Regulation of expression of glucose transporters by glucose: a review of studies in vivo and in cell cultures

Abstract

Glucose transporters are membrane-embedded proteins that mediate the uptake of glucose from the surrounding medium into the cell. Glucose is the main fuel for most cells, and its uptake is rate-limiting for glucose utilization. For this reason, it is expected that glucose transport is tightly regulated. Whereas rapid regulation of glucose transporters by hormones has been known for some time, the regulation of glucose transporters by substrate availability (i.e., by glucose itself) is less well understood. This question has been approached by scientists from two angles: one, by measuring the consequence of diabetic states (in which there is surplus of glucose availability) on the expression of glucose transporter genes, and another one, by measuring the effect of glucose availability and glucose deprivation in cell cultures on glucose transporter gene expression. The results from both camps are unfortunately not coincident, due in part to the coexistence of other variables in the diabetic animals, and to the lack of ideal cell cultures. In spite of these caveats, the profuse literature on both approaches propelled us to find commonalities within each approach. This review concludes that in animal studies, one isoform of glucose transporters, the GLUT4 type, is down-regulated by high levels of circulating glucose in muscle but not in fat cells. This down-regulation of the protein is independent of regulation of transcription. In contrast, in fat cells, high glucose levels depress GLUT4 mRNA levels. In cell culture studies, high glucose levels lead to lower expression of the GLUT1 transporter isoform relative to glucose-deprived cultures. Glucose levels do not affect the amount of GLUT4 transporter isoform. The down-regulation of the GLUT1 transporter protein is caused by pre- and post-transcriptional mechanisms, the prevalence of each being cell-type specific. No glucose-responsive elements have been identified on either the GLUT1 or GLUT4 genes, and no information is available on the glucose metabolites that mediate the response of glucose transporter gene expression to glucose availability.

Substrate autoregulation of glucose transport: hexose 6-phosphate mediates the cellular distribution of glucose transporters

“…Results from our [1-5, 20, 21] and other laboratories [9] over recent years convincingly demonstrated that extracellular glucose is an important feed-back regulator of its transport through the cell membrane. Glucose transport in skeletal muscle is the limiting step for hexose metabolism in toto, therefore regulation of this step by glucose can be expected to result in the modulation of all aspects of cellular glucose metabolism.…”

“…Glucose has been shown to regulate the expression and steady-state level of GLUT1 mRNA in several types of cells [9]. We have shown before that glucose reduces the content of GLUT1 mRNA in L8 myocytes in a dose-and time-dependent manner [5].…”

“…were found in a variety of cells (for a review see [9]). In addition, high glucose levels induced a time-dependent reduction in the GLUT1 mRNA abundance in L8 myocytes [5] and other cells studied [9].…”

“…In addition, high glucose levels induced a time-dependent reduction in the GLUT1 mRNA abundance in L8 myocytes [5] and other cells studied [9]. It has been proposed that the downregulation of glucose transport and utilisation in skeletal muscle via this autoregulatory mechanism may be important for the induction of reduced peripheral glucose utilisation and insulin resistance in diabetes mellitus [10][11][12].…”

Molecular Basis of Insulin-stimulated GLUT4 Vesicle Trafficking

“…In the postabsorptive state, insulin action in muscle and adipose tissue results in increased glucose uptake from the circulation, thereby maintaining plasma euglycemia and preventing hyperglycemia (1)(2)(3). Defects in this pathway result in insulin resistance, a condition in which excessive concentrations of insulin are required to reduce blood glucose levels and often precede the development of frank Type II diabetes (3,4).…”