Glucagon secretion is regulated by circulating glucose, but it has turned out that amino acids also play an important role and that hepatic amino acid metabolism and glucagon are linked in a mutual feedback cycle, the liver–α-cell axis. On the basis of this knowledge, we hypothesized that hepatic steatosis might impair glucagon’s action on hepatic amino acid metabolism and lead to hyperaminoacidemia and hyperglucagonemia. We subjected 15 healthy lean and 15 obese steatotic male participants to a pancreatic clamp with somatostatin and evaluated hepatic glucose and amino acid metabolism when glucagon was at basal levels and at high physiological levels. The degree of steatosis was evaluated from liver biopsy specimens. Total RNA sequencing of liver biopsy specimens from the obese steatotic individuals revealed perturbations in the expression of genes predominantly involved in amino acid metabolism. This group was characterized by fasting hyperglucagonemia, hyperaminoacidemia, and no lowering of amino acid levels in response to high levels of glucagon. Endogenous glucose production was similar between lean and obese individuals. Our results suggest that hepatic steatosis causes resistance to the effect of glucagon on amino acid metabolism. This results in increased amino acid concentrations and increased glucagon secretion, providing a likely explanation for fatty liver–associated hyperglucagonemia.

中文翻译：

---

患有肝脂肪变性的肥胖受试者在氨基酸转换水平上的胰高血糖素抵抗

胰高血糖素分泌受循环葡萄糖调节，但事实证明，氨基酸也起着重要作用，肝脏氨基酸代谢和胰高血糖素在相互反馈循环中相互关联，即肝-α-细胞轴。基于这些知识，我们假设肝脏脂肪变性可能会损害胰高血糖素对肝脏氨基酸代谢的作用，导致高氨基酸血症和高胰高血糖素血症。我们对 15 名健康的瘦人和 15 名肥胖的脂肪变性男性参与者进行了含有生长抑素的胰腺钳夹，并评估了胰高血糖素处于基础水平和高生理水平时的肝脏葡萄糖和氨基酸代谢。从肝活检标本评估脂肪变性的程度。来自肥胖脂肪变性个体的肝活检标本的总 RNA 测序揭示了主要参与氨基酸代谢的基因表达的扰动。该组的特征是空腹高胰高血糖素血症、高氨基酸血症，并且没有因高水平胰高血糖素而降低氨基酸水平。瘦人和肥胖个体之间的内源性葡萄糖产生相似。我们的结果表明，肝脂肪变性导致对胰高血糖素对氨基酸代谢作用的抵抗。这导致氨基酸浓度增加和胰高血糖素分泌增加，为脂肪肝相关的高胰高血糖素血症提供了可能的解释。并且不会因高水平的胰高血糖素而降低氨基酸水平。瘦人和肥胖个体之间的内源性葡萄糖产生相似。我们的结果表明，肝脂肪变性导致对胰高血糖素对氨基酸代谢作用的抵抗。这导致氨基酸浓度增加和胰高血糖素分泌增加，为脂肪肝相关的高胰高血糖素血症提供了可能的解释。并且不会因高水平的胰高血糖素而降低氨基酸水平。瘦人和肥胖个体之间的内源性葡萄糖产生相似。我们的结果表明，肝脂肪变性导致对胰高血糖素对氨基酸代谢作用的抵抗。这导致氨基酸浓度增加和胰高血糖素分泌增加，为脂肪肝相关的高胰高血糖素血症提供了可能的解释。