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.

摘要 在过去几十年中逐渐形成的久坐不动和饮食的生活方式已经被一种 代谢紊乱如高血压、血脂异常、肥胖症的发病率空前增加 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， 通过胰腺α细胞刺激肝葡萄糖产生和恢复 真的。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组成部分 这些作用在1型和2型糖尿病患者中得到了广泛研究。 新出现的证据表明，胰高血糖素调节一系列的行动，这可能是相当可取的， 代谢综合征患者。事实上，含有胰高血糖素激动作用的潜在药物靶点具有 成为治疗肥胖症和糖尿病的有前途的候选药物。然而，目标组织和分子 负责这些有益效果的机制尚不清楚。指导这一研究的科学假设 建议胰高血糖素，通过其肝受体（GcgR），加强TORC 2依赖性成分， 胰岛素信号级联，下丘脑GcgR信号进一步增强，以启动个体 以增强全身葡萄糖代谢。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，也参与增强随后胰岛素作用的机制。我们 根据我们的初步数据和已发表的数据，我们提出了一个假设，证明葡萄糖增加 在高胰岛素-正常血糖钳夹过程中， 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， 负责这些胰岛素/胰高血糖素联合作用的组织仍然没有得到解决。