A unified framework for prediction of liver steatosis dynamics in response to different diet and drug interventions.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder, characterized by the accumulation of excess fat in the liver, and is a driving factor for various severe liver diseases. These multi-factorial and multi-timescale changes are observed in different clinical studies, but these studies have not been integrated into a unified framework. In this study, we aim to present such a unified framework in the form of a dynamic mathematical model.

A multi-scale digital twin for adiposity-driven insulin resistance in humans: diet and drug effects.

Background: The increased prevalence of insulin resistance is one of the major health risks in society today. Insulin resistance involves both short-term dynamics, such as altered meal responses, and long-term dynamics, such as the development of type 2 diabetes. Insulin resistance also occurs on different physiological levels, ranging from disease phenotypes to organ-organ communication and intracellular signaling.

Mathematical models disentangle the role of IL-10 feedbacks in human monocytes upon proinflammatory activation.

Inflammation is one of the vital mechanisms through which the immune system responds to harmful stimuli. During inflammation, proinflammatory and anti-inflammatory cytokines interplay to orchestrate fine-tuned and dynamic immune responses. The cytokine interplay governs switches in the inflammatory response and dictates the propagation and development of the inflammatory response.

A comprehensive mechanistic model of adipocyte signaling with layers of confidence.

Adipocyte signaling, normally and in type 2 diabetes, is far from fully understood. We have earlier developed detailed dynamic mathematical models for several well-studied, partially overlapping, signaling pathways in adipocytes. Still, these models only cover a fraction of the total cellular response.

A systems biology analysis of lipolysis and fatty acid release from adipocytes in vitro and from adipose tissue in vivo.

Lipolysis and the release of fatty acids to supply energy fuel to other organs, such as between meals, during exercise, and starvation, are fundamental functions of the adipose tissue. The intracellular lipolytic pathway in adipocytes is activated by adrenaline and noradrenaline, and inhibited by insulin. Circulating fatty acids are elevated in type 2 diabetic individuals.

A systems biology analysis of adrenergically stimulated adiponectin exocytosis in white adipocytes.

Circulating levels of the adipocyte hormone adiponectin are typically reduced in obesity, and this deficiency has been linked to metabolic diseases. It is thus important to understand the mechanisms controlling adiponectin exocytosis. This understanding is hindered by the high complexity of both the available data and the underlying signaling network.

An Updated Organ-Based Multi-Level Model for Glucose Homeostasis: Organ Distributions, Timing, and Impact of Blood Flow.

Glucose homeostasis is the tight control of glucose in the blood. This complex control is important, due to its malfunction in serious diseases like diabetes, and not yet sufficiently understood. Due to the involvement of numerous organs and sub-systems, each with their own intra-cellular control, we have developed a multi-level mathematical model, for glucose homeostasis, which integrates a variety of data.

Mechanisms of a Sustained Anti-inflammatory Drug Response in Alveolar Macrophages Unraveled with Mathematical Modeling.

Both initiation and suppression of inflammation are hallmarks of the immune response. If not balanced, the inflammation may cause extensive tissue damage, which is associated with common diseases, e.g.

Perturbation biology links temporal protein changes to drug responses in a melanoma cell line.

Cancer cells have genetic alterations that often directly affect intracellular protein signaling processes allowing them to bypass control mechanisms for cell death, growth and division. Cancer drugs targeting these alterations often work initially, but resistance is common. Combinations of targeted drugs may overcome or prevent resistance, but their selection requires context-specific knowledge of signaling pathways including complex interactions such as feedback loops and crosstalk.

Trigger factors in takotsubo syndrome - A systematic review of case reports.

Introduction: Takotsubo syndrome is an acute heart failure syndrome often preceded by a trigger factor of physical or emotional origin, although the proportion is unclear. The aim of the present study was to determine how common different trigger factors are in takotsubo syndrome divided by sex and age in women.

Material And Methods: The study consisted of a systematic review of all available case reports in PubMed and Web of Science up to March 2018.

Inhibition of FOXO1 transcription factor in primary human adipocytes mimics the insulin-resistant state of type 2 diabetes.

Type 2 diabetes is characterized by insulin resistance in the expanding adipose tissue of obesity. The insulin resistance manifests in human adipocytes as system-wide impairment of insulin signalling. An exception is the regulation of transcription factor FOXO1 (forkhead box protein O1), which is phosphorylated downstream of mTORC2 (mammalian/mechanistic target of rapamycin in complex with raptor) and is therefore not exhibiting impaired response to insulin.

Systems biology reveals uncoupling beyond UCP1 in human white fat-derived beige adipocytes.

Pharmaceutical induction of metabolically active beige adipocytes in the normally energy storing white adipose tissue has potential to reduce obesity. Mitochondrial uncoupling in beige adipocytes, as in brown adipocytes, has been reported to occur via the uncoupling protein 1 (UCP1). However, several previous in vitro characterizations of human beige adipocytes have only measured UCP1 mRNA fold increase, and assumed a direct correlation with metabolic activity.

Mathematical modeling of white adipocyte exocytosis predicts adiponectin secretion and quantifies the rates of vesicle exo- and endocytosis.

Adiponectin is a hormone secreted from white adipocytes and takes part in the regulation of several metabolic processes. Although the pathophysiological importance of adiponectin has been thoroughly investigated, the mechanisms controlling its release are only partly understood. We have recently shown that adiponectin is secreted via regulated exocytosis of adiponectin-containing vesicles, that adiponectin exocytosis is stimulated by cAMP-dependent mechanisms, and that Ca and ATP augment the cAMP-triggered secretion.

