O-Glycosylation as an energy sensor: Related molecular mechanisms, disease associations, and therapeutic opportunities in type 2 diabetes

The pathogenesis of type 2 diabetes mellitus (T2DM) centers on pancreatic β-cell dysfunction and peripheral tissue insulin resistance, involving metabolic dysregulation of glucose, lipids, and amino acids across key metabolic organs such as the pancreas, liver, adipose tissue, and skeletal muscle. The hexosamine biosynthetic pathway (HBP) integrates glucose, lipid, and nucleotide metabolism, and its terminal product, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), serves as the substrate for both O-linked β-N-acetylglucosaminylation (O-GlcNAcylation) and O-linked N-acetylgalactosaminylation (O-GalNAcylation). Thus, these types of O-linked glycosylation modifications (O-glycosylation) are recognized as cellular nutrient sensors reflecting energy metabolism status. While the role of O-GlcNAcylation in T2DM is well documented, the pathophysiological significance of O-GalNAcylation remains largely unexplored. Recent studies utilizing clinical specimen sequencing and genetically engineered mouse models have demonstrated that both modifications play pivotal roles in T2DM progression. This review discusses the biological functions and reveals the precise mechanisms by which O-GlcNAcylation and O-GalNAcylation regulate pancreatic development and insulin secretion, adipocyte differentiation and secretion, hepatic glucose and lipid metabolism, skeletal muscle glucose metabolism, and peripheral tissue insulin resistance. Furthermore, we discuss the importance of these two O-glycosylations in the pathogenesis of diabetic complications and address technological advances and limitations in glycosylomics. This review thereby advances the understanding of O-GlcNAcylation and O-GalNAcylation networks in T2DM pathogenesis, and may provide new targets for the treatment and prevention of diabetes and its complications.