Glucagon secretion and action in humans

本申请的总体目的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的。餐后期间胰高血糖素分泌异常， 被认为在2型糖尿病的发病机制中起关键作用。胰高血糖素对葡萄糖的作用 代谢是合理的，很好的特点，很少有人了解为什么个人在他们的不同。 肝脏对这种激素的反应。更重要的是，胰高血糖素增强 在患有肝脂肪变性的人中，氨基酸的肝清除受损。尽管有证据表明 胰高血糖素刺激脂解和脂肪酸氧化，文献综述表明这些方面 胰高血糖素的作用被忽略了此外，不了解是否有能力 刺激内源性葡萄糖产生和葡萄糖异生不依赖于对氨基酸的作用， 脂质代谢在啮齿类动物中，α细胞质量部分受循环氨基酸浓度的调节， 继而刺激胰高血糖素分泌（增加氨基酸肝清除率）。不管这个肝脏α细胞 轴是否存在于人类中尚不确定。然而，我们的初步数据显示， 胰高血糖素与几种氨基酸的空腹浓度一致地降低。由于热量限制是 已知可改善肝脂肪变性和改善胰岛素作用，这提供了一个评估如何 肝脏脂肪含量的变化改变了对胰高血糖素的反应-特别是当它应用于碳水化合物时， 蛋白质和脂肪代谢。作为我们先前工作的一部分，我们已经开发了新的方法来定量胰高血糖素 因此，我们提出的实验也将检查循环氨基的急性变化， 酸浓度改变α细胞功能。我们提出的实验将提供关于以下方面的新信息： 胰高血糖素分泌和人体作用。

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.