Protein O-GlcNAcylation in diabetes and diabetic complications

Abstract

The post-translational modification of serine and threonine residues of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is highly ubiquitous, dynamic and inducible. Protein O-GlcNAcylation serves as a key regulator of critical biological processes including transcription, translation, proteasomal degradation, signal transduction and apoptosis. Increased O-GlcNAcylation is directly linked to insulin resistance and to hyperglycemia-induced glucose toxicity, two hallmarks of diabetes and diabetic complications. In this review, we briefly summarize what is known about protein O-GlcNAcylation and nutrient metabolism, as well as discuss the commonly used tools to probe changes of O-GlcNAcylation in cultured cells and in animal models. We then focus on some key proteins modified by O-GlcNAc, which play crucial roles in the etiology and progression of diabetes and diabetic complications. Proteomic approaches are also highlighted to provide a system view of protein O-GlcNAcylation. Finally, we discuss how aberrant O-GlcNAcylation on certain proteins may be exploited to develop methods for the early diagnosis of pre-diabetes and/or diabetes.

Figure 1. The hexosamine biosynthesis pathway and protein O-GlcNAcylation (see Table 1 for more information)

Figure 2. Protein O-GlcNAcylation attenuates insulin sensitivity

Insulin binding to its tyrosine kinase receptor activates intracellular substrates (e.g., IRS1/2), initiating PI3K-Akt pathways and thus increased glucose uptake and metabolism in cells. PI3K activation also gives rise to PIP3, recruiting OGT to the plasma membrane, where the O-GlcNAcylation of several proximal elements leads to insulin signaling attenuation. Upon chronic hyperglycemia (insulin resistance), a rich UDP-GlcNAc pool produced from the HBP flux results in abnormally high O-GlcNAcylation of proteins (including some key transcription factors and coactivators), stimulating gluconeogenic/lipogenic gene transcription, which further diminishes insulin sensitivity (light green circle denotes the O-GlcNAc moiety).