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：
10442194
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/10442194
关键词：
Acute Adipose tissue Agonist Alpha Cell Amino Acids Beta Cell Body Weight decreased Caloric Restriction Catabolism Cell physiology Cell secretion Cells Data Defect Fasting Fatty Liver Fatty acid glycerol esters Functional disorder Glucagon Glucagon Receptor Gluconeogenesis Glucose Health Hepatic Hepatocyte Heterogeneity Hormones Human 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.

该应用的总体目的是更好地了解臀部分泌和动作的异质性我们已经在非糖尿病患者中观察到。后期的异常胰高血糖素分泌是公认在2型糖尿病的发病机理中起关键作用。而胰高血糖素对葡萄糖的作用新陈代谢的特征是相当合理的，几乎没有理解个人的原因肝素对这种骑马的反应。更重要的是，似乎胰高血糖素对增强的作用肝脂肪变性患者受损氨基酸的肝清除率会受损。虽然有一些证据谷子刺激脂解和脂肪酸氧化，文献的评论表明这些方面胰高血糖素的作用被忽略了。此外，对是否能力是否有任何了解刺激内源性葡萄糖的产生和糖异生的作用与氨基酸的作用无关脂质代谢。在啮齿动物中，α细胞质量部分由循环氨基酸浓度调节，氨基酸浓度，该氨基酸浓度反过来刺激了胰高血糖素的分泌（氨基酸的肝清除率增加）。是否该肝脏-α细胞人类中的轴是不确定的。但是，我们的初步数据表明，使用热量限制禁食胰高血糖素与几种氨基酸的禁食浓度一致下降。由于热量限制是已知可以改善肝脂肪变性并改善胰岛素作用，这提供了一个机会来评估如何肝脂肪含量的变化改变了对胰高血糖素的反应 - 特别是适用于碳水化合物，蛋白质和脂肪代谢。作为我们先前工作的一部分，我们开发了量化胰高血糖素的新方法体内分泌，以便我们提出的实验还将检查循环氨基的急性变化酸浓度改变了α细胞功能。我们提出的实验将提供有关有关的新颖信息胰高血糖素的分泌和人类的作用。