The Adaptive Renal Response for Volume Homeostasis During 2 Weeks of Dapagliflozin Treatment in People With Type 2 Diabetes and Preserved Renal Function on a Sodium-Controlled Diet.

Introduction: Proximal tubule sodium uptake is diminished following sodium glucose cotransporter 2 (SGLT2) inhibition. We previously showed that during SGLT2 inhibition, the kidneys adapt by increasing sodium uptake at distal tubular segments, thereby maintaining body sodium balance. Despite continuous glycosuria, we detected no increased urine volumes.

Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis.

The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA-REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte-free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte-free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium.

Drug-disease modeling in the pharmaceutical industry - where mechanistic systems pharmacology and statistical pharmacometrics meet.

Modeling & simulation (M&S) methodologies are established quantitative tools, which have proven to be useful in supporting the research, development (R&D), regulatory approval, and marketing of novel therapeutics. Applications of M&S help design efficient studies and interpret their results in context of all available data and knowledge to enable effective decision-making during the R&D process. In this mini-review, we focus on two sets of modeling approaches: population-based models, which are well-established within the pharmaceutical industry today, and fall under the discipline of clinical pharmacometrics (PMX); and systems dynamics models, which encompass a range of models of (patho-)physiology amenable to pharmacological intervention, of signaling pathways in biology, and of substance distribution in the body (today known as physiologically-based pharmacokinetic models) - which today may be collectively referred to as quantitative systems pharmacology models (QSP).

Markers of inflammation collocate with increased wall stress in human coronary arterial plaque.

In this study, we hypothesized that spatial relationships exist between the local mechanical environment and inflammatory marker expression in atherosclerotic plaques, and that these relationships are plaque-progression dependent. Histologic cross-sections were collected at regular intervals along the length of diseased human coronary arteries and classified as early, intermediate, advanced, or mature based on their morphological features. For each cross-section, the spatial distribution of stress was determined using a 2D heterogeneous finite element model, and the corresponding distribution of selected inflammatory markers (macrophages, matrix metalloproteinase-1 [MMP-1], and nuclear factor-kappa B [NF-κB]) were determined immunohistochemically.