Al b-cell function and the maintenance of glucose homeostasis. In Type

Al b-cell function and the maintenance of MedChemExpress HIF-2��-IN-1 glucose homeostasis. In Type 2 diabetes (T2D), b-cells appear defective in sensing glucose, and this has recently been linked with diminished expression of both GLUT-1 and GLUT-2 glucose transporters[5,6]. Deficiency of glucose transporter expression and glucose uptake among normal b-cells causes b-cell dysfunction with loss of the GSIS response [7]. A MedChemExpress SR-3029 similar study in mice administered a high-fat diet indicated that diminished b-cell Glut-2 expression contributed to disease pathogenesis, while preservation of b-cell glucose transport and GSIS prevented b-cell failure and the onset of obesity-associated diabetes [8]. Those studies further reported a conserved sequence of molecular events in human and mouse bcells initiated by elevated levels of free fatty acids, transmitted by nuclear exclusion and down-modulation of HNF1A and FOXA2 transcription factors, and affected by GNT-4A glycosyltransferase deficiency. These events were found to diminish expression of GLUT-1 and GLUT-2 with markedly reduced glucose transport and loss of GSIS, and revealed that an acquired deficiency of bcell glucose transport promotes the pathogenesis of diabetes. Glucokinase (GK) activity is normally the limiting factor in bcell glucose utilization [9]. Upon entering the b-cell, glucose is rapidly phosphorylated by GK forming glucose-6-phosphate (G6P). This ensures that glucose cannot exit the b-cell through the same diffusive glucose transporters GLUT-1 and GLUT-2, and instead can enter glycolysis. Intracellular concentrations ofModeling Glucose Transport in Pancreatic b-CellsG6P normally increase in response to elevated blood glucose. This promotes glycolysis and subsequent events including the GSIS response. The inheritance of partial defects in GK activity by gene mutation impedes the formation of G6P and disables the GSIS response, as observed in the human disease known as Mature Onset Diabetes of the Young, MODY2 [10]. In understanding how the acquisition of deficient b-cell glucose transport may contribute to the pathogenesis of Type 2 diabetes, we have developed a mathematical model of glucose transport that integrates experimental findings that include human data from bcells of normal and T2D donors [7], with supporting data from rodent studies. This model includes the GLUT-1 and GLUT-2 glucose transporters of human b-cells as well as components of a molecular pathway that controls their expression [7]. Our findings indicate a physiological and metabolic threshold exists below which glucose entry, and not GK activity, is rate limiting in G6P production. Among b-cells isolated from animal models of diabetes and human T2D donors, we show that b-cell glucose transport is below this threshold while healthy humans and rodents maintain glucose transport well above the threshold. We further identify molecular nodes within this pathogenic pathway where therapeutic intervention would be most effective.is similar: when plasma glucose is increased to 16.8 mM, glucose enters the b-cell at a high rate because the extra-cellular glucose concentration is greatly above equilibrium considering the intracellular concentration. The glucose uptake rate is progressively compensated by the export rate until a steady-state is reached at a higher glucose concentration. The result is a rise in net glucose transport through each transporter 10781694 until this new steady-state is established. Due to the lower Vmax of GLUT-1, GLUT-2 accounts for m.Al b-cell function and the maintenance of glucose homeostasis. In Type 2 diabetes (T2D), b-cells appear defective in sensing glucose, and this has recently been linked with diminished expression of both GLUT-1 and GLUT-2 glucose transporters[5,6]. Deficiency of glucose transporter expression and glucose uptake among normal b-cells causes b-cell dysfunction with loss of the GSIS response [7]. A similar study in mice administered a high-fat diet indicated that diminished b-cell Glut-2 expression contributed to disease pathogenesis, while preservation of b-cell glucose transport and GSIS prevented b-cell failure and the onset of obesity-associated diabetes [8]. Those studies further reported a conserved sequence of molecular events in human and mouse bcells initiated by elevated levels of free fatty acids, transmitted by nuclear exclusion and down-modulation of HNF1A and FOXA2 transcription factors, and affected by GNT-4A glycosyltransferase deficiency. These events were found to diminish expression of GLUT-1 and GLUT-2 with markedly reduced glucose transport and loss of GSIS, and revealed that an acquired deficiency of bcell glucose transport promotes the pathogenesis of diabetes. Glucokinase (GK) activity is normally the limiting factor in bcell glucose utilization [9]. Upon entering the b-cell, glucose is rapidly phosphorylated by GK forming glucose-6-phosphate (G6P). This ensures that glucose cannot exit the b-cell through the same diffusive glucose transporters GLUT-1 and GLUT-2, and instead can enter glycolysis. Intracellular concentrations ofModeling Glucose Transport in Pancreatic b-CellsG6P normally increase in response to elevated blood glucose. This promotes glycolysis and subsequent events including the GSIS response. The inheritance of partial defects in GK activity by gene mutation impedes the formation of G6P and disables the GSIS response, as observed in the human disease known as Mature Onset Diabetes of the Young, MODY2 [10]. In understanding how the acquisition of deficient b-cell glucose transport may contribute to the pathogenesis of Type 2 diabetes, we have developed a mathematical model of glucose transport that integrates experimental findings that include human data from bcells of normal and T2D donors [7], with supporting data from rodent studies. This model includes the GLUT-1 and GLUT-2 glucose transporters of human b-cells as well as components of a molecular pathway that controls their expression [7]. Our findings indicate a physiological and metabolic threshold exists below which glucose entry, and not GK activity, is rate limiting in G6P production. Among b-cells isolated from animal models of diabetes and human T2D donors, we show that b-cell glucose transport is below this threshold while healthy humans and rodents maintain glucose transport well above the threshold. We further identify molecular nodes within this pathogenic pathway where therapeutic intervention would be most effective.is similar: when plasma glucose is increased to 16.8 mM, glucose enters the b-cell at a high rate because the extra-cellular glucose concentration is greatly above equilibrium considering the intracellular concentration. The glucose uptake rate is progressively compensated by the export rate until a steady-state is reached at a higher glucose concentration. The result is a rise in net glucose transport through each transporter 10781694 until this new steady-state is established. Due to the lower Vmax of GLUT-1, GLUT-2 accounts for m.