Modeling Studies of the Dynamic Control of Hepatic Glucose Balance

The survival of mammals is dependent upon a relatively constant, adequate supply of glucose to the central nervous system, despite large fluctuations in the amount of food available. When food is abundant, the liver stores ingested carbohydrate as glycogen, and during fasts, the stored glycogen is released at a precisely regulated rate to maintain the blood glucose level. The rates of storage and release of carbohydrate by the liver are determined by the plasma concentrations of several bloodborne signals; most important are the concentrations of glucose, and the hormones insulin and glucagon. To understand the complex control relationships of these three signals as they affect the liver, their individual dynamic influences have been determined experimentally, and they have been integrated by means of a computer simulation of the pathways of hepatic glycogen metabolism. The simulation studies have led to specific hypotheses about the biochemical effects of glucose and insulin on the liver. The simulation studies have also led to the conclusion that glucose exerts a rapid moment-to-moment influence of glucose on the rate of uptake of glucose by the liver. Insulin, however, by exerting a slower influence on the sensitivity of the liver to glucose, is very effective in “optimizing” the amount of glycogen which the liver stores food during food intake. Thus, integrated experimental and simulation studies can lead to a view of a physiological regulating system which does not emerge from either approach used alone.