Figure 1.
Overview of human hepatocyte model consisting of glycolysis, gluconeogenesis and glycogen metabolism.
Metabolic model compartmentalized in blood, cytosol and mitochondrion. Key enzymes of HGP are shown in red, key enzymes of HGU in green. Enzymes regulated via allosteric mechanisms are marked with a red A, interconvertible enzymes with a yellow P. Insulin, glucagon and epinephrine regulate the glucose metabolism by changing the phosphorylation state of key interconvertible enzymes, with insulin (
+) decreasing and epinephrine (
+) and glucagon (
) increasing
. See Methods for additional information. Reactions: (ALD) aldolase, (AK) adenylate kinase, (CS) citrate synthase, (EN) enolase, (FBP1) fructose-1,6 bisphosphatase, (FBP2) fructose-2,6 bisphosphatase, (GAPDH) glyceraldehyde phosphate dehydrogenase, (G1PI) glucose-1 phosphate 1,6-phosphomutase, (G6P) glucose-6 phosphatase, (GK) glucokinase, (GLUT2) glucose transporter 2, (GP) glycogen phosphorylase, (GPI) glucose-6 phosphate isomerase, (GS) glycogen synthase, (LDH) lactate dehydrogenase, (MALT) malate transporter, (MDH) malate dehydrogenase, (NDK) nucleoside diphospate kinase, (PC) pyruvate carboxylase, (PEPCK) phosphoenolpyruvate cyrboxykinase, (PEPT) phosphoenolpyruvate transporter, (PDH) pyruvate dehydrogenase, (PFK1) phosphofructokinase 1, (PFK2) phosphofructokinase 2, (PGK) phosphoglycerate kinase, (PGM) 3-phosphoglycerate mutase, (PK) pyruvate kinase, (PPASE) pyrophosphate phosphohydrolase, (PYRT) pyruvate transporter, (TPI) triose phosphate isomerase, (UGT) UTP:glucose-1 phosphate uridylyltransferase. Metabolites: (13P2G) 1,3-bisphospho glycerate, (2PG) 2-phospho glycerate, (3PG) 3-phospho glycerate, (ACoA) acetyl-coA, (Cit) citrate, (CoA) coenzyme A, (DHAP) dihydroxyacetone phosphate, (Fru16P2) fructose-1,6 bisphosphate, (Fru26P2) fructose-2,6 bisphosphate, (Fru6P) fructose-6 phosphate, (Glc) glucose, (Glc1P) glucose-1 phosphate, (Glc6P) glucose-6 phosphate, (GRAP) glyceraldehyde 3-phosphate, (Lac) lactate, (OA) oxalacetate, (Mal) malate, (P) phosphate, (PEP) phosphoenolpyruvate, (PP) pyrophosphate, (Pyr) pyruvate, (UDP-Glc) UDP-glucose.
Figure 2.
Glucose-Hormone Responses (GHR) of insulin, glucagon and epinephrine and phosphorylation state .
Experimental data from multiple studies based on oral glucose tolerance tests and hypoglycemic, hyperinsulinemic clamp studies and the corresponding fitted GHR curves. Parameters for the GHR curves in Table 1 and experimental data in Dataset S1. (A) Glucagon GHR. Glucagon increases with decreasing blood glucose from a basal concentration of 37.9 pmol/l to a maximal concentration of 190.0 pmol/l with the inflection point at 3.01 mM (B) Epinephrine GHR. Epinephrine increases with decreasing glucose from a basal concentration of 100 pmol/l to a maximal concentration of 6090 pmol/l with the inflection point at 3.1 mM (C) Insulin GHR. Insulin increases with increasing glucose from a basal concentration of 0 pmol/l to a maximal concentration of 818.9 pmol/l with the inflection point at 8.6 mM (D) Resulting phosphorylation state (Equation 5) based on the GHRs for insulin, glucagon and epinephrine decreasing with increasing glucose from phosphorylated to dephosphorylated.
Table 1.
Fit functions and parameters for the insulin, glucagon and epinephrine GHR.
Table 2.
Experimental data for HGP, gluconeogenesis (GNG), glycogenolysis (GLY).
Figure 3.
HGP, gluconeogenesis (GNG), glycogenolysis (GLY) and GNG/HGP in short term fasting over 70 h.
