Stefanovski, Darko
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Publication Consistency of the Disposition Index in the Face of Diet Induced Insulin Resistance: Potential Role of FFA(2011-03-30) Stefanovski, Darko; Richey, Joyce M; Woolcott, Orison; Lottati, Maya; Zheng, Dan; Harrison, Lisa N; Ionut, Viorica; Kim, Stella P; Bergman, Richard NObjective Insulin resistance induces hyperinsulinemic compensation, which in turn maintains almost a constant disposition index. However, the signal that gives rise to the hyperinsulinemic compensation for insulin resistance remains unknown. Methods In a dog model of obesity we examined the possibility that potential early-week changes in plasma FFA, glucose, or both could be part of a cascade of signals that lead to compensatory hyperinsulinemia induced by insulin resistance. Results Hypercaloric high fat feeding in dogs resulted in modest weight gain, and an increase in adipose tissue with no change in the non-adipose tissue size. To compensate for the drop in insulin sensitivity, there was a significant rise in plasma insulin, which can be attributed in part to a decrease in the metabolic clearance rate of insulin and increased insulin secretion. In this study we observed complete compensation for high fat diet induced insulin resistance as measured by the disposition index. The compensatory hyperinsulinemia was coupled with significant changes in plasma FFAs and no change in plasma glucose. Conclusions We postulate that early in the development of diet induced insulin resistance, a change in plasma FFAs may directly, through signaling at the level of β-cell, or indirectly, by decreasing hepatic insulin clearance, result in the observed hyperinsulinemic compensation.Publication The Minimal Glucose Models(2020-12-03) Stefanovski, Darko; Boston, Raymond CThis session: A set of 6 PK/PD studies from Gabrielsson and Weiner’s book Pharmacokinetic & pharmacodynamic data analysis : concepts and applications will be solved demonstrating a variety of new approaches.Publication A Better Index of Body Adiposity(2011-05-01) Bergman, Richard N; Stefanovski, Darko; Buchanan, Thomas A; Sumner, Anne E; Reynolds, James C; Sebring, Nancy G; Xiang, Anny H; Watanabe, Richard MObesity is a growing problem in the United States and throughout the world. It is a risk factor for many chronic diseases. The BMI has been used to assess body fat for almost 200 years. BMI is known to be of limited accuracy, and is different for males and females with similar %body adiposity. Here, we define an alternative parameter, the body adiposity index (BAI = ((hip circumference)/((height)1.5)–18)). The BAI can be used to reflect %body fat for adult men and women of differing ethnicities without numerical correction. We used a population study, the “BetaGene” study, to develop the new index of body adiposity. %Body fat, as measured by the dual-energy X-ray absorptiometry (DXA), was used as a “gold standard” for validation. Hip circumference (R = 0.602) and height (R = −0.524) are strongly correlated with %body fat and therefore chosen as principal anthropometric measures on which we base BAI. The BAI measure was validated in the “Triglyceride and Cardiovascular Risk in African-Americans (TARA)” study of African Americans. Correlation between DXA-derived %adiposity and the BAI was R = 0.85 for TARA with a concordance of C_b = 0.95. BAI can be measured without weighing, which may render it useful in settings where measuring accurate body weight is problematic. In summary, we have defined a new parameter, the BAI, which can be calculated from hip circumference and height only. It can be used in the clinical setting even in remote locations with very limited access to reliable scales. The BAI estimates %adiposity directly.Publication Protocol and Response Specification for PK Systems(2020-11-19) Stefanovski, Darko; Boston, RaymondThis session: Surgeons, anesthetists, and nutritionists all need access to PK/PD tools to help plan and interpret clinical interventions. The WinSAAM software has convincingly demonstrated its facility here where we have solved the 200 or so Kinetic Investigations in the book Pharmacokinetic & pharmacodynamic data analysis : concepts and applications by Gabrielsson and Weiner (4th Edn.).Publication Overview of Modeling with WinSAAM(2020-10-22) Stefanovski, Darko; Boston, RaymondDemonstrations of some basic WinSAAM models reflecting how common problems are addressed.Publication The Utility of Macro and Micro Disposition models(2020-11-12) Stefanovski, Darko; Boston, RaymondThis session: Missing and damaged data are perennial problems of kinetics and in this