New approaches to treat type 2 diabetes (T2D) are needed. Therefore, the overall objective of this proposal is to validate a novel T2D target, free fatty acid receptor-2 (FFAR2). Our group, originally, discovered this potential target through gene expression studies, where these data indicate that FFAR2 may mediate the adaption of pancreatic beta cells to insulin resistance. As the major mechanism to adapt to insulin resistance is by increased glucose stimulated insulin secretion (GSIS) and beta cell mass (BCM) expansion, we explored the role of FFAR2 in pancreatic beta cells and have evidence to suggest that FFAR2 contributes to both GSIS and BCM regulation. As a primary goal of many T2D based therapies is to enhance GSIS and regulate BCM, further exploring these data is needed. Of importance, these above studies are limited by the mouse model used to generate these data, where this model was a global FFAR2 knockout model. Therefore, we have developed more-specific and relevant mouse models to dissect our important question, if FFAR2 regulates GSIS and BCM. These models include a pancreatic beta cell specific KO mice which will be generated through crossing our recently developed floxed FFAR2 model with the pancreatic beta cell- specific inducible Cre model (MIP-Cre) and a mouse model with human-inducible FFAR2 overexpressed in pancreatic beta cells (on a mouse background deficient in FFAR2). These models will allow us to genetically dissect and address our specific hypothesis, that FFAR2 regulates GSIS and BCM in pancreatic beta cells. In Aim 1, we will utilize these models to examine the in vitro and in vivo role of FFAR2 in GSIS studies, and the outcome will be that we can definitively answer if and how FFAR2 contributes to GSIS. Next, in Aim 2, we will utilize these models to explore beta cell proliferation properties and BCM regulation through in vitro and in vivo studies. Collectively, these data will answer our overall question if FFAR2 mediates GSIS and BCM, and if these data confirm our overall hypothesis, we will establish that FFAR2 is a novel T2D target, through its function in pancreatic beta cells.
|Effective start/end date||2/1/15 → 8/31/16|
- University of Chicago (FP035726-02-E//P30DK020595)
- National Institute of Diabetes and Digestive and Kidney Diseases (FP035726-02-E//P30DK020595)
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