Mitic acid exhibit reduced glucose transporter expression, diminished glucose uptake and impairedG6P production, compared to normal b-cells [7]. Underlying this functional impairment there are multiple network disruptions including decreased HNF1A and FOXA2 nuclear localization, reduced transcription of the MGAT4A, GLUT1 and GLUT2 genes, and decreased abundance of plasma membrane-resident glucose transporters [7]. We verified that the model was able to capture all these experimental observations by simply perturbing the network at the level of HNF1A and FOXA2 translocation to the nucleus (Figure 3, red arrows). Introducing an inhibitory factor acting on these translocations produces, by itself, all the other observed alterations as well as the impairment of glucose transport. The complete model structure, parameter values and comparisons between model results and human experimental data are provided in the (Text S2), and are summarized in the Methods section. We also verified the model with glucose uptake measurements from normal b-cells co-cultured with LacNAc and (LacNAc)3 glycans [7] (Figure 4). These glycans compete with the GNT-4A-glycosylated glucose transporters for binding to b-cell lectins that promote cell surface residency, thereby resulting in reduced expression of GLUT-1 (75 of normal with LacNAc and 57 with (LacNAc)3) and GLUT-2 (80 and 48 , respectively). In healthy human b-cells, GLUT-1 is the predominantly expressed transporter; however, GLUT-2 is also expressed at lower level [7,12,24]. From these and other observations, we assumed that, in healthy human b-cells, ,80 of plasma membrane glucose transporters are GLUT-1 and ,20 are GLUT-2. Nevertheless, the higher value of Vmax ,healthy for GLUT2 means that a KPT-9274 single molecule of GLUT-2 transports more glucose than a single molecule 18325633 of GLUT-1. Therefore, GLUT-2 accounts for the majority of glucose transport even if it is expressed at much lower levels than GLUT-1. Simulating glucose transporter expression in a b-cell from a T2D donor, by inhibiting HNF1A and FOXA2 translocation to the nucleus, without further modifications, we calculated that in disease conditions 92 of the glucose transporters present at the b-cell surface are GLUT-1 and 8 are GLUT-2. Thus, also in human T2D b-cells, GLUT-1 remains the most abundant transporter at plasma membrane.Modeling Glucose Transport in Pancreatic b-CellsFigure 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 IOX2 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. ?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. doi:10.1371/journal.pone.0053130.gControl Point IdentificationThe full mathematical model provides a link between glucose transporter expression and specific intracellular biological components affecting their residency at the cell membrane. Thus, points of this regulatory network that are more sensitive targets of therapeutic intervention can be investigated to identify best strategies for restoring normal glucose transport and b-cell function.We used the.Mitic acid exhibit reduced glucose transporter expression, diminished glucose uptake and impairedG6P production, compared to normal b-cells [7]. Underlying this functional impairment there are multiple network disruptions including decreased HNF1A and FOXA2 nuclear localization, reduced transcription of the MGAT4A, GLUT1 and GLUT2 genes, and decreased abundance of plasma membrane-resident glucose transporters [7]. We verified that the model was able to capture all these experimental observations by simply perturbing the network at the level of HNF1A and FOXA2 translocation to the nucleus (Figure 3, red arrows). Introducing an inhibitory factor acting on these translocations produces, by itself, all the other observed alterations as well as the impairment of glucose transport. The complete model structure, parameter values and comparisons between model results and human experimental data are provided in the (Text S2), and are summarized in the Methods section. We also verified the model with glucose uptake measurements from normal b-cells co-cultured with LacNAc and (LacNAc)3 glycans [7] (Figure 4). These glycans compete with the GNT-4A-glycosylated glucose transporters for binding to b-cell lectins that promote cell surface residency, thereby resulting in reduced expression of GLUT-1 (75 of normal with LacNAc and 57 with (LacNAc)3) and GLUT-2 (80 and 48 , respectively). In healthy human b-cells, GLUT-1 is the predominantly expressed transporter; however, GLUT-2 is also expressed at lower level [7,12,24]. From these and other observations, we assumed that, in healthy human b-cells, ,80 of plasma membrane glucose transporters are GLUT-1 and ,20 are GLUT-2. Nevertheless, the higher value of Vmax ,healthy for GLUT2 means that a single molecule of GLUT-2 transports more glucose than a single molecule 18325633 of GLUT-1. Therefore, GLUT-2 accounts for the majority of glucose transport even if it is expressed at much lower levels than GLUT-1. Simulating glucose transporter expression in a b-cell from a T2D donor, by inhibiting HNF1A and FOXA2 translocation to the nucleus, without further modifications, we calculated that in disease conditions 92 of the glucose transporters present at the b-cell surface are GLUT-1 and 8 are GLUT-2. Thus, also in human T2D b-cells, GLUT-1 remains the most abundant transporter at plasma membrane.Modeling Glucose Transport in Pancreatic b-CellsFigure 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. ?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. doi:10.1371/journal.pone.0053130.gControl Point IdentificationThe full mathematical model provides a link between glucose transporter expression and specific intracellular biological components affecting their residency at the cell membrane. Thus, points of this regulatory network that are more sensitive targets of therapeutic intervention can be investigated to identify best strategies for restoring normal glucose transport and b-cell function.We used the.

Mitic acid exhibit reduced glucose transporter expression, diminished glucose uptake and

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