session we will show how Kinetic Analysis affords us new approaches to Data Imputation using Macro Rate Constants.Publication Getting Started using WinSAAM(2020-10-29) Stefanovski, Darko; Boston, RaymondThis session: A second tier of problems tackled using WinSAAM models. Here we would welcome your own contribution to our material so that our WS will have a best possible relevance for you.Publication Infectious Diseases Modeled with WinSAAM(2020-12-17) Stefanovski, Darko; Boston, RaymondThis session: Infectious Disease Epidemics. Never has the time been more poised for the exploitation of models to follow, monitor, and control the spread of infectious diseases. Here we show how variants of the SIR model (attributable to Kermack, and McKendrick, 1927) can be explored and manipulated using just 2 or 3 WinSAAM modeling constructs.Publication Dimensional Analysis of MINMOD Leads to Definition of the Disposition Index of Glucose Regulation and Improved Simulation Algorithm(2006-07-14) Nittala, Aparna; Ghosh, Soumitra; Stefanovski, Darko; Bergman, Richard; Wang, XujingBackground Frequently Sampled Intravenous Glucose Tolerance Test (FSIVGTT) together with its mathematical model, the minimal model (MINMOD), have become important clinical tools to evaluate the metabolic control of glucose in humans. Dimensional analysis of the model is up to now not available. Methods A formal dimensional analysis of MINMOD was carried out and the degree of freedom of MINMOD was examined. Through re-expressing all state variable and parameters in terms of their reference scales, MINMOD was transformed into a dimensionless format. Previously defined physiological indices including insulin sensitivity, glucose effectiveness, and first and second phase insulin responses were re-examined in this new formulation. Further, the parameter estimation from FSIVGTT was implemented using both the dimensional and the dimensionless formulations of MINMOD, and the performances were compared utilizing Monte Carlo simulation as well as real human FSIVGTT data. Results The degree of freedom (DOF) of MINMOD was found to be 7. The model was maximally simplified in the dimensionless formulation that normalizes the variation in glucose and insulin during FSIVGTT. In the new formulation, the disposition index (Dl), a composite parameter known to be important in diabetes pathology, was naturally defined as one of the dimensionless parameters in the system. The numerical simulation using the dimensionless formulation led to a 1.5–5 fold gain in speed, and significantly improved accuracy and robustness in parameter estimation compared to the dimensional implementation. Conclusion Dimensional analysis of MINMOD led to simplification of the model, direct identification of the important composite factors in the dynamics of glucose metabolic control, and better simulations algorithms.Publication Non-Equilibrium Dynamics Contribute to Ion Selectivity in the KcsA Channel(2014-01-17) Ngo, Van; Stefanovski, Darko; Haas, Stephen; Farley, Robert AThe ability of biological ion channels to conduct selected ions across cell membranes is critical for the survival of both animal and bacterial cells. Numerous investigations of ion selectivity have been conducted over more than 50 years, yet the mechanisms whereby the channels select certain ions and reject others are not well understood. Here we report a new application of Jarzynski’s Equality to investigate the mechanism of ion selectivity using non-equilibrium molecular dynamics simulations of Na+ and K+ ions moving through the KcsA channel. The simulations show that the selectivity filter of KcsA adapts and responds to the presence of the ions with structural rearrangements that are different for Na+ and K+. These structural rearrangements facilitate entry of K+ ions into the selectivity filter and permeation through the channel, and rejection of Na+ ions. A mechanistic model of ion selectivity by this channel based on the results of the simulations relates the structural rearrangement of the selectivity filter to the differential dehydration of ions and multiple-ion occupancy and describes a mechanism to efficiently select and conduct K+. Estimates of the K+/Na+ selectivity ratio and steady state ion conductance for KcsA from the simulations are in good quantitative agreement with experimental measurements. This model also accurately describes experimental observations of channel block by cytoplasmic Na+ ions, the “punch through” relief of channel block by cytoplasmic positive voltages, and is consistent with the knock-on mechanism of ion permeation.
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