A key aspect of type 2 diabetes (T2D) is the failure of β-cells to secrete sufficient insulin to tightly control blood glucose. Nutrient sensor mTORC1 balances cell growth and degradative process (autophagy) to maintain β-cell health and function. Changes to mTORC1 activity and autophagy are linked with T2D and β-cell failure; however, the underlying mechanisms driving these relationships remain unclear. Our work highlights nutrient sensor O-GlcNAc Transferase (OGT) as a critical regulator of β-cell health; β-cell OGT deletion (βOGTKO) causes diabetes due to severe β-cell mass loss and insulin secretion deficits. In response to changes in nutrient levels, OGT glycosylates key target proteins to impact multiple cellular processes. We hypothesize that under nutrient stress, OGT directly modulates the mTORC1 pathway, and thereby, autophagy-dependent β-cell function. βOGTKO islets exhibited decreased mTORC1 activity and increased autophagy. To delineate the untested signaling crosstalk between OGT and mTORC1 pathways, we generated a mouse model of increased mTORC1 activity, by deleting TSC2 (mTORC1 inhibitor) in βOGTKO mice. The βTSC2/OGTKO mice exhibited complete rescue in the diabetic phenotype of the βOGTKO mice. Normalization of blood glucose was associated with full rescue in β-cell mass deficit, but not improvement in secretory function, which suggests non-overlapping biological processes between OGT and mTORC1. Of these downstream processes, we tested whether mTORC1-driven autophagy affects OGT dependent β-cell function. To do this, we deleted ULK1 (autophagy initiator downstream of mTORC1) in the βOGTKO mice. Supporting our hypothesis directly, βULK/OGTKO mice showed improved glucose tolerance with attenuated hyperglycemia compared to the βOGTKO mice by increasing β-cell function but not mass. Altogether our data show a novel and important role of OGT as a master nutrient-sensor affecting downstream mTORC1 and autophagy to drive β-cell function and mass.
S.Jo: None. E.Alejandro: None.
National Institute of Health (DK115720)