Biomedical subjects

Darko Stefanovski

Publications and source records attributed to Darko Stefanovski.

7 recordsLinked to original sources

PubMed2026

Research updates in cystic fibrosis related diabetes: Understanding pathophysiology, expanding animal and human islet models, and advancing clinical and translational research.

In 2024-2025, the Cystic Fibrosis Foundation (US) and Cystic Fibrosis Trust (UK) hosted an International CFRD Consortium round-table webinar series for basic science, translational, and clinical researchers with the goal of sharpening mechanistic understanding of CFRD pathogenesis and prioritizing therapeutic development. This review summarizes the research priorities identified in the International CFRD Consortium, including (i) further investigation into the role of pancreatic fibrosis, vascular abnormalities, and α-cell dysfunction in the development of CFRD; (ii) the creation and refinement of novel animal and human cell- and tissue-based models to understand the complex interplay of exocrine and endocrine cells in the CF pancreas; (iii) development and validation of circulating and imaging biomarkers, together with dynamic glucose testing to explore β-cell function and kinetics in people with CF across the dysglycemia spectrum; and (iv) prospective clinical studies to guide CFRD treatment options and investigate the changing landscape of aging, increasing prevalence of obesity and diabetes and their complications in the era of cystic fibrosis transmembrane conductance regulator (CFTR) modulators. Collectively, these priorities aim to accelerate transition from mechanism to intervention and expand evidence-based care for people with CF at risk of, or living with, CFRD.

Humans↗

PubMed2006

Dimensional analysis of MINMOD leads to definition of the disposition index of glucose regulation and improved simulation algorithm.

BACKGROUND: 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.

Algorithms↗

PubMed2006

Exogenously imposed postprandial-like rises in systemic glucose and GLP-1 do not produce an incretin effect, suggesting an indirect mechanism of GLP-1 action.

The insulinotropic intestinal hormone GLP-1 is thought to exert one of its effects by direct action on the pancreatic beta-cell receptors. GLP-1 is rapidly degraded in plasma, such that only a small amount of the active form reaches the pancreas, making it questionable whether this amount is sufficient to produce a direct incretin effect. The aim of our study was to assess, in a dog model, the putative incretin action of GLP-1 acting directly on the beta-cell in the context of postprandial rises in GLP-1 and glucose. Conscious dogs were fed a high-fat, high-carbohydrate meal, and insulin response was measured. We also infused systemic glucose plus GLP-1, or glucose alone, to simulate the meal test values of these variables and measured insulin response. The results were as follows: during the meal, we measured a robust insulin response (52 +/- 9 to 136 +/- 14 pmol/l, P < 0.05 vs. basal) with increases in portal glucose and GLP-1 but only limited increases in systemic glucose (5.3 +/- 0.1 to 5.7 +/- 0.1 mmol/l, P = 0.1 vs. basal) and GLP-1 (6 +/- 0 to 9 +/- 1 pmol/l, P = 0.5 vs. basal). Exogenous infusion of systemic glucose and GLP-1 produced a moderate increase in insulin (43 +/- 5 to 84 +/- 15 pmol/l, 43% of the meal insulin). However, infusion of glucose alone, without GLP-1, produced a similar insulin response (37 +/- 6 to 82 +/- 14 pmol, 53% of the meal insulin, P = 0.7 vs. glucose and GLP-1 infusion). In conclusion, in dogs with postprandial rises in systemic glucose and GLP-1, the hormone might not have a direct insulinotropic effect and could regulate glycemia via indirect, portohepatic-initiated neural mechanisms.

Animals↗

PubMed2005

AKA-Glucose: a program for kinetic and epidemiological analysis of frequently sampled intravenous glucose tolerance test data using database technology.

