurately predict external preclinical IVGTT data and may be useful in facilitating translations of preclinical research into the clinic.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-339699 (URN)10.1002/psp4.12247 (DOI)000418823400009 ()28960826 (PubMedID)
Available from: 2018-01-29 Created: 2018-01-29 Last updated: 2018-02-26Bibliographically approved
2. Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
Open this publication in new window or tab >>Semi-mechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes
Show others...
2016 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 56, no 3, p. 340-348Article in journal (Refereed) Published
Abstract [en]

The integrated glucose-insulin (IGI) model is a previously published semi-mechanistic model, which describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semi-physiological model developed performed better than previously published empirical models and allows for better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose.

National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-259411 (URN)10.1002/jcph.602 (DOI)000370162700011 ()26224050 (PubMedID)
Available from: 2015-08-03 Created: 2015-08-03 Last updated: 2018-02-26
3. Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
Open this publication in new window or tab >>Mathematical modelling of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 following ingestion of glucose
Show others...
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.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-279065 (URN)10.1111/bcpt.12792 (DOI)000409507900013 ()28374974 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 115156
Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2018-02-26Bibliographically approved
4. Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucose
Open this publication in new window or tab >>Mechanism-Based model for beta cell function in healthy individuals and patients with type 2 diabetes for intravenous and oral glucose
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-343114 (URN)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26
5. An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 Diabetes
Open this publication in new window or tab >>An Integrated Glucose Homeostasis Model of Glucose, Insulin, C-peptide, GLP-1, GIP and Glucagon in Healthy Subjects and Patients with Type 2 Diabetes
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Pharmacology and Toxicology
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-343115 (URN)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2018-02-26

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