Abstract
Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases.
Highlights
The human plasma glucose is kept in a narrow range between minimum values of,3 mM after prolonged fasting or extensive muscle activity and maximum values of,9 mM reached postprandially [1,2]
Blood glucose is controlled in a narrow range to guarantee constant supply and on the other hand avoid damages associated with elevated glucose levels
Our model enables for the first time to simulate hepatic glucose metabolism in depth
Summary
The human plasma glucose is kept in a narrow range between minimum values of ,3 mM after prolonged fasting or extensive muscle activity and maximum values of ,9 mM reached postprandially [1,2]. Homoeostasis of plasma glucose is crucial for the organism: Hyperglycemia results in non-enzymatic glycosylation (glycation) and loss-of-function of proteins [3], glucose induced oxidative damage [4,5] and other adverse effects [6,7]. Switching between HGP and HGU is a switch between positive (i.e. export of glucose) and negative (i.e. import of glucose) net hepatic glucose balance. This crucial metabolic function of the liver is performed by hepatocytes which exhibit high capacity of glycogenesis, glycogenolysis, glycolysis and gluconeogenesis enabling them to transiently store substantial amounts of glucose as glycogen, to synthesize glucose from lactate, glycerol and glucoplastic amino acids and to convert excess glucose into triglycerides [2,8,9]
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