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

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.

Sodium Butyrate Attenuates AGEs-Induced Oxidative Stress and Inflammation by Inhibiting Autophagy and Affecting Cellular Metabolism in THP-1 Cells

“…Uridine diphospho-N-acetylglucosamine (UDP-Nacetylglucosamine) is a donor substrate for nucleoplasmic proteins modified with serine and threonine residues by N-acetylglucosamine (O-GlcNAc), which is the final product of the hexosamine biosynthesis pathway. The activation of the hexosamine pathway leads to the production of uridine dipho-sphate N-acetylglucosamine (UDP-GlcNAc) from glucose and glutamine, in which acetyl-CoA and UTP are consumed [52], and O-GlCNAc acetylation promotes inflammation [53]. In this study, the intervention with NaB had a callback effect on glutamine and reduced the concentration of UDP-GlcNAc.…”

Role of Branched-Chain Amino Acid Metabolism in Type 2 Diabetes, Obesity, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease

“…In conclusion, many independent studies have convincingly demonstrated that high levels of circulating BCAAs are strongly associated with IR, T2D, obesity, CVD and NAFLD (Figures 2 and 3) [43][44][45]. However, the presence of BCAAs in many metabolic pathways and their essential role in several physiological processes-protein synthesis, modulation of glucose metabolism, regulation of appetite and adiposity [19,20]-make it very challenging to establish whether BCAAs are the cause or biomarkers of IR and IR-associated disease [20].…”

Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options

“…Increased hexosamine pathway flux produces the activated amino sugar UDP-GlcNAc that is a critical substrate for protein O-GlcNA cylation. This is a dynamic and reversible post-translational glycosylation of serine and threonine residues in target proteins that control angiogenesis and a range of cellular processes, including inflammation [ 38 , 39 ].…”