Skeletal muscle fuel utilization in healthy and dysregulated states

industrial collaborators:	Unilever
academic collaborators:	ESGI59
initiated :	2007/08/31
last updated:	2010/05/25

Study group report 2007: skeletal muscle (Unilever)
This is the final report on the problem of developing a mathematical model of skeletal muscle fuel utilisation, brought to ESGI59 by Unilever. Click on the link at the bottom to download the full report as a pdf document.

Report authors
Jonathan Wattis (University of Nottingham)

Executive summary

The average human diet consists of a combination of carbohydrates (50%) and lipids (fats, 30%), delivered as meals in a discontinuous manner. Human physiology has evolved mechanisms that enable it to cope with discontinuities in the supply of and the demand for energy. In the healthy state, the organs respond to plasma (blood) nutrient levels through a series of well-controlled mechanisms, such that energy is stored at times of surplus and is released at times of requirement. Efficient handling of post-prandial nutrients results in a minimal glucose response, appropriate insulin secretion, suppression of stored lipid mobilization and oxidation, along with activation of energy uptake into tissues for storage. Thus healthy carbohydrate and lipid metabolism is dependent upon the coordinated regulation of the organs governing carbohydrate and lipid fluxes, namely the brain, pancreas, liver, skeletal muscle and adipose tissue.

In lean, healthy individuals there is a high reliance upon lipid oxidation with high rates of fatty acid uptake during fasting conditions. In addition healthy tissue displays metabolic flexibility, that is, it is capable of switching between lipid oxidation in the fasted state and the suppression of lipid oxidation in favour of increased glucose uptake, oxidation and storage during the fed state [2]. In obese subjects, there is a lesser reliance on lipid and a greater reliance on glucose oxidation in both the fed and the fasted states.

This reduction in the ability to switch between fuel types in obese subjects is characteristic of insulin resistant states such as obesity and Type 2 diabetes [6]. Subjects with such conditions exhibit failure to increase lipid oxidation in the fasted state and failure to suppress lipid oxidation in response to increased insulin levels.

In skeletal muscle of a lean, healthy individual, insulin strongly suppresses lipid oxidation during insulin-stimulated (fed) conditions and induces a high reliance upon glucose oxidation, whereas in skeletal muscle of an obese, insulin resistant individual, there is less stimulation of glucose oxidation by insulin and blunted suppression of lipid oxidation. Thus, in the skeletal muscle of obese, insulin resistant individuals, there is a constricted range in switching between lipid and glucose oxidation compared to the dynamic switching observed in lean, healthy individuals. This constrained homeostatic adjustment to the transitions between fasting and insulin-stimulated conditions in obese, insulin resistant individuals has been described as ‘metabolic inflexibility’ of skeletal muscle.

We aim to develop a mathematical model of skeletal muscle fuel utilization, that will enable an investigation of the dynamics of skeletal muscle glucose and lipid handling in response to a meal. The model should:

• initially aim to reproduce data that describe the effect of an individual’s fat mass and insulin sensitivity on the preference for fat/glucose oxidation in myocytes (metabolic flexibility of muscle cells);
• aim to simulate the effects of different rates of delivery of glucose and lipid to skeletal muscle in the fed and fasted states;
• allow us to investigate the effects of varying glucose and fatty acid availability on preference for fat oxidation in individuals with different phenotypes (varied body mass index, fat mass and insulin sensitivity).

In Section 2, we construct a model of a muscle cell, including

• the transport of glucose and lipids from the blood stream into the cells,
• the cell’s internal storage of glucose as glycogen, and
• the glucose and lipid oxidation processes.

We show that the system has a physically-relevant steady-state solution (Section 2.2). When nondimensionalising the model (Section 2.3) to make the numerical solutions more straightforward we obtain a number of constraints on the relative sizes of parameter groups (Section 2.4). Section 3 contains a description of the results of our numerical solutions, and conclusions are drawn in Section 4.

 

related resources:

	Skeletal muscle fuel utilization in healthy and dysregulated states
»	Study group report 2007: skeletal muscle (Unilever)

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