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

Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
PLoS Computational Biology (Impact Factor: 4.83). 12/2011; 7(12):e1002272. DOI: 10.1371/journal.pcbi.1002272
Source: PubMed

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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Glycogen is a highly branched polymer of glucose, functioning as a blood-glucose buffer. It comprises relatively small beta-particles, which may be joined as larger aggregate alpha-particles. The size distributions from size-exclusion chromatography (SEC, also known as GPC) of liver glycogen from non-diabetic and diabetic mice show that diabetic mice have impaired alpha-particle formation, shedding new light on diabetes. SEC data also suggest the type of bonding holding beta-particles together in alpha-particles. SEC characterisation of liver glycogen at various time points in a day/night cycle indicates that liver glycogen is initially synthesised as beta-particles, and then joined by an unknown process to form alpha-particles. These alpha-particles are more resistant to degradation, presumably because of their lower surface area-to-volume ratio. These findings have important implications for new drug targets for diabetes management.
    Australian Journal of Chemistry 01/2014; 67(4):538. DOI:10.1071/CH13573 · 1.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The preproglucagon gene (Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis. Copyright © 2015 the American Physiological Society.
    Physiological Reviews 04/2015; 95(2):513-548. DOI:10.1152/physrev.00013.2014 · 29.04 Impact Factor
  • Journal of Parenteral and Enteral Nutrition 09/2014; 39(3). DOI:10.1177/0148607114551026 · 3.14 Impact Factor