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.

Keywords::

• diabetes
• diabetic complications
• hyperglycemia
• insulin resistance
• O-GlcNAc
• O-GlcNAcomics
• proteomics

Acknowledgments

The authors especially thank Kaoru Sakabe and Ronald Copeland for critical reading and suggestions of this manuscript and the Hart laboratory.

Financial & competing interests disclosure

Original research in the author’s laboratory is supported by NIH R01CA42486, R01DK61671 and P01HL107153. Dr. Hart receives a share of royalty received by the university on sales of the CTD 110.6 antibody, which are managed by JHU. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.