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

FFAR2 作为胰腺 β 细胞功能新型调节剂的研究

• 批准号: 8837825
• 负责人: Stephanie Renee Niemczyk
• 金额: $ 3.87万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8837825
• 关键词: Acetates; Agonist; Apoptosis; Beta Cell; Biological Assay; Cell Line; Cell Proliferation; Cell physiology; Cells; Coupling; Data; Development; Diabetes Mellitus; Diet; Dissection; Drug Design; Drug Targeting; Evaluation; Exhibits; Failure; Fatty acid glycerol esters; Female; Financial compensation; G-Protein-Coupled Receptors; GTP-Binding Protein alpha Subunits, Gs; GTP-Binding Proteins; Genes; Genetic; Glucose; Hyperglycemia; Hyperplasia; Hypertrophy; Insulin; Insulin Resistance; Investigation; Islets of Langerhans; Lead; Ligands; Mediating; Mediator of activation protein; Metabolism; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Outcome Study; Pancreas; Pertussis Toxin; Phospholipase C; Pregnancy; Property; Regulation; Role; Signal Pathway; Signal Transduction; Structure of beta Cell of islet; Testing; Time; Volatile Fatty Acids; Work; base; blood glucose regulation; citrate carrier; effective therapy; genetic approach; impaired glucose tolerance; insulin secretion; insulin signaling; islet; male; mouse free fatty acid 2 receptor; mouse model; new therapeutic target; novel; preference; pregnant; protein kinase D; public health relevance; receptor; research study; response; sex

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.

描述（由申请人提供）：新药靶点的鉴定对于开发2型糖尿病（T2 D）的有效疗法至关重要。我们实验室和其他人最近的工作发现，最近去孤儿化的GPCR（游离脂肪酸受体2（FFAR 2））的胰岛表达在胰岛素抵抗小鼠模型（例如怀孕、肥胖和糖尿病）中上调。这些研究结果表明，受体可能参与的机制？细胞适应胰岛素抵抗，因此是T2 D的新治疗靶点。到目前为止，使用妊娠作为胰岛素抵抗的模型，我们的实验室已经发现FFAR 2（FFAR 2-/-）的遗传缺失导致FFAR 2-/-女性胰岛素分泌减少导致葡萄糖耐量受损。此外，我们发现FFAR 2-/-女性表现出不完整的？由于胰腺β细胞的受损增生和肥大，妊娠期间细胞团扩张。总之，这些数据支持FFAR 2在调节？细胞功能因此，我们将直接研究FFAR 2在调节葡萄糖刺激的胰岛素分泌和胰腺？正常条件下和饮食诱导的肥胖症下雄性小鼠的细胞质量。此外，拟议的研究将确定FFAR 2介导胰腺？细胞功能这些研究的结果将有助于评估T2 D的这种潜在的新型治疗靶点。