Glucagon Mediated Potentiation of Insulin Sensitivity in Glucose Metabolism

胰高血糖素介导的葡萄糖代谢中胰岛素敏感性的增强

• 批准号: 9286994
• 负责人: Kirk Michael Habegger
• 金额: $ 33.41万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9286994
• 关键词: Acute; Agonist; Bile Acids; Bionics; Brain; Cell Nucleus; Chemosensitization; Chronic; Companions; Complement; Complex; Coupling; Data; Diabetes Mellitus; Diet; Drug Targeting; Dyslipidemias; Eating; Energy Metabolism; Euglycemic Clamping; Event; FRAP1 gene; Fasting; Fatty acid glycerol esters; Future; GLP-I receptor; Glucagon; Glucagon Receptor; Glucose; Glucose Intolerance; Glycogen; Hepatic; Hepatocyte; Hormones; Hyperglycemia; Hypertension; Hypoglycemia; Hypothalamic structure; Incidence; Individual; Infusion procedures; Insulin; Insulin Receptor; Investigation; Life; Life Style; Light; Lipids; Lipolysis; Liver; Measures; Mediating; Metabolic; Metabolic syndrome; Metabolism; Molecular; Mus; Neuroendocrine Cell; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Plague; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Receptor Activation; Receptor Signaling; Regulation; Reporting; Role; Satiation; Signal Pathway; Signal Transduction; Sirolimus; Site; Skeletal Muscle; Structure of alpha Cell of islet; Technology; Testing; Thermogenesis; Tissues; Work; blood glucose regulation; density; design; diabetic; diabetic patient; diabetogenic; fatty acid oxidation; glucose disposal; glucose metabolism; glucose production; glucose tolerance; glucose uptake; improved; insight; insulin secretion; insulin sensitivity; insulin signaling; interest; ketogenesis; lipid metabolism; phosphoproteomics; prevent; programs; receptor; receptor expression; scaffold; sedentary; therapeutic candidate; type I diabetic

Abstract The sedentary and dietary life style that evolved during the last decades has been paralleled by an unprecedented increase in the incidence of metabolic disturbances such as hypertension, dyslipidemia, obesity and type-2 diabetes. Glucagon, the key counter-regulatory hormone opposing insulin action, is released during periods of hypoglycemia by pancreatic alpha-cells to stimulate hepatic glucose production and restore euglycemia. Accordingly, excessive glucagon signaling is a crucial pathophysiological component of diabetes mellitus and these actions have been widely studied in both type 1 and 2 diabetic patients. Emerging evidence suggests that glucagon regulates a range of actions that may be quite desirable in patients with the metabolic syndrome. Indeed, potential drug targets that contain glucagon agonism have emerged as promising therapeutic candidates for obesity and diabetes. Yet, the targeted tissues and molecular mechanisms responsible for these beneficial effects are yet unknown. The scientific hypothesis that guides this proposal is that glucagon, via its hepatic receptors (GcgR), potentiates TORC2-dependent components of insulin-signaling cascade, which is further potentiated by hypothalamic GcgR signaling, to prime an individual for enhanced whole-body glucose disposal. Under our hypothesis, the counterregulatory actions of glucagon that maintain euglycemia during fasting, also engage mechanisms to potentiate subsequent insulin action. Our hypothesis is formulated both on our preliminary and published data demonstrating enhanced glucose tolerance and improved insulin sensitivity during hyperinsulinemic-euglycemic clamp in mice pretreated with glucagon, or a potent glucagon-receptor agonist. However, how glucagon regulates insulin action, and the tissues responsible for these combined insulin/glucagon-effects remain unresolved.

抽象的 过去几十年演变的久坐和饮食生活方式与 高血压、血脂异常、肥胖等代谢紊乱的发生率空前增加 和2型糖尿病。胰高血糖素是对抗胰岛素作用的关键反调节激素，在 胰腺α细胞刺激肝葡萄糖产生和恢复的低血糖期 血糖正常。因此，过度的胰高血糖素信号传导是糖尿病的重要病理生理学组成部分 以及这些作用已在 1 型和 2 型糖尿病患者中进行了广泛研究。 新出现的证据表明，胰高血糖素可调节一系列可能在以下方面非常理想的作用： 患有代谢综合征的患者。事实上，含有胰高血糖素激动作用的潜在药物靶点已经 成为肥胖和糖尿病有前途的治疗候选者。然而，目标组织和分子 造成这些有益作用的机制尚不清楚。指导这一点的科学假设 建议认为胰高血糖素通过其肝受体 (GcgR) 增强 TORC2 依赖性成分 胰岛素信号级联，通过下丘脑 GcgR 信号进一步增强，以启动个体 增强全身葡萄糖的处理。根据我们的假设，胰高血糖素的反调节作用 在禁食期间维持血糖正常的药物，还涉及增强随后胰岛素作用的机制。我们的 假设是根据我们的初步数据和已发表的数据制定的，这些数据表明血糖升高 预处理的小鼠在高胰岛素-正常血糖钳夹过程中的耐受性和胰岛素敏感性的改善 胰高血糖素，或有效的胰高血糖素受体激动剂。然而，胰高血糖素如何调节胰岛素作用以及 负责这些胰岛素/胰高血糖素联合效应的组织仍未解决。