BACKGROUND: The Bergman Minimal Model enables estimation of two key indices of glucose/ insulin dynamics: glucose effectiveness and insulin sensitivity. METHODS AND RESULTS: In this paper we describe AKA-Glucose, a program that combines MINMOD Millennium (minimal model analysis software) with relational database technologies. AKA-Glucose enables the fitting of individual frequently sampled intravenous glucose tolerance test (FSIGT) data sets to the Minimal Model and the secure storage in a dedicated database (and retrieval from) of thousands of individual subjects' demographic data, their individual FSIGT data, and each subject's parameters and indices derived from minimal model analysis. AKA-Glucose also enables the population analysis of various strata or subpopulations within the database. AKA-Glucose has all of the capabilities of MINMOD Millennium, provides Minimal Model parameter estimates that are concordant with estimates from previous MINMOD software, and allows importation of data files from earlier versions of the MINMOD software. CONCLUSIONS: By combining FSIGT data fitting, population analysis, and relational database technologies, AKA-Glucose is the first minimal model software designed specifically for researchers confronted with minimal model and epidemiological analysis of large numbers of either human or animal FSIGT data sets.

Adult↗

PubMed2003

Cornerstones to shape modeling for the 21st century: introducing the AKA-Glucose project.

In this paper, we have reflected on the historical development during the twentieth century of several major cornerstones on which the edifice of mathematical modeling in nutrition and the health sciences was built. When we consider the scope and magnitude of problems in nutrition and the health sciences that have been addressed and solved by mathematical modeling, we as a group can justifiably feel a certain amount of satisfaction. But we should not be complacent. So much more remains to be done. The increasing pace of developments in biology (e.g., the human genome project) places a whole new range of challenges before us. We can also reflect on the mathematical basis of modeling and consider that we enter the twenty-first century with a solid foundation on which to build bigger and better models. At the same time, we have at our disposal computers of immense power. At the start of the twentieth century, no one could have foreseen where we are today. In our lifetimes, computers have been developed from lumbering behemoths with the calculating ability of an abacus to the present day machines with calculating capabilitie that we are only beginning to appreciate. There is general consensus that developments in the field of computing will continue far into the twenty-first century. Therefore, w can confidently assert that developments in modeling will not be greatly limited by our present mathematical foundation or by the capabilities of computers. In this paper, we have mainly dwelt on three cornerstones: the model development environment model dissemination and database technologies data exchange and post-fitting analysis. We have focused on SAAM, WinSAAM, and AKA-Glucose as illustrating these cornerstones, while acknowledging that there are many other modeling programs that also represent them. However, a building usually has four cornerstones. If one cornerstone is missing, then there may be a structural weakness in the entire building. We contend that, at the start of the twenty-first century, the edifice of modeling is missing the important fourth cornerstone: a modeling community. As modelers, we should cease to bowl alone. Now is the time to make a new beginning, to give modeling some formality, structure, and direction. We should form a community of modelers as we move into the 21st century.

Computer Simulation↗

PubMed2003

WinSAAM: a windows-based compartmental modeling system.

Over the last 50 years, complex, dynamic, compartmental models have been used to describe and to make predictions on a host of pharmacokinetic, metabolic, and biological systems. Sophisticated modeling software is required to fit data to such models and to make predictions using these compartmental models. WinSAAM is one such modeling program. The purpose the current report is to describe the features of WinSAAM that make this program suited for modeling all manner of biological systems. We highlight new features, especially those that are unique to WinSAAM, and illustrate with examples how WinSAAM is used to construct models of metabolic systems, to simulate the effects of experiments on systems, and to fit models to data.

Blood Glucose↗

PubMed2003

MINMOD Millennium: a computer program to calculate glucose effectiveness and insulin sensitivity from the frequently sampled intravenous glucose tolerance test.

The Bergman Minimal Model enables estimation of two key indices of glucose/insulin dynamics: glucose effectiveness and insulin sensitivity. In this paper we describe MINMOD Millennium, the latest Windows-based version of minimal model software. Extensive beta testing of MINMOD Millennium has shown that it is user-friendly, fully automatic, fast, accurate, reproducible, repeatable, and highly concordant with past versions of MINMOD. It has a simple interface, a comprehensive help system, an input file editor, a file converter, an intelligent processing kernel, and a file exporter. It provides publication-quality charts of glucose and insulin and a table of all minimal model parameters and their error estimates. In contrast to earlier versions of MINMOD and some other minimal model programs, Millennium provides identified estimates of insulin sensitivity and glucose effectiveness for almost every subject.

Blood Glucose↗