Type 2 diabetes (T2D) is a major public health concern worldwide. Chronic hyperglycemia and hyperlipidemia are causative factors for T2D by inducing pancreatic ?-cell failure. Two of the mechanisms causing ?-cell failure include mitochondrial dysfunction and disruption of protein quality control systems and pathological unfolded protein response (UPR) in the Endoplasmic Reticulum (ER) leading to death of insulin- producing ?-cells. O-GlcNAc modification (O-GlcNAcylation) onto proteins by the enzyme OGT (O-GlcNAc Transferase) is crucial for many important biological processes including mitochondrial function, ER stress response and metabolism. Global reduction of O-GlcNAcylation (by deleting OGT in ?-cells) causes T2D and ?-cell failure, in part, due to enhanced ER stress and hyperproinsulinemia. We hypothesize that OGT regulates survival and function by regulating the O-GlcNAcylation state of mitochondrial, ER-UPR, cytoplasmic, and nuclear proteins. Identification of O-GlcNAc modified proteins in ?-cells have not been done before and may lead to new targets for treatment for diabetes.
Specific Aim1 will determine and quantify changes in proteome and to identify OGT targets in islets with conditional and inducible loss or gain-of-function OGT in ?- cells.
Specific Aim2 will identify the mechanisms of hyperproinsulinemia and determine mitochondrial dysfunction in islets of mice with loss and gain-of-function OGT in ?-cells. Identification, site mapping, and quantification of O-GlcNAc proteins are a prerequisite to decipher their functions and to gain insights in the factors that determine structure- function relationship. In long term, this project will identify potential new pharmacological targets to improve ?-cell mass and function.
Disruption of O-GlcNAcylation, a post-translational modification process involving the addition of an O-GlcNAc group onto proteins, induces protein quality control stress and mitochondrial dysfunction in pancreatic ?-cells of diabetic mice. To understand the molecular mechanisms of O-GlcNAcylation in ER stress and mitochondrial function and to gain a greater picture of the unknown landscape of proteins modified by O-GlcNAcylation in ?-cells, this grant will identify proteins modified with O-GlcNAc with the hope to identify potential new targets for improving ?-cell mass and function for type 2 diabetes treatment.
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