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Type 2 diabetes (T2D) occurs when pancreatic β cells fail to produce sufficient insulin to effectively regulate blood glucose levels. Aberrant nutrient sensing via O-GlcNAcylation and mTORC1 has been linked to T2D and the dysfunction of insulin-producing β cells. However, the precise mechanisms underlying their crosstalk in β cells remain largely unexplored. Recently, O-GlcNAcylation, a post-translational modification regulated by the enzymes O-GlcNAc transferase and O-GlcNAcase (OGT/OGA), has emerged as a key regulator of β cell health via modulation of apoptosis, mitochondrial function, ER stress, insulin processing, and cell identity. Deficiencies in either enzyme leads to β cell failure.

This seminar will explore the role of OGT as a master orchestrator of nutrient signaling pathways in β cells, drawing on several studies that utilize loss- and gain-of-function approaches for OGT and other proteins to investigate their mechanisms. For example, we recently tested the hypothesize that OGT interacts with mTORC1 to negatively regulate autophagy, thus maintaining β cell mass and functional homeostasis. We showed that OGT and mTORC1 activity are reduced in islets from a preclinical β cell dysfunction model and in islets from humans with obesity. Using loss- and gain-of-function approaches for OGT, we found that O-GlcNAcylation positively regulates mTORC1 signaling and autophagy in β cells.

In summary, the seminar will highlight OGT’s central role in regulating nutrient signaling pathways in β cells and explore its potential as a target for β cell preservation, offering new therapeutic strategies for treating diabetes.