2123-P: Targeted Deletion of Grb10 in Pancreatic ß-Cells Increases ß-Cell Mass via mTORC-Dependent Inhibition of Cell Dedifferentiation

Growth factor receptor-bound protein 10 (Grb10) is an adaptor protein that negatively regulates insulin and mTORC1 signaling. Grb10 is highly expressed in mouse islets, but its role in β-cells function remains unclear. Here we show that Grb10 is highly expressed in human islets and the expression levels of Grb10 are markedly induced in the islets of diabetic mice as well as aged humans. β-cell-specific knockout of Grb10 in mice increased β-cell mass, reduced apoptosis, and improved glucose-stimulated insulin secretion. Mechanistically, knockout of Grb10 in β-cells enhanced mTORC1 signaling and inhibited β-cell dedifferentiation, which could be blocked by rapamycin administration in vivo. Our findings revealed a mechanism by which the Grb10/mTORC1 axis regulates β-cell dedifferentiation and function. Identification of key regulators of β-cell dedifferentiation will shed new light on the development of effective therapeutic strategies for treating both type 1 diabetes (T1D) and type 2 diabetes (T2D).