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Review
. 2022 Feb 17;11(4):705.
doi: 10.3390/cells11040705.

Targeting Protein O-GlcNAcylation, a Link between Type 2 Diabetes Mellitus and Inflammatory Disease

Israel Olapeju Bolanle  1 , Timothy M Palmer  1
Affiliations
Review

Targeting Protein O-GlcNAcylation, a Link between Type 2 Diabetes Mellitus and Inflammatory Disease

Israel Olapeju Bolanle et al. Cells. .

Abstract

Unresolved hyperglycaemia, a hallmark of type 2 diabetes mellitus (T2DM), is a well characterised manifestation of altered fuel homeostasis and our understanding of its role in the pathologic activation of the inflammatory system continues to grow. Metabolic disorders like T2DM trigger changes in the regulation of key cellular processes such as cell trafficking and proliferation, and manifest as chronic inflammatory disorders with severe long-term consequences. Activation of inflammatory pathways has recently emerged as a critical link between T2DM and inflammation. A substantial body of evidence has suggested that this is due in part to increased flux through the hexosamine biosynthetic pathway (HBP). The HBP, a unique nutrient-sensing metabolic pathway, produces the activated amino sugar UDP-GlcNAc which is a critical substrate for protein O-GlcNAcylation, a dynamic, reversible post-translational glycosylation of serine and threonine residues in target proteins. Protein O-GlcNAcylation impacts a range of cellular processes, including inflammation, metabolism, trafficking, and cytoskeletal organisation. As increased HBP flux culminates in increased protein O-GlcNAcylation, we propose that targeting O-GlcNAcylation may be a viable therapeutic strategy for the prevention and management of glucose-dependent pathologies with inflammatory components.

Keywords: O-GlcNAcylation; diabetes; inflammation; metabolism.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic of the hexosamine biosynthetic pathway. fructose-6P (fructose-6-phosphate), glucosamine-6P (glucosamine-6-phosphate), GFAT (glutamine:fructose-6-phosphate amidotransferase), OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) GNA1/GNPNAT1 (glucosamine-6-phosphate N-acetyltransferase), GlcNAc-6P (N-acetylglucosamine-6-Phosphate), GlcNAc-1P (N-acetylglucosamine-1-phosphate), PGM3/AGM1 (phosphoglucomutase), UDP-GlcNAc (uridine diphosphate-N-acetylglucosamine), UAP/AGX1 (UDP-N-acetylhexosamine pyrophosphorylase).
Figure 2
Figure 2
Subcellular distribution of the O-GlcNAcome. Median confidence scores of human O-GlcNAcylated proteins (n = 4969) are from [22].
Figure 3
Figure 3
Schematic of the pro-inflammatory downstream signalling modulation by O-GlcNAcylation. O-GlcNAc (O-linked β-N-acetylglucosamine), OGT (O-linked β-N-acetylglucosamine transferase), NF-κB (nuclear factor kappa light chain enhancer of activated B cells), STAT3 (signal transducer and activator of transcription3), TAK 1 (Transforming growth factor-β activated kinase 1), TAB1 (TAK1-binding protein 1), Nod2 (nucleotide-binding oligomerization domain-containing protein 2), IL-1,6,8, and 12 (Interleukin-1,6,8, and 12), Sp1 (substrate of Keap1), CXCL1 (chemokine ligand 1), VEGF-A (vascular endothelial growth factor), ICAM-1 (intercellular Adhesion Molecule 1), TNF-α (tumor necrosis factor alpha).
Figure 4
Figure 4
Schematic of the anti-inflammatory downstream signaling by O-GlcNAcylation. GlcN (Glucosamine), OGA (O-linked β-N-acetylglucosaminidase), PUGNAc (O-(2-acetamido-2-deoxy-d-glucopyranosyliden)amino-N-phenylcarbamate), iNOS (inducible nitric oxide synthase), IL-6 (interleukin-6), TNF-α (tumor necrosis factor alpha), NF-κB (nuclear factor kappa light chain enhancer of activated B cells), COX2 (cyclooxygenase-2).
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