Pancreatic ß-Cell Specific Knockout of Grb10 Improves ß-Cell Function by Enhancing ß-Cell Differentiation and Suppressing ß-Cell Dedifferentiation

Abstract

Aim: Defects in β cell differentiation are associated with type 2 diabetes in humans. Understanding the basis for β cell differentiation defects may reveal new strategies for diabetes therapy. Results: We found that Growth factor receptor binding protein 10 (Grb10) is highly expressed in mouse and human pancreas and islets and that β cell-specific knockout of Grb10 in mice increased β-cell mass and insulin content, enhanced insulin secretion from β-cells, and up-regulated mTOR and insulin signaling in islets. Pancreatic β cell-specific disruption of Grb10 expression also improved glucose tolerance in mice fed with a high fat diet and protected adult mice from STZ-induced β cell death. Pancreas-specific knockout Grb10 promoted endocrine progenitors differentiate into β cells during embryonic development. In addition, knockout Grb10 in islets alleviated STZ or high fat diet-induced β cell dedifferentiation. Conclusion: We have identified Grb10 as a key regulator of β cells differentiation/dedifferentiation and demonstrated that reducing the expression level of Grb10 has a protective effect on β-cell function. Our findings suggest a potential effective therapeutic treatment of both type 1 and type 2 diabetes. Disclosure J. Zhang: None. Z. Cai: None.