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Pharmacometric Models of Glucose Homeostasis in Healthy Subjects and Diabetes Patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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. , 77 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 212
Keyword [en]
Glucose homeostasis, Type 2 diabetes, IGI model, Mechanismbased, NONMEM, pharmacometrics
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-274239ISBN: 978-91-554-9499-5 (print)OAI: oai:DiVA.org:uu-274239DiVA: diva2:907493
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: 2016-04-12
List of papers
1. Modeling of 24-Hour Glucose and Insulin Profiles in Patients With Type 2 Diabetes Mellitus Treated With Biphasic Insulin Aspart
Open this publication in new window or tab >>Modeling of 24-Hour Glucose and Insulin Profiles in Patients With Type 2 Diabetes Mellitus Treated With Biphasic Insulin Aspart
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2014 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 54, no 7, 809-817 p.Article in journal (Refereed) Published
Abstract [en]

Insulin therapy for diabetes patients is designed to mimic the endogenous insulin response of healthy subjects and thereby generate normal blood glucose levels. In order to control the blood glucose in insulin-treated diabetes patients, it is important to be able to predict the effect of exogenous insulin on blood glucose. A pharmacokinetic/pharmacodynamic model for glucose homoeostasis describing the effect of exogenous insulin would facilitate such prediction. Thus the aim of this work was to extend the previously developed integrated glucose-insulin (IGI) model to predict 24-hour glucose profiles for patients with Type 2 diabetes following exogenous insulin administration. Clinical data from two trials were included in the analysis. In both trials, 24-hour meal tolerance tests were used as the experimental setup, where exogenous insulin (biphasic insulin aspart) was administered in relation to meals. The IGI model was successfully extended to include the effect of exogenous insulin. Circadian variations in glucose homeostasis were assessed on relevant parameters, and a significant improvement was achieved by including a circadian rhythm on the endogenous glucose production in the model. The extended model is a useful tool for clinical trial simulation and for elucidating the effect profile of new insulin products.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-219250 (URN)10.1002/jcph.270 (DOI)000337627100010 ()24446385 (PubMedID)
Available from: 2014-02-25 Created: 2014-02-25 Last updated: 2017-12-05Bibliographically approved
2. Insulin aspart pharmacokinetics: An assessment of its variability and underlying mechanisms
Open this publication in new window or tab >>Insulin aspart pharmacokinetics: An assessment of its variability and underlying mechanisms
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2014 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 62, 65-75 p.Article, review/survey (Refereed) Published
Abstract [en]

Background: Insulin aspart (IAsp) is used by many diabetics as a meal-time insulin to control postprandial glucose levels. As is the case with many other insulin types, the pharmacokinetics (PK), and consequently the pharmacodynamics (PD), is associated with clinical variability, both between and within individuals. The present article identifies the main physiological mechanisms that govern the PK of IAsp following subcutaneous administration and quantifies them in terms of their contribution to the overall variability. Material and methods: CT scanning data from Thomsen et al. (2012) are used to investigate and quantify the properties of the subcutaneous depot. Data from Brange et al. (1990) are used to determine the effects of insulin chemistry in subcutis on the absorption rate. Intravenous (i.v.) bolus and infusion PK data for human insulin are used to understand and quantify the systemic distribution and elimination (Porksen et al., 1997; Sjostrand et al., 2002). PK and PD profiles for type 1 diabetics from Chen et al. (2005) are analyzed to demonstrate the effects of IAsp antibodies in terms of bound and unbound insulin. PK profiles from Thorisdottir et al. (2009) and Ma et al. (2012b) are analyzed in the nonlinear mixed effects software Monolix (R) to determine the presence and effects of the mechanisms described in this article. Results: The distribution of IAsp in the subcutaneous depot show an initial dilution of approximately a factor of two in a single experiment. Injected insulin hexamers exist in a chemical equilibrium with monomers and dimers, which depends strongly on the degree of dilution in subcutis, the presence of auxiliary substances, and a variety of other factors. Sensitivity to the initial dilution in subcutis can thus be a cause of some of the variability. Temporal variations in the PK are explained by variations in the subcutaneous blood flow. IAsp antibodies are found to be a large contributor to the variability of total insulin PK in a study by Chen et al. (2005), since only the free fraction is eliminated via the receptors. The contribution of these and other sources of variability to the total variability is quantified via a population PK analysis and two recent clinical studies (Thorisdottir et al., 2009; Ma et al., 2012b), which support the presence and significance of the identified mechanisms. Conclusions: IAsp antibody binding, oligomeric transitions in subcutis, and blood flow dependent variations in absorption rate seem to dominate the PK variability of IAsp. It may be possible via e.g. formulation design to reduce some of these variability factors. (C) 2014 Elsevier B.V. All rights reserved.

Keyword
Insulin aspart, Subcutaneous injections, Insulin variability, Insulin antibodies, Insulin pharmacokinetics
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
urn:nbn:se:uu:diva-231475 (URN)10.1016/j.ejps.2014.05.010 (DOI)000340301500009 ()
Available from: 2014-09-10 Created: 2014-09-08 Last updated: 2017-12-05Bibliographically approved
3. The Effects of a GLP-1 Analog on Glucose Homeostasis in Type 2 Diabetes Mellitus Quantified by an Integrated Glucose Insulin Model
Open this publication in new window or tab >>The Effects of a GLP-1 Analog on Glucose Homeostasis in Type 2 Diabetes Mellitus Quantified by an Integrated Glucose Insulin Model
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2015 (English)In: CPT: Pharmacometrics & Systems Pharmacology, ISSN 2163-8306, Vol. 4, no 1, 1-9 p.Article in journal (Refereed) Published
Abstract [en]

In recent years, several glucagon-like peptide-1 (GLP-1)-based therapies for the treatment of type 2 diabetes mellitus (T2DM) have been developed. The aim of this work was to extend the semimechanistic integrated glucose-insulin model to include the effects of a GLP-1 analog on glucose homeostasis in T2DM patients. Data from two trials comparing the effect of steady-state liraglutide vs. placebo on the responses of postprandial glucose and insulin in T2DM patients were used for model development. The effect of liraglutide was incorporated in the model by including a stimulatory effect on insulin secretion. Furthermore, for one of the trials an inhibitory effect on glucose absorption was included to account for a delay in gastric emptying. As other GLP-1 receptor agonists have similar modes of action, it is believed that the model can also be used to describe the effect of other receptor agonists on glucose homeostasis.

National Category
Pharmaceutical Sciences
Research subject
Pharmacokinetics and Drug Therapy
Identifiers
urn:nbn:se:uu:diva-244286 (URN)10.1002/psp4.11 (DOI)
Available from: 2015-02-13 Created: 2015-02-13 Last updated: 2016-04-12Bibliographically approved
4. 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
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2016 (English)In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 56, no 3, 340-348 p.Article 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: 2017-12-04
5. 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
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2017 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 121, no 4, 290-297 p.Article 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: 2017-11-29Bibliographically approved
6. Mathematical model for beta cell function in healthy individuals and patients with type 2 diabetes
Open this publication in new window or tab >>Mathematical model for beta cell function in healthy individuals and patients with type 2 diabetes
(English)Manuscript (preprint) (Other academic)
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-279063 (URN)
Available from: 2016-02-29 Created: 2016-02-29 Last updated: 2016-04-12

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Røge, Rikke Meldgaard

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