Investigation of FFAR2 as a novel regulator of pancreatic beta cell function

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DESCRIPTION (provided by applicant): The identification of novel drug targets is critical to the development of effective therapies for type 2 diabetes (T2D). Recent work by our lab and others has found that pancreatic islet expression of the recently de-orphanized GPCR, Free Fatty Acid Receptor 2 (FFAR2), is up regulated in mouse models of insulin resistance, such as pregnancy, obesity, and diabetes. These findings suggest that the receptor may be involved in mechanisms of ? cell adaptation to insulin resistance, and therefore a novel therapeutic target for T2D. Thus far, using pregnancy as a model of insulin resistance, our lab has found genetic deletion of FFAR2 (FFAR2-/-) to result in impaired glucose tolerance from diminished insulin secretion in FFAR2-/- females. Further, we have found that FFAR2-/- females exhibit incomplete ? cell mass expansion during pregnancy as a result of impaired hyperplasia and hypertrophy of the pancreatic beta cells. Together, these data support a role for FFAR2 in the regulation of ? cell function. Therefore, we will directly investigate the role of FFAR2 in regulating glucose stimulated insulin secretion and pancreatic ? cell mass in male mice under normal conditions and diet-induced obesity. Additionally, the proposed studies will define the mechanism by which FFAR2 mediates pancreatic ? cell function. The results of these studies will help in the evaluation of this potential novel therapeutic target for T2D.