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

描述（由申请人提供）：鉴定新的药物靶点对于开发有效的2型糖尿病（T2D）治疗方法至关重要。我们的实验室和其他人最近的研究发现，在妊娠、肥胖和糖尿病等胰岛素抵抗小鼠模型中，最近去孤体化的GPCR游离脂肪酸受体2 （FFAR2）的胰岛表达上调。这些发现表明该受体可能参与了？细胞对胰岛素抵抗的适应性，因此是T2D的新治疗靶点。到目前为止，使用妊娠作为胰岛素抵抗模型，我们的实验室已经发现FFAR2基因缺失（FFAR2-/-）导致FFAR2-/-女性胰岛素分泌减少导致糖耐量受损。此外，我们发现FFAR2-/-雌性表现出不完整？妊娠期间由于胰腺细胞增生受损和肥大造成的细胞团扩增。总之，这些数据支持FFAR2在调节？细胞的功能。因此，我们将直接研究FFAR2在调节葡萄糖刺激胰岛素分泌和胰？正常情况下雄性小鼠的细胞质量和饮食引起的肥胖。此外，拟议的研究将确定FFAR2介导胰？细胞的功能。这些研究的结果将有助于评估这种潜在的新型T2D治疗靶点。

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.