Role of Short Chain Fatty Acids and their Receptors in Islet Function

胰腺β细胞通过调节胰岛素分泌来补偿不断变化的胰岛素需求， 生产糖尿病发生时，补偿不足。营养素是这一过程的关键介质 赔偿虽然营养素如葡萄糖、脂肪酸和氨基酸已经很好地描述了在 胰腺β细胞补偿，其他营养素如短链脂肪酸（SCFAs）的作用不是 清楚有趣的是，SCFAs是通过发酵从肠道植物群中获得的，最近一个协会 肠道植物群和肥胖之间的关系已经被揭示。因此，我们研究了SCFAs是否可以调节 胰腺β细胞功能探索这种可能性，我们观察到SCFAs在生理 在循环中观察到的浓度可以调节小鼠和人胰岛中的胰岛素分泌。这如何 发生的调整是未知的。与此相关的是，来自G蛋白的特异性受体 受体（GPCR）家族，其由SCFA激活，游离脂肪酸受体2和-3（FFAR 2和FFAR 3）， 最近被鉴定，我们观察到FFAR 2和FFAR 3都在小鼠中表达， 人类胰腺β细胞沿着这些数据，我们还观察到胰岛素抵抗状态改变， 这些受体在小鼠胰岛中的表达。总的来说，这些数据表明SCFA及其 胰腺β细胞功能中的受体。鉴于这些令人信服的调查结果，本提案的目标是 定义SCFAs通过其受体FFAR 2和FFAR 3信号传导在调节 胰腺β细胞功能，特别是胰岛素分泌和产生。使用多种鼠标 PI获得和/或创建的模型，这些研究将通过体外（目标1）探索上述目标 和体内（Aim 2）模型。此外，人类胰岛的转化研究也将探索这些 路径（目标3）。这些研究的数据将促进我们对胰腺癌中这一新途径的理解。 β细胞，并揭示肠道植物群与肥胖之间可能存在的联系。最后，考虑到这些 受体是GPCR，一个主要药物靶点的受体家族，这些研究可能揭示令人兴奋的新的 糖尿病的治疗目标。

Pancreatic beta cells compensate to changing insulin demands by the regulation of insulin secretion and production. Diabetes develops when inadequate compensation occurs. Nutrients are key mediators of this compensation. While nutrients such as glucose, fatty acids, and amino acids have well described role in pancreatic beta cell compensation, the role of others nutrients such as short chain fatty acids (SCFAs) are not clear. Interestingly, SCFAs are derived via fermentation from the gut flora, and recently an association between the gut flora and obesity has been revealed. Because of this, we examined if SCFAs can regulate pancreatic beta cell function. Exploring this possibility, we have observed that SCFAs at physiologic concentrations seen in circulation can regulate insulin secretion in both mouse and human islets. How this regulation occurs is not known. Of relevance here is that specific receptors from the G-protein coupled receptor (GPCR) family that are activated by SCFAs, free fatty acid receptor 2 and -3 (FFAR2 and FFAR3), have recently been identified and we have observed that both FFAR2 and FFAR3 are expressed in mouse and human pancreatic beta cells. Along with these data, we have also observed that insulin resistant states alter the expression of these receptors in mouse islets. Overall, these data suggest a role of SCFAs and their receptors in pancreatic beta cell function. Given these compelling findings, the goal of this proposal is to define the role of SCFAs signaling through their receptors, FFAR2 and FFAR3, in the regulation of pancreatic beta cell function, in particular insulin secretion and production. Using a variety of mouse models obtained and/or created by the PI, these studies will explore the above goal through in vitro (Aim 1) and in vivo (Aim 2) models. Additionally, translational studies with human islets will also explore these pathways (Aim 3). Data from these studies will advance our understanding of this novel pathway in pancreatic beta cells, and reveal a possible link between the gut flora and obesity. And finally, considering that these receptors are GPCRs, a family of receptors that are major drug targets, these studies may reveal exciting new therapeutic targets for diabetes.