Clinical Metabolic PhysiologySteno Diabetes Center Copenhagen, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
Department of Clinical Medicine Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Eur J Endocrinol. 2018 Jun;178(6):R267-R280. doi: 10.1530/EJE-18-0197. Epub 2018 Apr 20.
Hyperglucagonaemia (in the fasting as well as in the postprandial state) is considered a core pathophysiological component of diabetes and is found to contribute substantially to the hyperglycaemic state of diabetes. Hyperglucagonaemia is usually viewed upon as a consequence of pancreatic alpha cell insensitivity to the glucagon-suppressive effects of glucose and insulin. Since we observed that the well-known hyperglucagonaemic response to oral glucose in patients with type 2 diabetes is exchanged by normal suppression of plasma glucagon levels following isoglycaemic intravenous glucose administration in these patients, we have been focusing on the gut and gut-derived factors as potential mediators of diabetic hyperglucagonaemia. In a series of clinical experiments, we have elucidated the role of gut-derived factors in diabetic hyperglucagonaemia and shown that glucose-dependent insulinotropic polypeptide promotes hyperglucagonaemia and that glucagon, hitherto considered a pancreas-specific hormone, may also be secreted from extrapancreatic tissues - most likely from proglucagon-producing enteroendocrine cells. Furthermore, our observation that fasting hyperglucagonaemia is unrelated to the diabetic state, but strongly correlates with obesity, liver fat content and circulating amino acids, has made us question the common 'pancreacentric' and 'glucocentric' understanding of hyperglucagonaemia and led to the hypothesis that steatosis-induced hepatic glucagon resistance (and reduced amino acid turnover) and compensatory glucagon secretion mediated by increased circulating amino acids constitute a complete endocrine feedback system: the liver-alpha cell axis. This article summarises the physiological regulation of glucagon secretion in humans and considers new findings suggesting that the liver and the gut play key roles in determining fasting and postabsorptive circulating glucagon levels.
高胰高血糖素血症（无论是在空腹状态还是餐后状态）被认为是糖尿病的核心病理生理组成部分，并且被发现对糖尿病的高血糖状态有很大贡献。高胰高血糖素血症通常被认为是胰腺α细胞对葡萄糖和胰岛素的胰高血糖素抑制作用不敏感的结果。由于我们观察到，在 2 型糖尿病患者中，口服葡萄糖会引起众所周知的高胰高血糖素血症反应，但在这些患者中，经等葡萄糖静脉内葡萄糖给药后，血浆胰高血糖素水平会正常抑制，因此我们一直关注肠道和肠道来源的因素作为糖尿病高胰高血糖素血症的潜在介质。在一系列临床实验中，我们阐明了肠道来源的因素在糖尿病高胰高血糖素血症中的作用，并表明葡萄糖依赖性胰岛素释放肽促进高胰高血糖素血症，而胰高血糖素，迄今为止被认为是一种胰腺特异性激素，也可能从胰腺外组织分泌 - 最有可能来自产生胰高血糖素的肠内分泌细胞。此外，我们观察到空腹高胰高血糖素血症与糖尿病状态无关，但与肥胖、肝脂肪含量和循环氨基酸强烈相关，这使我们对常见的“胰腺中心”和“糖中心”对高胰高血糖素血症的理解产生了质疑，并提出了假说，即脂肪变性诱导的肝胰高血糖素抵抗（和减少的氨基酸周转率）和通过增加的循环氨基酸介导的代偿性胰高血糖素分泌构成了一个完整的内分泌反馈系统：肝-α细胞轴。本文总结了人类胰高血糖素分泌的生理调节，并考虑了新的发现，表明肝脏和肠道在决定空腹和吸收后循环胰高血糖素水平方面发挥关键作用。
