Glucagon secretion and action in humans

胰高血糖素在人体中的分泌和作用

• 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
• 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

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.

这项应用的总体目标是更好地了解高血糖素分泌和作用的异质性。 这是我们在非糖尿病受试者中观察到的。餐后高血糖素分泌异常是 被认为在2型糖尿病的发病机制中起着关键作用。而胰高血糖素对葡萄糖的作用 新陈代谢是相当好的特征，对于为什么个体在他们的 肝脏对这种激素的反应。更重要的是，似乎胰升糖素的增强作用 患有肝脏脂肪变性的人，肝脏对氨基酸的清除受到损害。尽管有一些证据表明 胰高血糖素刺激脂肪分解和脂肪酸氧化，一篇文献综述表明，这些方面 高血糖素的作用一直被忽视。此外，没有人理解是否有能力 刺激内源性葡萄糖的产生和糖异生不依赖于对氨基酸和 脂类代谢。在啮齿动物中，α细胞的质量部分地受循环氨基酸浓度的调节， 反过来刺激胰升糖素的分泌(增加肝脏对氨基酸的清除)。这个肝α细胞 轴在人类中是否存在是不确定的。然而，我们的初步数据显示，在限制热量的情况下，禁食 随着几种氨基酸的空腹浓度的降低，胰高血糖素也会降低。因为卡路里限制是 已知可以改善肝脏脂肪变性和改善胰岛素作用，这提供了一个机会来评估如何 肝脏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， 蛋白质和脂肪代谢。作为我们先前工作的一部分，我们开发了新的方法来量化高血糖素 体内分泌，因此我们提议的实验也将检查循环中氨基的剧烈变化 酸浓度改变了α细胞的功能。我们提出的实验将提供新的关于 人体内高血糖素的分泌和作用。