Experimental data from 25 separately published studies based on a variety of different labeling approaches listed in Table 2 and given in Dataset S1. Simulation time courses (dashed lines) start at t = 10 h with glycogen partially filled glycogen stores (350 mM). Blood glucose is varied between 3.6 mM (red) and 4.6 mM (green) in steps of 0.2 mM. The blue curve corresponds to a situation where the plasma glucose concentration changes over the time of fasting from 4.2 mM to 3.6 mM in 70 h. (A) HGP decreases with increasing fasting time and reaches constant levels after around 25 h. With decreasing blood glucose HGP increases. (B) gluconeogenesis is almost constant over time. With decreasing blood glucose GNG increases (C) glycogenolysis decreases over time with decreasing glycogen. Lower blood glucose results in an initially higher GLY rate (D) GNG/HGP. The relative contribution of gluconeogenesis to the hepatic glucose production increases over time. After 40 h fasting over 90% of the produced glucose comes from de novo synthesis.
Figure 4.
Glycogen metabolism and hormone perturbations.
(A) Decrease in glycogen during short term fasting over 60 h. Experimental data from [22] (individual data) and [23] (mean data with STD) given in Dataset S1. Simulation time courses (dashed lines) start from filled glycogen stores (500 mM). Blood glucose is varied between 3.6 mM (red) and 5.0 mM (green) in steps of 0.2 mM (black). The blue curve corresponds to a situation where the plasma glucose concentration changes from initially 5 mM to 3.6 mM in 60 h. Higher blood glucose results in a slower decrease in glycogen. (B) Increase in glycogen after a glucose load. Experimental data from [8], [24], [25] given in Dataset S1. Simulation time courses (dashed lines) start from initial glycogen concentration of 200 mM. Blood glucose concentrations are varied between 5.5 mM (red) and 8.0 mM (green) in steps of 0.5 mM (black). The blue line corresponds to 7 mM. Higher blood glucose results in a faster increase in glycogen after a glucose load. (C) Change in HGP and plasma glucose in insulin deficiency. Insulin (blue) and glucagon (red) time courses for an idealized hormone perturbation (left), the experimental data from [27] (middle), and a simulation taking the experimental profile of hormones and glucose utilization into account are shown in the top row. Middle row depicts the time courses of HGP (red) and whole-body glucose utilization GU (black). Bottom row shows the resulting change in plasma glucose as a consequence of the changes in HGP. Insulin deficiency increases HGP relative to GU resulting in an increase in plasma glucose. After insulin normalization HGP decreases and falls below GU due to the increased blood glucose. (D) Changes in HGP during the infusion period (135–200 min) relative to the pre-infusion period (85–135 min) for the simulations and experiments and the various hormone perturbations. Saline infusion (Figure S1) and somatostatin infusion with insulin and glucagon restauration (Figure S5) have no effect on basal HGP. Insulin and glucagon deficiency (Figure S2) and glucagon deficiency alone (Figure S3) decrease HGP relative to basal values. Insulin deficiency increases basal HGP (Figure 4C, Figure S4).
Figure 5.
Steady state solution of time course simulations under constant glycogen and blood glucose concentration (every data points correspond to a single simulation to steady state). Glycogen is varied between 0 and 500 mM in steps of 5 mM, blood glucose is varied between 2 and 14 mM in steps of 0.05 mM. (A) HGP (red)/HGU (green) ([]) corresponding to GLUT2 flux. The liver switches between HGP and HGU depending on the blood glucose and glycogen. The set point varies between 5.4 mM for empty and 7.5 mM for completely filled glycogen stores (6.6 mM at glycogen 250 mM). (B) HGRC ([
]). Response of the liver to changes in the blood glucose. Two main regions of high response exist: A hypoglycemic region below 4 mM, and a hyperglycemic region above 8 mM glucose. (C) gluconeogenesis (red)/glycolysis (green) ([
]) corresponding to glucose-6p isomerase (GPI) flux. The gluconeogenesis/glycolysis set point varies between 8.8 mM for empty and 7.0 mM for filled glycogen stores. (D) glycogenolysis (red)/glycogenesis (green) ([
]) corresponding to flux through glucose-1p isomerase (G1PI).
Table 3.
Comparison of model predictions and experiments.