Regulation of alpha-cell glucagon secretion by mitochondrial anaplerosis-cataplerosis

线粒体回补-回补对α细胞胰高血糖素分泌的调节

• 批准号: 10607392
• 负责人: Emily Knuth
• 金额: $ 3.65万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-12 至 2025-12-11
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607392
• 关键词: Adult; Affect; Alpha Cell; American; Amino Acids; Beta Cell; Biological Assay; Biosensor; Blood Glucose; Calcium; Cell membrane; Cell physiology; Cell secretion; Cellular Metabolic Process; Characteristics; Cyclic AMP; D Cells; Data; Defect; Diabetes Mellitus; Diagnosis; Disease; Enzymes; Failure; Genetic; Genetic Models; Glucagon; Glucose; Goals; Hormone secretion; Hormones; Human; Hypoglycemia; Insulin; Intervention; Islets of Langerhans; Knock-out; Learning; Leucine; Light; Mediating; Metabolism; Microscopy; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Organ; Oxaloacetates; Paracrine Communication; Pathway interactions; Persons; Phosphoenolpyruvate; Phosphoenolpyruvate Carboxylase; Play; Prediabetes syndrome; Public Health; Pyruvate Kinase; Regulation; Role; Second Messenger Systems; Signal Transduction; Somatostatin; Techniques; Testing; Therapeutic; Total Internal Reflection Fluorescent; Training; United States; blood glucose regulation; combat; experimental study; impaired glucose tolerance; improved; in vivo; innovation; insight; insulin secretion; islet; metabolic abnormality assessment; mouse model; new therapeutic target; novel; novel therapeutics; pancreatic juice; paracrine; response; success; targeted treatment

Project Summary Type 2 diabetes (T2D) is an extremely prevalent disease in the United States, affecting approximately 1 in 10 adults, and it is estimated that 640 million people will be diagnosed with diabetes by 2040. While T2D is associated with β-cell failure, defects in both insulin and glucagon secretion from the pancreatic islet contribute to dysregulated blood glucose. As current therapies that target β-cells to increase insulin secretion have limited success, innovative ideas that focus on novel mechanisms for regulation of blood glucose are necessary to create new therapeutics to combat T2D. Glucagon secretion by α-cells has strong control over the magnitude of insulin secretion, making α-cells an attractive target for new therapies. The second messenger cAMP is a strong determinant of glucagon secretion. Glucose has been shown to regulate α-cell cAMP intrinsically and extrinsically. Preliminary studies show that leucine strongly reduces α-cell cAMP independently of islet paracrine signaling, KATP channel effects, or calcium. Furthermore, in a similar fashion, glucose and leucine can dampen amino acid-stimulated glucagon secretion. Glucose and leucine are both strongly anaplerotic, and preliminary data suggests that the mitochondrial enzyme phosphoenolpyruvate carboxykinase (PCK2), an essential effector of mitochondrial anaplerosis-cataplerosis, plays an important role in the regulation of amino acid-dependent glucagon secretion. We hypothesize that anaplerotic fuels such as leucine and glucose will decrease cAMP through PCK2 to inhibit glucagon release. To study this hypothesis we will: 1) Determine the intrinsic vs. paracrine (via β/δ-cells) effects of leucine on α-cell cAMP and 2) Determine whether α-cell PCK2 mediates the inhibitory effects of anaplerotic fuels. These aims will be studied by TIRF and lightsheet microscopy in combination with novel genetic mouse models and biosensors, to examine role of anaplerotic fuels on α-cell cAMP and glucagon secretion. Successful completion of this project will characterize new connections between anaplerosis and cAMP signaling, train the PI in state of the art techniques for the study of metabolism, and potentially unlock a new pathway to target for the treatment of T2D.

项目摘要 2型糖尿病（T2D）在美国是一种极为普遍的疾病，影响约1 在10名成年人中，据估计，到2040年，有6.4亿人将被诊断出患有糖尿病。而T2D是 与β细胞衰竭相关，胰岛胰岛胰岛素和臀部分泌的缺陷有助于 使血糖失调。由于目前靶向β细胞增加胰岛素分泌的疗法有限 成功，专注于调节血糖的新机制的创新思想对于 创建新的疗法来对抗T2D。 α细胞分泌的胰高血糖素对大小的强度控制 胰岛素分泌，使α细胞成为新疗法的有吸引力的靶标。第二信使训练营是一个强大的 胰高血糖素分泌的决定因素。已显示葡萄糖本质上调节α细胞营地 外在。初步研究表明，亮氨酸与胰岛旁分泌独立于α细胞营地强烈降低 信号传导，KATP通道效应或钙。此外，以类似的方式，葡萄糖和亮氨酸可以跳舞 氨基酸刺激的胰高血糖素分泌。葡萄糖和亮氨酸都是强烈的变性，并且初步 数据表明，线粒体酶磷酸烯醇丙酮酸羧基酶（PCK2）是必不可少的效应器 线粒体散脂性 - 综合症的作用，在氨基酸依赖性的调节中起重要作用 胰高血糖素分泌。我们假设，亮氨酸和葡萄糖等变质燃料会减少cAMP 通过PCK2抑制胰高血糖素的释放。为了研究这一假设，我们将：1）确定固有的VS。 亮氨酸（通过β/δ细胞）对α细胞营地的作用，2）确定α细胞PCK2是否介导 无抗性燃料的抑制作用。这些目标将通过TIRF和灯表显微镜研究 与新型的遗传小鼠模型和生物传感器结合，以检查变性燃料在α细胞上的作用 营地和麸质分泌。该项目的成功完成将表征 旋律和cAMP信令，以最先进的技术来训练PI的新陈代谢研究和 有可能解锁用于治疗T2D的新途径。