Regulation of glucose transport by hypoxia – american journal of kidney diseases anoxia villosa

Fig 3

Cellular mechanisms mediating stimulation of glucose transport in response to hypoxia. The attendant inhibition of oxidative phosphorylation resulting from exposure of cells to hypoxic conditions leads to acute stimulation of glucose transport. This can be achieved through activation of plasma membrane-bound glut1 proteins, or by translocation of gluts from intracellular stores to the cell surface. In addition, chronic exposure to hypoxia can further enhance glucose transport by causing an increase in total cell glut1 protein. With regard to glut1 expression, this latter effect is secondary to an increase in glut1 mrna content resulting from enhanced glut1 gene transcription and increase glut1 mrna stability.Anoxia villosa


interestingly, exposure to lowered oxygen concentration, independent of inhibition of oxidative phosphorylation, stimulates glut1 gene transcription via activation of HIF-1 and its interaction with glut1 HIE. Finally, after its translocation to the plasma membrane in response to insulin, glut4 may require to be activated to become functional for glucose transport.

Fig 4

Mechanisms mediating the response to hypoxia. Effects of hypoxia are mediated by at least two pathways: (1) inhibition of oxidative phosphorylation (left), and (2) stimulation of an oxygen signaling pathway (right). It is also highly likely that hypoxia may inhibit or stimulate other pathways (arrows with ??? Marks). Chemicals such as azide and cyanide or mitochondrial uncouplers also inhibit oxidative phosphorylation, whereas certain transition metal ions, including cobalt, nickel, and manganese (in the presence of oxygen), stimulate the oxygen signaling pathway.Anoxia villosa events after inhibition of oxidative phosphorylation leading to stimulation of glut1 gene transcription are not known. Stimulation of the oxygen-signaling pathway, acting through HIF-1, stimulate the transcription of a number of genes, including EPO, VEGF, some of the glycolytic enzymes, and glut1. It should be noted that inhibition of oxidative phosphorylation per se does not stimulate the oxygen signaling pathway. Interestingly, glut1 gene transcription is stimulated after both inhibition of oxidative phosphorylation and by the oxygen signaling pathway.

Transport of glucose into most mammalian cells and tissues is rate-controlling for its metabolism. Glucose transport is acutely stimulated by hypoxic conditions, and the response is mediated by enhanced function of the facilitative glucose transporters (glut), glut1, glut3, and glut4.Anoxia villosa the expression and activity of the glut-mediated transport is coupled to the energetic status of the cell, such that the inhibition of oxidative phosphorylation resulting from exposure to hypoxia leads to a stimulation of glucose transport. The premise that the glucose transport response to hypoxia is secondary to inhibition of mitochondrial function is supported by the finding that exposure of a variety of cells and tissues to agents such as azide or cyanide, in the presence of oxygen, also leads to stimulation of glucose transport. The mechanisms underlying the acute stimulation of transport include translocation of gluts to the plasma membrane (glut1 and glut4) and activation of transporters pre-exiting in the plasma membrane (glut1).Anoxia villosa A more prolonged exposure to hypoxia results in enhanced transcription of the glut1 glucose transporter gene, with little or no effect on transcription of other glut genes. The transcriptional effect of hypoxia is mediated by dual mechanisms operating in parallel, namely, (1) enhancement of glut1 gene transcription in response to a reduction in oxygen concentration per se, acting through the hypoxia-signaling pathway, and (2) stimulation of glut1 transcription secondary to the associated inhibition of oxidative phosphorylation during hypoxia. Among the various hypoxia-responsive genes, glut1 is the first gene whose rate of transcription has been shown to be dually regulated by hypoxia. In addition, inhibition of oxidative phosphorylation per se, and not the reduction in oxygen tension itself, results in a stabilization of glut1 mrna.Anoxia villosa the increase in cell glut1 mrna content, resulting from its enhanced transcription and decreased degradation, leads to increased cell and plasma membrane glut1 content, which is manifested by a further stimulation of glucose transport during the adaptive response to prolonged exposure to hypoxia.