Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism

König, Matthias; Bulik, Sascha; Holzhütter, Hermann−Georg

doi:10.1371/journal.pcbi.1002577

Cited by 184 publications

(175 citation statements)

References 61 publications

(69 reference statements)

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“…Herein, we have contributed with a link to intracellular knowledge from adipocyte insulin signaling, but there are models of liver metabolism [214,215], pancreatic insulin release [216,217], and brain control of glucose homeostasis [218,219], which could potentially further expand the presented multi-level model. Of great interest are, of course, also models of control of skeletal muscle insulin signaling and metabolism.…”

Section: General Discussion and Future Perspectivesmentioning

confidence: 99%

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Nyman¹

2014

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Type 2 diabetes is characterized by raised blood glucose levels caused by an insufficient insulin control of glucose homeostasis. This lack of control is expressed both through insufficient release of insulin by the pancreatic beta-cells, and through insulin resistance in the insulin-responding tissues. We find insulin resistance of the adipose tissue particularly interesting since it appears to influence other insulin-responding tissues, such as muscle and liver, to also become insulin resistant.The insulin signaling network is highly complex with cross-interacting intermediaries, positive and negative feedbacks, etc. To facilitate the mechanistic understanding of this network, we obtain dynamic, information-rich data and use model-based analysis as a tool to formally test different hypotheses that arise from the experimental observations. With dynamic mathematical models, we are able to combine knowledge and experimental data into mechanistic hypotheses, and draw conclusions such as rejection of hypotheses and prediction of outcomes of new experiments.We aim for an increased understanding of adipocyte insulin signaling and the underlying mechanisms of the insulin resistance that we observe in adipocytes from subjects diagnosed with type 2 diabetes. We also aim for a complete picture of the insulin signaling network in primary human adipocytes from normal and diabetic subjects with a link to relevant clinical parameters: plasma glucose and insulin. Such a complete picture of insulin signaling has not been presented before. Not for adipocytes and not for other types of cells.In this thesis, I present the development of the first comprehensive insulin signaling model that can simulate both normal and diabetic data from adipocytes -and that is linked to a whole-body glucose-insulin model. In the linking process we conclude that at least two glucose uptake parameters differ between the in vivo and in vitro conditions (Paper I). We also perform a model analysis of the early insulin signaling dynamics in rat adipocytes and conclude that internalization is important for an apparent reversed order of phosphorylation seen in these cells (Paper II). In the development of the first version of the comprehensive insulin signaling model, we introduce a key parameter for the diabetic state -an attenuated feedback (Paper III). We finally continue to build on the comprehensive model and include signaling to nuclear transcription via ERK and report substantial crosstalk in the insulin signaling network (Paper IV). Populärvetenskaplig sammanfattningTyp 2-diabetes är en vanligt förekommande sjukdom där kroppens vävnader förlorar sin känslighet mot hormonet insulin. Insulinets uppgift är att hålla en jämn blodsockernivå dygnet runt. Insulin utsöndras i samband med måltider och påverkar muskel-och fettvävnader att ta upp socker och levern att sluta producera socker. Det är viktigt att hålla en jämn blodsockernivå eftersom låga nivåer kan vara direkt dödligt och höga nivåer är skadligt för blodkärlen, vilket i sin tur kan led...

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Section: General Discussion and Future Perspectivesmentioning

confidence: 99%

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Nyman¹

2014

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“…[54] The liver is a central player in buffering plasma glucose contributing either by net hepatic glucose utilization or net hepatic glucose production depending on the plasma glucose level. [55] P. longum has revealed hepatoprotective action [56] and balances enzymatic and non-enzymatic antioxidants levels by lessening oxidative stress which is the major contributor of diabetes. [57] Nabi et al have reported duel action of Piper longum by presenting antidiabetic (reducing blood glucose level) action as well as hepatoprotective (significantly reduced the level of triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, very LDL -cholesterol, and serum enzymes) action.…”

Section: Indications Referencesmentioning

confidence: 99%

Untitled

Reddy

2017

IJGP

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Over the past three decades, the number of people with diabetes mellitus (DM) has doubled globally, making it one of the most important public health challenges to all nations. This has been stimulating the development of novel and potentially more effective therapeutic approaches to treat the disease. Even after the availability of a massive amount of hypoglycemic drugs in conventional system, herbals are gaining much attention because of its spectacular therapeutic potential and also help to sustain the healthy condition of the body. In this review article, a highly valuable drug Pippali (Piper longum) has been evaluated on the basis of its pharmacognostical, pharmacological, and therapeutical background. The plant possesses significant antidiabetic activity. The systemic dysfunction associated with DM can also be cured by Pippali. Plant through exhibiting synergistic action gives a valuable response in hepatic, digestive, cardiac, and respiratory disorders. The purpose of this review is to enlighten all the remedial aspects of P. longum with a special focus on its antidiabetic potential.

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“…In many cases, the processes represented in the model contain several intermediate enzymes and the constants were based on the literature for the rate limiting enzyme in the process. Previous models have represented each individual enzyme separately (e.g., Konig et al 44 ). However, here we focus on key rate limiting enzymes, and those which show variation in activity across the sinusoid.…”

Section: Zonated Model Of Glucose and Lipid Metabolismmentioning

confidence: 99%

Liver function as an engineering system

et al. 2016

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Process Systems Engineering has tackled a wide range of problems including manufacturing, the environment, and advanced materials design. Here we discuss how tools can be deployed to tackle medical problems which involve complex chemical transformations and spatial phenomena looking in particular at the liver system, the body's chemical factory. We show how an existing model has been developed to model distributed behavior necessary to predict the behavior of drugs for treating liver disease. The model has been used to predict the effects of suppression of de novo lipogenesis, stimulation of b-oxidation and a combination of the two. A reduced model has also been used to explore the prediction of behavior of hormones in the blood stream controlling glucose levels to ensure that levels are kept within safe bounds using interval methods. The predictions are made resulting from uncertainty in two key parameters with oscillating input resulting from regular feeding. V C 2016 The Authors AIChE Journal published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers AIChE J, 62: 3285-3297, 2016 Keywords: mathematical modeling, biomedical engineering, systems biology, medical, controlThe liver, its regulation, and its diseases Why systems engineering of the liver?Systems Engineering is the discipline of the management of complex engineering systems over their whole life cycle. Process Systems Engineering is the study of complex process engineering systems involving chemical and physical change. Prof Roger Sargent was a pioneer from the 1950s in seeing the potential that computers could have to revolutionize the way that we tackled these problems.1 He also saw the way Chemical Engineering was broadening its base into molecular and biological systems to improve manufacturing. 1,2The liver is one part of a very complex processing system which ensures that all parts of the body receive the energy and nutrients that they need, that waste products are removed efficiently from the various streams, and that short and long term well being are maintained. It is the body's central chemical processing organ. Considering the liver system as one which controls chemical and physical change within the body, particularly of nutrition, makes it a legitimate area of study for Process Systems Engineers. A number of Chemical Engineers have also contributed to the use for Process Systems Engineering to a range of medical applications. Bogle 3 reviews recent

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Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism

Cited by 184 publications

References 61 publications

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Insulin signaling dynamics in human adipocytes : Mathematical modeling reveals mechanisms of insulin resistance in type 2 diabetes

Untitled

Liver function as an engineering system

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