Developing and validating a new comprehensive glucose-insulin pharmacokinetics and pharmacodynamics model
Thesis DisciplineMechanical Engineering
Degree GrantorUniversity of Canterbury
Degree NameDoctor of Philosophy
Type 2 diabetes has reached epidemic proportions worldwide. The resulting increase in chronic and costly diabetes related complications has potentially catastrophic implications for healthcare systems, and economics and societies as a whole. One of the key pathological factors leading to type 2 diabetes is insulin resistance (IR), which is the reduced or impaired ability of the body to make use of available insulin to maintain safe glucose concentrations in the bloodstream.
It is essential to understand the physiology of glucose and insulin when investigating the underlying factors contributing to chronic diseases such as diabetes and cardiovascular disease. For many years, clinicians and researchers have been working to develop and use model-based methods to increase understanding and aid therapeutic decision support. However, the majority of practicable tests cannot yield more than basic metrics that allow only a threshold-based assessment of the underlying disorder.
This thesis gives an overview on several dynamic model-based methodologies with different clinical applications in assessing glycaemia via measuring effects of treatment or medication on insulin sensitivity. Other tests are clinically focused, designed to screen populations and diagnose or detect the risk of developing diabetes. Thus, it is very important to observe sensitivity metrics in various clinical and research settings.
Interstitial insulin kinetics and their influence on model-based insulin sensitivity observation was analysed using data from the clinical pilot study of the dynamic insulin sensitivity and secretion (DISST) test and the glucose-insulin PK-PD models. From these inputs, a model of interstitial insulin dose-response that best links insulin action in plasma to response in blood glucose levels was developed. The critical parameters influencing interstitial insulin pharmacokinetics (PKs) are saturation in insulin receptor binding (αG) and the plasma-interstitium diffusion rate (nI). Population values for these parameters are found to be [αG, nI]=[0.05,0.055].
Critically ill patients are regularly fed via constant enteral (EN) nutrition infusions. The impact of incretin effects on endogenous insulin secretion in this cohort remains unclear. It is hypothesised that the identified SI would decrease during interruptions of EN and would increase when EN is resumed, where, for short periods around transition, the true patient SI would be assumed constant. The model-based analysis was able to elucidate incretin effects by tracking the identified model-based insulin sensitivity (SI) in a cohort of critically ill patients. Thus, changes in model-based SI given the fixed assumed endogenous secretion by the model would support the presence of an EN-related incretin effect in the population of non-diabetic, critically ill patients studied.
The PD feedback-control model of Uen was designed to investigate endogenous insulin secretion amongst subjects with different metabolic states and levels of insulin resistance. The underlying effects that influence insulin secretion i.e. incretin effects were also defined by tracking the control model gain/response and the identified insulin sensitivity (SI) using intravenous (IV) bolus and oral glucose responses of insulin sensitivity tests. This new PD control model allowed the characterisation of both static (basal) and dynamic insulin responses, which defined the pancreatic β-cell glucose sensitivity parameters. However, incretin effects were unobserved during oral glucose responses as the PD control gains failed to simulate the true endogenous insulin secretion due to potentially inaccurate glucose appearance rates and low data resolution of glucose concentrations.
The net effect of haemodialysis (HD) treatment on glycaemic regulation and insulin sensitivity in a critically ill cohort was investigated. It was hypothesized that the observed SI would decrease during HD due to enhanced insulin clearance compared to the model, and would be recaptured again when HD is stopped. The changes in model-based SI metric at HD transitions in a cohort of critically ill patients were evaluated. Significant changes of -29% in model-based SI was observed during HD therapy. However, there were insignificant changes when HD treatment was ended. Thus, the changes in model-based SI would thus offer a unique observation on insulin kinetics and action in this population of critically ill patients with ARF that would better inform metabolic care.