O-GlcNAcylation modulates mTORC1 and autophagy in β-cells, driving diabetes progression.

Type 2 diabetes (T2D) arises when pancreatic β-cells fail to produce sufficient insulin to control blood glucose appropriately. Aberrant nutrient sensing by O-GlcNAcylation and mTORC1 is linked to T2D and the failure of insulin-producing β-cells. However, the nature of their crosstalk in β-cells remains unexplored. Recently, O-GlcNAcylation, a post-translation modification controlled by enzymes OGT/OGA, emerged as a pivotal regulator for β-cell health; deficiency in either enzyme causes β-cell failure. The present study investigates the previously unidentified connection between nutrient sensor OGT and mTORC1 crosstalk to regulate β-cell mass and function in vivo. We show reduced OGT and mTORC1 activity in islets of preclinical β-cell dysfunction model and obese human islets. Using loss or gain of function of OGT, we identified that O-GlcNAcylation positively regulates mTORC1 signaling in β-cells. O-GlcNAcylation negatively modulates autophagy, as the removal of OGT increases autophagy, while the deletion of OGA decreases it. Increasing mTORC1 signaling, via deletion of TSC2, alleviates the diabetic phenotypes by increasing β-cell mass but not β-cell function in OGT deficient mice. Downstream phospho-protein signaling analysis reveal diverging impact on MKK4 and calmodulin signaling between islets with OGT, TSC2, or combined deletion. These data provide new evidence of OGT's significance as an upstream regulator of mTORC1 and autophagy, crucial for the regulation of β-cell function and glucose homeostasis.