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.

项目概要 2 型糖尿病 (T2D) 在美国是一种极其流行的疾病，影响大约 1 10 名成人患有糖尿病，预计到 2040 年将有 6.4 亿人被诊断出患有糖尿病。 胰岛胰岛素和胰高血糖素分泌缺陷与 β 细胞衰竭相关 由于目前针对β细胞增加胰岛素分泌的疗法有限。 成功的关键是关注血糖调节新机制的创新理念 创造新的疗法来对抗 α 细胞的胰高血糖素分泌，可以强有力地控制胰高血糖素的大小。 胰岛素分泌，使 α 细胞成为新疗法的有吸引力的靶点 第二信使 cAMP 是一种强大的药物。 葡萄糖已被证明可以内在调节 α 细胞 cAMP，并且 初步研究表明，亮氨酸可独立于胰岛旁分泌强烈降低 α 细胞 cAMP。 此外，葡萄糖和亮氨酸可以以类似的方式抑制信号传导、KATP 通道效应或钙。 氨基酸刺激的胰高血糖素分泌均具有强烈的回补性和初步性。 数据表明，线粒体酶磷酸烯醇丙酮酸羧激酶 (PCK2) 是一种重要的效应子 线粒体回补-回补，在氨基酸依赖性调节中发挥重要作用 我们敢说亮氨酸和葡萄糖等回补燃料会降低 cAMP 的分泌。 通过 PCK2 抑制胰高血糖素释放 为了研究这一假设，我们将： 1) 确定内在与外在的差异。 亮氨酸对 α 细胞 cAMP 的旁分泌（通过 β/δ 细胞）影响，以及 2) 确定 α 细胞 PCK2 是否介导 这些目标将通过 TIRF 和光片显微镜进行研究。 与新型遗传小鼠模型和生物传感器相结合，检查回补燃料对 α 细胞的作用 cAMP 和胰高血糖素分泌的成功完成将揭示两者之间的新联系。 回补和 cAMP 信号传导，以最先进的技术培训 PI 进行代谢研究，以及 潜在地开辟一条治疗 T2D 的新靶点途径。