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A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism.

ABSTRACT: The capacity of the liver to convert the metabolic input received from the incoming portal and arterial blood into the metabolic output of the outgoing venous blood has three major determinants: The intra-hepatic blood flow, the transport of metabolites between blood vessels (sinusoids) and hepatocytes and the metabolic capacity of hepatocytes. These determinants are not constant across the organ: Even in the normal organ, but much more pronounced in the fibrotic and cirrhotic liver, regional variability of the capillary blood pressure, tissue architecture and the expression level of metabolic enzymes (zonation) have been reported. Understanding how this variability may affect the regional metabolic capacity of the liver is important for the interpretation of functional liver tests and planning of pharmacological and surgical interventions. Here we present a mathematical model of the sinusoidal tissue unit (STU) that is composed of a single sinusoid surrounded by the space of Disse and a monolayer of hepatocytes. The total metabolic output of the liver (arterio-venous glucose difference) is obtained by integration across the metabolic output of a representative number of STUs. Application of the model to the hepatic glucose metabolism provided the following insights: (i) At portal glucose concentrations between 6-8 mM, an intra-sinusoidal glucose cycle may occur which is constituted by glucose producing periportal hepatocytes and glucose consuming pericentral hepatocytes, (ii) Regional variability of hepatic blood flow is higher than the corresponding regional variability of the metabolic output, (iii) a spatially resolved metabolic functiogram of the liver is constructed. Variations of tissue parameters are equally important as variations of enzyme activities for the control of the arterio-venous glucose difference.

SUBMITTER: Berndt N

PROVIDER: S-EPMC5841820 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism.

Berndt Nikolaus N Horger Marius Stefan MS Bulik Sascha S Holzhütter Hermann-Georg HG

PLoS computational biology 20180215 2

The capacity of the liver to convert the metabolic input received from the incoming portal and arterial blood into the metabolic output of the outgoing venous blood has three major determinants: The intra-hepatic blood flow, the transport of metabolites between blood vessels (sinusoids) and hepatocytes and the metabolic capacity of hepatocytes. These determinants are not constant across the organ: Even in the normal organ, but much more pronounced in the fibrotic and cirrhotic liver, regional va ...[more]

PMID: 29447152

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Project description:Stable isotopes are currently used to measure glucose fluxes responsible for observed glucose concentrations, providing information on hepatic and peripheral insulin sensitivity. The determination of glucose turnover, along with fasting and postprandial glucose concentrations, is relevant for inferring insulin sensitivity levels. At equilibrium (e.g. during the fasting state) the rate of glucose entering the circulation equals its rate of disappearance from the circulation. If under these conditions tracer is infused at a constant rate and Specific Activity (SA) or Tracer to Tracee (TTR) ratio is computed, the Rate of Appearance (RA) equals the Rate of Disappearance (RD) and equals the ratio between infusion rate and TTR or SA. In the post-prandial situation or during perturbation studies, however, estimation of RA and RD becomes more complex because they are not necessarily equal and, furthermore, may vary over time due to gastric emptying, glucose absorption, appearance of ingested or infused glucose, variations of EGP and glucose disappearance. Up to now, the most commonly used approach to compute RA, RD and EGP has been the single-pool model by Steele. Several authors, however, report pitfalls in the use of this method, such as "paradoxical" increase in EGP immediately after meal ingestion and "negative" rates of EGP. Different attempts have been made to reduce the impact of these errors, but the same problems are still encountered. In the present work a completely different approach is proposed, where cold and labeled [6, 6-2H2] glucose observations are simultaneously fitted and where both RD and EGP are represented by simple but reasonable functions. As an example, this approach is applied to an intra-venous experiment, where cold glucose is infused at variable rates to reproduce a desired glycaemic time-course. The goal of the present work is to show that appropriate, if simple, modelling of the whole infusion procedure together with the underlying physiological system allows robust estimation of EGP with single-tracer administration, without the artefacts produced by the Steele method.

Dataset Information

A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism.

Publications

A multiscale modelling approach to assess the impact of metabolic zonation and microperfusion on the hepatic carbohydrate metabolism.

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