Intravenous Glucose Tolerance Test Modeling Research Articles

A novel IVGTT model including interstitial insulin

Minimal Model (MM) is the top-scoring model for assessing physiological characteristics to diagnose the potential or onset of type 2 diabetes mellitus (T2DM) through the intravenous glucose tolerance test (IVGTT) for the past four decades. Nevertheless it has been arguable that MM method either overestimates glucose effectiveness (GE) or underestimates insulin sensitivity (IS) in some cases by both biologists through in vivo experiments and mathematicians by analysis and/or simulations. We propose a novel model including the interstitial insulin according to physiology and adapted from the well accepted Sturis’ model for the glucose-insulin metabolic system suitable to the IVGTT setting. Our model consistently overcomes the aforementioned defects in a subgroup of subjects. In addition, the variable X for insulin action in MM might be appropriately interpreted as an increment of insulin in the interstitial space in response to the bolus stimulus, rather than being proportional to the interstitial insulin as believed.

Positive input observer‐based controller design for blood glucose regulation for type 1 diabetic patients: A backstepping approach

In practice, there are many physical systems that can have only positive inputs, such as physiological systems. Most conventional control methods cannot ensure that the main system input is positive. A positive input observer‐based controller is designed for an intravenous glucose tolerance test model of type 1 diabetes mellitus (T1DM). The backstepping (BS) approach is employed to design the feedback controller for artificial pancreas (AP) systems, based on the Extended Bergman's Minimal Model (EBMM). The EBMM represents the T1DM in terms of the blood glucose concentration (BGC), insulin concentration, and plasma level and the disturbance of insulin during medication due to either meal intake or burning sugar by doing some physical exercise. The insulin concentration and plasma level are estimated using observers, and these estimations are applied as feedback to the controller. The asymptotic stability of the observer‐based controller is proved using the Lyapunov theorem. Moreover, it is proved that the system is bounded input‐bounded output (BIBO) stable in the presence of uncertainties generated by uncertain parameters and external disturbance. For realistic situations, we consider only the BGC to be available for measurement and additionally inter‐and intra‐patient variability of system parameters is considered.

Oscillatory dynamics of an intravenous glucose tolerance test model with delay interval.

Type 2 diabetes mellitus (T2DM) has become prevalent pandemic disease in view of the modern life style. Both diabetic population and health expenses grow rapidly according to American Diabetes Association. Detecting the potential onset of T2DM is an essential focal point in the research of diabetes mellitus. The intravenous glucose tolerance test (IVGTT) is an effective protocol to determine the insulin sensitivity, glucose effectiveness, and pancreatic β-cell functionality, through the analysis and parameter estimation of a proper differential equation model. Delay differential equations have been used to study the complex physiological phenomena including the glucose and insulin regulations. In this paper, we propose a novel approach to model the time delay in IVGTT modeling. This novel approach uses two parameters to simulate not only both discrete time delay and distributed time delay in the past interval, but also the time delay distributed in a past sub-interval. Normally, larger time delay, either a discrete or a distributed delay, will destabilize the system. However, we find that time delay over a sub-interval might not. We present analytically some basic model properties, which are desirable biologically and mathematically. We show that this relatively simple model provides good fit to fluctuating patient data sets and reveals some intriguing dynamics. Moreover, our numerical simulation results indicate that our model may remove the defect in well known Minimal Model, which often overestimates the glucose effectiveness index.

On Construction of stability methods for IVGTT Glucose-Insulin Model with Two Distributed Delays

The intravenous glucose tolerance test (IVGTT) has been considered as the most accurate method todetermine the insulin sensitivity and glucose eectiveness. In this paper, we present the extensions ofvarious stability theorems for IVGTT model with two distributed delays. Sensitivity analysis for glucoseinsulin IVGTT system suggests that the parameter value has a major impact on the model dynamics. Inaddition, the numerical calculations in this paper are fully incorporated with initial conditions, which isnatural and more appropriate in IVGTT model.

An acute rat in vivo screening model to predict compounds that alter blood glucose and/or insulin regulation

IntroductionDrug-induced glucose dysregulation and insulin resistance have been associated with weight gain and potential induction and/or exacerbation of diabetes mellitus in the clinic suggesting they may be safety biomarkers when developing antipsychotics. Glucose and insulin have also been suggested as potential efficacy biomarkers for some oncology compounds. The objective of this study was to qualify a medium throughput rat in vivo acute Intravenous Glucose Tolerance Test (IVGTT) for predicting compounds that will induce altered blood glucose and/or insulin levels. MethodsAcute and sub-chronic studies were performed to qualify an acute IVGTT model. Double cannulated male rats (Han–Wistar and Sprague–Dawley) were administered vehicle, olanzapine, aripiprazole or other compounds at t=−44min for acute studies and at time=−44min on the last day of dosing for sub-chronic studies, treated with dextrose (time=0min; i.v.) and blood collected using an automated Culex® system for glucose and insulin analysis (time=−45, −1, 2, 10, 15, 30, 45, 60, 75, 90, 120, 150 and 180min). ResultsOlanzapine significantly increased glucose and insulin area under the curve (AUC) values while aripiprazole AUC values were similar to control, in both acute and sub-chronic studies. All atypical antipsychotics evaluated were consistent with literature references of clinical weight gain. As efficacy biomarkers, insulin AUC but not glucose AUC values were increased with a compound known to have insulin growth factor-1 (IGF-1) activity, compared to control treatment. DiscussionThese studies qualified the medium throughput acute IVGTT model to more quickly screen compounds for 1) safety — the potential to elicit glucose dysregulation and/or insulin resistance and 2) efficacy — as a surrogate for compounds affecting the glucose and/or insulin regulatory pathways. These data demonstrate that the same in vivo rat model and assays can be used to predict both clinical safety and efficacy of compounds.

The range of time delay and the global stability of the equilibrium for an IVGTT model

Diabetes mellitus has become a prevalent disease in the world. Diagnostic protocol for the onset of diabetes mellitus is the initial step in the treatments. The intravenous glucose tolerance test (IVGTT) has been considered as the most accurate method to determine the insulin sensitivity and glucose effectiveness. It is well known that there exists a time delay in insulin secretion stimulated by the elevated glucose concentration level. However, the range of the length of the delay in the existing IVGTT models are not fully discussed and thus in many cases the time delay may be assigned to a value out of its reasonable range. In addition, several attempts had been made to determine when the unique equilibrium point is globally asymptotically stable. However, all these conditions are delay-independent. In this paper, we discuss the range of the time delay and provide easy-to-check delay-dependent conditions for the global asymptotic stability of the equilibrium point for a recent IVGTT model through Liapunov function approach. Estimates of the upper bound of the delay for global stability are given in corollaries. In addition, the numerical simulation in this paper is fully incorporated with functional initial conditions, which is natural and more appropriate in delay differential equation systems.