Nutrient-sensor O-GlcNAc Transferase Regulation of Autophagy in Homeostatis of Pancreatic Beta-cell Mass and Function

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PROJECT SUMMARY/ABSTRACT O-GlcNAc transferase (OGT) is a nutrient and stress sensor protein highly expressed in pancreatic β-cells. This enzyme exclusively catalyzes the post-translational glycosylation of target cytosolic and nucleic proteins (O- GlcNAcylation). β-cell OGT knockout mice develop severe diabetic phenotype, suggesting that OGT is crucial in shaping glucose homeostasis. The long-term goal of this research is to understand the mechanisms of how protein O-GlcNAcylation shape β-cell health and function. O-GlcNAcylation, mTORC1 and AMPK signaling are dysregulated in many diseases including Type 2 diabetes. Although we have made advancements in our understanding of the roles of nutrient sensor proteins mTORC1, AMPK, and OGT by studying them independently, how they crosstalk in vivo is largely unknown. Our research work for the past six years reveal that OGT promotes optimal β-cell health through its ability to sense nutrient levels and orchestrate a cohesive cellular response to maintain β-cell mass and elicit sufficient insulin release. In this current proposal, we will test the main hypothesis that OGT elicits crosstalk with mTORC1 and AMPK, and their downstream target ULK, to negatively regulate autophagy to maintain β-cell mass and function homeostasis. Diabetes is associated with dysregulated autophagy in β-cells and interventions ameliorating autophagy homeostasis could be beneficial in reducing functional impairments in islets caused by glucolipotoxicity. We will leverage innovative in vivo models with increased or reduced function of OGT, mTORC1, AMPK, and ULK to test the crosstalk among these nutrient-sensor proteins regulating autophagy-dependent β-cell function and mitochondrial homeostasis. Specific Aim 1: To delineate molecular mechanisms through which OGT regulates mTORC1 signaling in β-cells. Specific Aim 2: To delineate the role of OGT on autophagy in β- cells. This new proposal is innovative because there are currently no studies linking OGT and mTORC1 crosstalk in pancreatic islets and their regulation of autophagy-dependent β-cell mass and insulin secretion. A greater understanding of the complex interactions between major nutrient and stress sensors OGT, mTOR and AMPK signaling is critical in optimizing β-cell health. Our results will reveal the central function of OGT as a master orchestrator of nutrient signaling pathways in β-cells that may be valuable targets for β-cells preservation, providing new therapeutic models for treating patients with diabetes.