Mechanisms of Metabolicand GLP-1 receptor signaling on Islet hormone secretion

项目摘要 糖尿病是一种影响全世界人民的突出疾病，而且正在迅速变得更加流行；它是 据估计，到2040年，将有6.4亿人被诊断出患有这种疾病。胰腺β细胞代谢缺陷 胰岛对胰岛素的分泌有负面影响，并与糖尿病有关。β-细胞新陈代谢也受到控制 通过胰岛中的另一种细胞类型，α细胞，在糖尿病患者中过度分泌胰高血糖素。目前的糖尿病治疗方法， 像胰高血糖素样肽1受体(GLP1R)激动剂一样，都有副作用，如恶心，这可以防止它 完全激活β细胞。因此，有必要寻找一种辅助疗法来完全治疗2型。 糖尿病。在这个方案中，我们确定了丙酮酸激酶(PK)，它可以转化ADP和磷酸烯醇式丙酮酸 在糖酵解的最后一步，将(PEP)转化为ATP和丙酮酸，作为新的糖尿病治疗的潜在靶点。 我们已经发现，β细胞PK，凭借其结合和失活KATP通道的能力，足以 启动和放大胰岛素的分泌。初步研究表明，PK激活剂有可能 提高GLP1R激动剂的疗效。总体而言，这一建议将揭示PK 激活会在分子水平上增加胰岛素的分泌。我们的假设是PK控制α-和β-细胞 通过关闭对ATP敏感的K+通道来分泌激素。为了研究这一假设，我们将：1)确定 PK激活对α细胞代谢和激素分泌的直接影响2)决定治疗 PK激活剂(PKA)和GLP1R激动剂联合应用促进肥胖小鼠胰岛素分泌 人类的小岛。利用荧光生物传感器研究PK对α-和β-细胞代谢的影响 成像、电生理学和新开发的3D光片成像。实现这些目标将引领 PK在α细胞代谢中的作用特征，并最终改善对2型的治疗 糖尿病。

Project Summary Diabetes is a prominent disease that affects people worldwide and is rapidly becoming more prevalent; it is estimated that 640 million people will be diagnosed with it by 2040. Defects in β-cell metabolism in pancreatic islets negatively impact insulin secretion and are associated with diabetes. β-cell metabolism is also controlled by another cell type in islets, the α-cell, which hypersecretes glucagon in diabetics. Current diabetes therapies, like glucagon-like peptide 1 receptor (Glp1r) agonists, have side effects like nausea, which prevents it from completely activating β-cells. Therefore, it is necessary to find an adjuvant therapy to fully treat type 2 diabetes. In this proposal, we identify pyruvate kinase (PK), which converts ADP and phosphoenolpyruvate (PEP) to ATP and pyruvate in the final step of glycolysis, as a potential target for a new diabetes therapeutic. We have discovered that β-cell PK, by virtue of its ability to bind and inactivate KATP channels, is sufficient to initiate and amplify insulin secretion. Preliminary studies suggest that PK activators have the potential to improve the efficacy of Glp1r agonists. Overall, this proposal will reveal the mechanisms by which PK activation increases insulin secretion on the molecular level. Our hypothesis is that PK controls α- and β-cell hormone secretion by closing ATP-sensitive K+ channels. To study this hypothesis, we will: 1) Determine the direct effect of PK activation on α-cell metabolism and hormone secretion and 2) Determine the therapeutic potential of combining PK activators (PKa) with Glp1r agonists to enhance insulin secretion in obese mice and human islets. The effects of PK on α- and β-cell metabolism will be studied using fluorescent biosensor imaging, electrophysiology, and newly developed 3D light-sheet imaging. Achieving these aims will lead the characterization of PK’s role in α-cell metabolism and, ultimately, improvement in the treatment of type 2 diabetes.