Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Aug 28;8(9):999.
doi: 10.3390/cells8090999.

Hyperglycemia-Induced Aberrant Cell Proliferation; A Metabolic Challenge Mediated by Protein O-GlcNAc Modification

Tamás Nagy  1 , Viktória Fisi  2 , Dorottya Frank  3 , Emese Kátai  2 , Zsófia Nagy  2 , Attila Miseta  2
Affiliations
Review

Hyperglycemia-Induced Aberrant Cell Proliferation; A Metabolic Challenge Mediated by Protein O-GlcNAc Modification

Tamás Nagy et al. Cells. .

Abstract

Chronic hyperglycemia has been associated with an increased prevalence of pathological conditions including cardiovascular disease, cancer, or various disorders of the immune system. In some cases, these associations may be traced back to a common underlying cause, but more often, hyperglycemia and the disturbance in metabolic balance directly facilitate pathological changes in the regular cellular functions. One such cellular function crucial for every living organism is cell cycle regulation/mitotic activity. Although metabolic challenges have long been recognized to influence cell proliferation, the direct impact of diabetes on cell cycle regulatory elements is a relatively uncharted territory. Among other "nutrient sensing" mechanisms, protein O-linked β-N-acetylglucosamine (O-GlcNAc) modification emerged in recent years as a major contributor to the deleterious effects of hyperglycemia. An increasing amount of evidence suggest that O-GlcNAc may significantly influence the cell cycle and cellular proliferation. In our present review, we summarize the current data available on the direct impact of metabolic changes caused by hyperglycemia in pathological conditions associated with cell cycle disorders. We also review published experimental evidence supporting the hypothesis that O-GlcNAc modification may be one of the missing links between metabolic regulation and cellular proliferation.

Keywords: O-GlcNAc; cancer; cell cycle; diabetes; hyperglycemia; proliferation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The effect of hyperglycemia on intracellular signaling pathways and cell cycle regulation. The primary metabolic changes caused by excess amount of intracellular are increased levels of diacyl-glycerol (DAG), reactive oxygen species (ROS), advanced end-glycation products (AGEs), sorbitol (Polyol), and protein O-Glycosylation (O-GlcNAc). Dozens of secondary messengers and signaling elements are activated (or de-activated) that are connected to the cell cycle regulatory system and eventually influencing cell proliferation by either directly influencing cyclins, cyclin-dependents kinases and cell cycle inhibitors such as p21 or altering their expression level through influencing transcriptional activity. The figure shows some of these connections; positive or negative effects inherent to the interactions are indicated by green or red lines between proteins, respectively. The effect of hyperglycemia (if it is known) on the activity of individual signaling elements are indicated by green (up-regulation) or red (down-regulation) background coloring. For clarity, the connections of O-GlcNAc are omitted from this figure, however please note that increasing number of evidences suggest that the majority of intracellular signaling elements are modified and influenced by O-GlcNAc modification.
Figure 2
Figure 2
Metabolites of the hexosamine biosynthesis pathway (HBP) and protein O-Glycosylation (O-GlcNAc) modification. HBP branches off from glycolysis at fructose-6P. Thus, the amount of the end-product of HBP; UDP-N-acetyl-glucosamine (UDP-GlcNAc) depends on the rate of glucose entering the cells, but also on the rate of glycolysis that process the majority of fructose-6P. Increased glucose uptake or a block in glycolysis (e.g. inhibition of GAPDH by ROS) will increase the flux through HBP. It has to be noted that lipid (acetylation), protein (transfer of the amino group from glutamine) and nucleotide (linkage of N-acetyl-glucosamine to UDP) homeostasis may also influence HBP apart from carbohydrate metabolism [189]. UDP-GlcNAc is a substrate for many complex biomolecules and post-translational modifications. In particular, protein O-GlcNAc. As O-GlcNAc is recognized to modify and influence hundreds if not thousands of proteins, piling evidence suggests that it may be a direct mediator and feed-back mechanism between metabolic challenges and cellular adaptation and regulatory functions, including cell proliferation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Jacob F., Monod J. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 1961;3:318–356. doi: 10.1016/S0022-2836(61)80072-7. - DOI - PubMed
    1. Loomis W.F., Magasanik B. Glucose-lactose diauxie in Escherichia coli. J. Bacteriol. 1967;93:1397–1401. - PMC - PubMed
    1. Stoebel D.M., Dean A.M., Dykhuizen D.E. The cost of expression of Escherichia coli lac operon proteins is in the process, not in the products. Genetics. 2008;178:1653–1660. doi: 10.1534/genetics.107.085399. - DOI - PMC - PubMed
    1. World Health Organization Global Report on Diabetes. [(accessed on 11 July 2019)]; Available online: https://www.who.int/diabetes/global-report/en/
    1. Forouhi N.G., Wareham N.J. Epidemiology of diabetes. Medicine (Abingdon) 2014;42:698–702. doi: 10.1016/j.mpmed.2014.09.007. - DOI - PMC - PubMed

Publication types