LASSIM-A network inference toolbox for genome-wide mechanistic modeling.

Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM), which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE) for gene regulatory networks (GRNs). LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets.

A systems biology analysis connects insulin receptor signaling with glucose transporter translocation in rat adipocytes.

Type 2 diabetes is characterized by insulin resistance, which arises from malfunctions in the intracellular insulin signaling network. Knowledge of the insulin signaling network is fragmented, and because of the complexity of this network, little consensus has emerged for the structure and importance of the different branches of the network. To help overcome this complexity, systems biology mathematical models have been generated for predicting both the activation of the insulin receptor (IR) and the redistribution of glucose transporter 4 (GLUT4) to the plasma membrane.

Cross-talks via mTORC2 can explain enhanced activation in response to insulin in diabetic patients.

The molecular mechanisms of insulin resistance in Type 2 diabetes have been extensively studied in primary human adipocytes, and mathematical modelling has clarified the central role of attenuation of mammalian target of rapamycin (mTOR) complex 1 (mTORC1) activity in the diabetic state. Attenuation of mTORC1 in diabetes quells insulin-signalling network-wide, except for the mTOR in complex 2 (mTORC2)-catalysed phosphorylation of protein kinase B (PKB) at Ser (PKB-S473P), which is increased. This unique increase could potentially be explained by feedback and interbranch cross-talk signals.

Systems-wide Experimental and Modeling Analysis of Insulin Signaling through Forkhead Box Protein O1 (FOXO1) in Human Adipocytes, Normally and in Type 2 Diabetes.

Insulin resistance is a major aspect of type 2 diabetes (T2D), which results from impaired insulin signaling in target cells. Signaling to regulate forkhead box protein O1 (FOXO1) may be the most important mechanism for insulin to control transcription. Despite this, little is known about how insulin regulates FOXO1 and how FOXO1 may contribute to insulin resistance in adipocytes, which are the most critical cell type in the development of insulin resistance.

Requirements for multi-level systems pharmacology models to reach end-usage: the case of type 2 diabetes.

We are currently in the middle of a major shift in biomedical research: unprecedented and rapidly growing amounts of data may be obtained today, from in vitro, in vivo and clinical studies, at molecular, physiological and clinical levels. To make use of these large-scale, multi-level datasets, corresponding multi-level mathematical models are needed, i.e.

Model-Based Quantification of the Systemic Interplay between Glucose and Fatty Acids in the Postprandial State.

In metabolic diseases such as Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease, the systemic regulation of postprandial metabolite concentrations is disturbed. To understand this dysregulation, a quantitative and temporal understanding of systemic postprandial metabolite handling is needed. Of particular interest is the intertwined regulation of glucose and non-esterified fatty acids (NEFA), due to the association between disturbed NEFA metabolism and insulin resistance.

Mathematical modeling improves EC50 estimations from classical dose-response curves.

Unlabelled: The β-adrenergic response is impaired in failing hearts. When studying β-adrenergic function in vitro, the half-maximal effective concentration (EC50 ) is an important measure of ligand response. We previously measured the in vitro contraction force response of chicken heart tissue to increasing concentrations of adrenaline, and observed a decreasing response at high concentrations.

A single mechanism can explain network-wide insulin resistance in adipocytes from obese patients with type 2 diabetes.

The response to insulin is impaired in type 2 diabetes. Much information is available about insulin signaling, but understanding of the cellular mechanisms causing impaired signaling and insulin resistance is hampered by fragmented data, mainly obtained from different cell lines and animals. We have collected quantitative and systems-wide dynamic data on insulin signaling in primary adipocytes and compared cells isolated from healthy and diabetic individuals.

Insulin signaling in type 2 diabetes: experimental and modeling analyses reveal mechanisms of insulin resistance in human adipocytes.

Type 2 diabetes originates in an expanding adipose tissue that for unknown reasons becomes insulin resistant. Insulin resistance reflects impairments in insulin signaling, but mechanisms involved are unclear because current research is fragmented. We report a systems level mechanistic understanding of insulin resistance, using systems wide and internally consistent data from human adipocytes.

Insulin signaling - mathematical modeling comes of age.

Signaling pathways that only a few years ago appeared simple and understandable, albeit far from complete, have evolved into very complex multi-layered networks of cellular control mechanisms, which in turn are integrated in a similarly complex whole-body level of control mechanisms. This complexity sets limits for classical biochemical reasoning, such that a correct and complete analysis of experimental data while taking the full complexity into account is not possible. In this Opinion we propose that mathematical modeling can be used as a tool in insulin signaling research, and we demonstrate how recent developments in modeling - and the integration of modeling in the experimental process - provide new possibilities to approach and decipher complex biological systems more efficiently.

Mechanistic explanations for counter-intuitive phosphorylation dynamics of the insulin receptor and insulin receptor substrate-1 in response to insulin in murine adipocytes.

Insulin signaling through insulin receptor (IR) and insulin receptor substrate-1 (IRS1) is important for insulin control of target cells. We have previously demonstrated a rapid and simultaneous overshoot behavior in the phosphorylation dynamics of IR and IRS1 in human adipocytes. Herein, we demonstrate that in murine adipocytes a similar overshoot behavior is not simultaneous for IR and IRS1.

A hierarchical whole-body modeling approach elucidates the link between in Vitro insulin signaling and in Vivo glucose homeostasis.

Type 2 diabetes is a metabolic disease that profoundly affects energy homeostasis. The disease involves failure at several levels and subsystems and is characterized by insulin resistance in target cells and tissues (i.e.