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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结