A Whole-Body Model for Glycogen Regulation Reveals a Critical Role for Substrate Cycling in Maintaining Blood Glucose Homeostasis

Abstract

Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active) and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile) cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into “whole-body” contextual models that mimic in vivo conditions.

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

“…Taken together, metabolic regulation via phosphorylation/dephosphorylation of key enzymes in combination with futile cycles plays a key role in our model, in line with the results presented by Xu et al [34].…”

Enteral Energy and Macronutrients in End‐Stage Liver Disease

“…Hepatic dysfunction has been associated with enhanced futile metabolic cycles, as well as loss of energy in the form of heat 17 , 27 . Examples of futile cycles include the conversion of glucose to glycogen, which is then followed by glycogenolysis and glucose recycling, as well as the hydrolysis of triglycerides to free fatty acids, which are then reesterified to triglycerides.…”

“…Examples of futile cycles include the conversion of glucose to glycogen, which is then followed by glycogenolysis and glucose recycling, as well as the hydrolysis of triglycerides to free fatty acids, which are then reesterified to triglycerides. These cycles also occur at low levels in healthy people, primarily in the fasted state; they are thought to expedite the response time from the fed to the fasted state and vice versa 27 . Loss of energy as heat occurs during the futile metabolic cycles and also during the uncoupling of oxidative phosphorylation from respiration, mediated by the effects of free fatty acids 17 …”

The Molecular Size Distribution of Glycogen and its Relevance to Diabetes

“…The second is shear scission; however, for highly branched molecules of the size of glycogen, this effect can be minimised with an appropriate flow rate. [32] Technical Improvements in SEC Characterisation of Glycogen While past studies that have obtained size distributions of native glycogen using SEC have employed a dimethyl sulfoxide/ lithium bromide (DMSO/LiBr) eluent, it has recently been shown [33] that aqueous SEC results in significantly improved resolution, with the a-and b-particle peaks being better separated than in DMSO. There have however been several encouraging studies using aqueous SEC to characterise synthetic and commercial glycogen.…”