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

代谢和 GLP-1 受体信号传导对胰岛激素分泌的机制

基本信息

批准号：
10311485
负责人：
Sophie Lewandowski Fernandez
金额：
$ 3.55万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10311485
关键词：
3-Dimensional Adjuvant Therapy Advanced Development Affect Agonist Alpha Cell American Beta Cell Binding Biosensor Calcium Cell membrane Cells Cellular Metabolic Process Chronic Cyclic AMP Data Defect Diabetes Mellitus Diagnosis Dietary Intervention Disease Dose Electrophysiology (science)Enzymes Failure Functional disorder G-Protein-Coupled Receptors GLP-I receptor Genetic Glucagon Glucose Glycolysis Goals Hormone secretion Hormones Human Image Intervention Intervention Studies Islets of Langerhans Lead Light Membrane Metabolic Metabolism Mitochondria Molecular Mus Nausea Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Peptides Personal Satisfaction Persons Phase III Clinical Trials Phenotype Phosphoenolpyruvate Physiological Potassium Channel Prevention Public Health Pyruvate Pyruvate Kinase Receptor Signaling Regimen Regulation Role Signal Transduction Structure of beta Cell of islet Testing Therapeutic Three-Dimensional Imaging base cell type diabetes mellitus therapy diabetic diet-induced obesity exenatide imaging platform improved in vivo insulin secretion islet novel patch clamp physiologic model pre-clinical predictive modeling prevent pyruvate kinase deficiency receptor response side effect small molecule

项目摘要

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.

项目概要糖尿病是一种影响全世界人民的重要疾病，并且正在迅速变得更加流行。据估计，到 2040 年，将有 6.4 亿人被诊断出患有该病。胰腺 β 细胞代谢缺陷胰岛对胰岛素分泌有负面影响，并且与糖尿病相关的β细胞代谢也受到控制。胰岛中的另一种细胞类型是α细胞，它在糖尿病患者中分泌过多的胰高血糖素，像胰高血糖素样肽 1 受体 (Glp1r) 激动剂一样，具有恶心等副作用，从而阻止其因此，有必要寻找一种辅助疗法来全面治疗2型。在本提案中，我们确定了丙酮酸激酶 (PK)，它可转化 ADP 和磷酸烯醇丙酮酸。 (PEP) 在糖酵解的最后一步中转化为 ATP 和丙酮酸，作为新糖尿病治疗的潜在靶点。我们发现，β 细胞 PK 凭借其结合和灭活 KATP 通道的能力，足以初步研究表明 PK 激活剂具有启动和放大胰岛素分泌的潜力。总体而言，该提案将揭示 PK 的机制。我们的假设是 PK 控制 α 细胞和 β 细胞。通过关闭 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) 确定治疗方案 PK 激活剂 (PKa) 与 Glp1r 激动剂相结合可增强肥胖小鼠胰岛素分泌的潜力将使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 光片成像将引领这一目标。表征 PK 在 α 细胞代谢中的作用，并最终改善 2 型细胞的治疗糖尿病。