Glucagon secretion and action in humans

胰高血糖素在人体中的分泌和作用

基本信息

批准号：
10630964
负责人：
Adrian Vella
金额：
$ 52.05万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630964
关键词：
Acute Adipose tissue Agonist Alpha Cell Amino Acids Beta Cell Body Weight decreased Caloric Restriction Catabolism Cell physiology Cell secretion Data Defect Dissociation Fasting Fatty Liver Fatty acid glycerol esters Functional disorder Glucagon Glucagon Receptor Gluconeogenesis Glucose Health Hepatic Hepatocyte Heterogeneity Hormones Human Hydrolysis Hyperglycemia Impairment Individual Insulin Lead Leucine Lipase Lipolysis Liver Measures Methods Non-Insulin-Dependent Diabetes Mellitus Obesity Palmitates Pathogenesis Persons Play Postprandial Period Prediabetes syndrome Proteins Reporting Review Literature Rodent Role Series Thinness Tissues Triglycerides Work adult obesity antagonist carbohydrate metabolism diabetes pathogenesis diabetes risk experimental study fasting glucose fatty acid oxidation glucose metabolism glucose production improved in vivo lipid metabolism liver metabolism non-diabetic novel obese person protein metabolism response restoration transamination uptake

项目摘要

The overall aim of this application is to better understand the heterogeneity in glucagon secretion and action that we have observed in nondiabetic subjects. Abnormal glucagon secretion in the post-prandial period is recognized to play a key role in the pathogenesis of type 2 diabetes. While glucagon’s actions on glucose metabolism are reasonably well characterized, there is little understanding as to why individuals differ in their hepatic responses to this hormone. More importantly, it appears that the actions of glucagon to enhance hepatic clearance of amino acids is impaired in people with hepatic steatosis. Although there is some evidence that glucagon stimulates lipolysis and fatty acid oxidation, a review of the literature suggests that these aspects of glucagon’s actions have been ignored. In addition, there is no understanding as to whether the ability to stimulate endogenous glucose production and gluconeogenesis is independent of actions on amino acid and lipid metabolism. In rodents, α-cells mass is, in part, regulated by circulating amino acid concentrations which, in turn stimulate glucagon secretion (increasing hepatic clearance of amino acids). Whether this liver-α-cell axis is extant in humans is uncertain. However, our preliminary data shows that with caloric restriction fasting glucagon decreases in concert with fasting concentrations of several amino acids. Since caloric restriction is known to ameliorate hepatic steatosis and improve insulin action, this provides an opportunity to assess how changes in hepatic fat content alter the response to glucagon – specifically as it applies to carbohydrate, protein, and fat metabolism. As part of our prior work we have developed new methods to quantify glucagon secretion in vivo so that our proposed experiments will also examine how acute changes in circulating amino acid concentrations alter α-cell function. The experiments we propose will provide novel new information about glucagon secretion and action in humans.

该应用的总体目标是更好地了解胰高血糖素分泌和作用的异质性我们在非糖尿病受试者中观察到餐后胰高血糖素分泌异常。胰高血糖素对葡萄糖的作用被认为在 2 型糖尿病的发病机制中发挥着关键作用。新陈代谢的特征相当清楚，但对于为什么个体的新陈代谢不同却知之甚少。更重要的是，肝脏对这种激素的反应似乎增强了。尽管有一些证据表明，肝脂肪变性患者的肝脏氨基酸清除率受到损害。胰高血糖素刺激脂肪分解和脂肪酸氧化，文献综述表明这些方面此外，尚不清楚胰高血糖素的作用是否有能力。刺激内源性葡萄糖产生和糖异生独立于氨基酸和在啮齿类动物中，α细胞质量部分受到循环氨基酸浓度的调节，反过来刺激胰高血糖素分泌（增加肝脏的氨基酸清除率）。然而，我们的初步数据表明，在限制热量禁食的情况下，轴是否存在于人类中尚不确定。由于热量限制是胰高血糖素与几种氨基酸的空腹浓度一致而降低的。已知可以改善肝脂肪变性并改善胰岛素作用，这提供了一个评估如何肝脂肪含量的变化改变了对胰高血糖素的反应——特别是当它适用于碳水化合物时，作为我们之前工作的一部分，我们开发了量化胰高血糖素的新方法。体内分泌，因此我们提出的实验还将检查循环氨基酸的急剧变化我们提出的实验将提供有关酸浓度改变α细胞功能的新信息。胰高血糖素在人体中的分泌和作用。