Figure 1.
Intracellular kinetics of the first steps of pancreatic β-cell glycolysis in health and T2D.
A change in plasma glucose concentration from 2.8 mM to 16.8 mM was applied as an input to the model. Net GLUT1-dependent glucose uptake was calculated as the difference between inwards and outwards rates, and
. Net GLUT2-dependent uptake was calculated analogously. Phosphorylated glucose concentration includes also the concentration of its derivates in the pathway that are not explicitly modeled. Black lines refer to the behavior of healthy β-cells, gray lines represent behavior of β-cells from T2D donors.
Figure 2.
Comparison of glucose transport and phosphorylation in health and T2D β-cells.
(A) GLUT-1 and GLUT-2 outwards rates ( and
, respectively), and GK kinetics as a function of intra-cellular glucose concentration for normal (
) glucose transporters’ expression and reduced GLUT-2 expression (
). (B) Steady-state GK rate calculated at 16.8 mM extra-cellular glucose concentration as a function of concerted GLUT-1 and GLUT-2 deficiency. ε1 and ε2 are the fractions of GLUT-1 and GLUT-2, respectively, compared to normal. The solid line indicates the threshold between transport- and phosphorylation-limited G6P formation (derived in (A)), whereas asterisks indicate the positions of T2D patients β-cells. Inset represents an enlargement of the lower left region.
Figure 3.
Schematic representation of the processes included in the mathematical model.
The six subsystems discussed in the text are highlighted and denoted by roman numbers. Thick blue arrows indicate activation of transcription by promoter binding and histone hyperacetylation, thin blue arrows activation only by promoter binding; red bars indicate an inhibitory effect on nuclear residency of transcription factors. Ø symbol indicates degradation, hexagons the glycosylated forms of the proteins. Green arrows show the path of glucose entrance into the cell, its phosphorylation, and the ultimate activation of insulin secretion.
Figure 4.
Glucose uptake as a function of membrane glucose transporters’ expression.
Comparison between experimental data (white) (Ohtsubo et al., 2011) and model results (black) of glucose uptake at 10 mM extracellular glucose concentration, for β-cells from healthy and T2D patients, and for cells from healthy donors treated with LacNAc and (LacNAc)3, as indicated. Error bars represent standard deviation of the data. The percentage of GLUT-1 and GLUT-2 expression compared to healthy β-cells is also indicated in each case.
Figure 5.
Therapeutic sensitivity analysis among pathway components.
Steady-state sensitivity of GK rate in T2D cells with respect to elevation in the RNA abundance of the genes indicated, at two plasma glucose concentrations, as shown in the legend. The sensitivity coefficients are normalized with respect to the GK rate and abundance of the RNAs among β-cells.