Glucagon and Amino Acids Are Linked in a Mutual Feedback Cycle: The Liver–α-Cell Axis

Abstract

Glucagon is usually viewed as an important counterregulatory hormone in glucose metabolism, with actions opposing those of insulin. Evidence exists that shows glucagon is important for minute-to-minute regulation of postprandial hepatic glucose production, although conditions of glucagon excess or deficiency do not cause changes compatible with this view. In patients with glucagon-producing tumors (glucagonomas), the most conspicuous signs are skin lesions (necrolytic migratory erythema), while in subjects with inactivating mutations of the glucagon receptor, pancreatic swelling may be the first sign; neither condition is necessarily associated with disturbed glucose metabolism. In glucagonoma patients, amino acid turnover and ureagenesis are greatly accelerated, and low plasma amino acid levels are probably at least partly responsible for the necrolytic migratory erythema, which resolves after amino acid administration. In patients with receptor mutations (and in knockout mice), pancreatic swelling is due to α-cell hyperplasia with gross hypersecretion of glucagon, which according to recent groundbreaking research may result from elevated amino acid levels. Additionally, solid evidence indicates that ureagenesis, and thereby amino acid levels, is critically controlled by glucagon. Together, this constitutes a complete endocrine system; feedback regulation involving amino acids regulates α-cell function and secretion, while glucagon, in turn, regulates amino acid turnover.

Evidence of a liver–alpha cell axis in humans: hepatic insulin resistance attenuates relationship between fasting plasma glucagon and glucagonotropic amino acids

“…These observations support our hypothesis that impaired hepatic glucagon signalling, potentially due to fat accumulation in the liver and resulting hepatic insulin resistance [14], impairs glucagon's ability to lower plasma levels of non-BCAAs. Taken together, the current findings support the proposed existence and importance of a liver-alpha cell axis in humans [8].…”

“…In addition, prolonged administration of non-BCAAs to rodents results in alpha cell hyperplasia and hyperglucagonaemia [7,29]. These observations have led to the proposal of the existence of a hitherto neglected feedback loop between the pancreatic alpha cells and the liver [8,30]. Consistent with this proposed feedback loop, individuals with glucagon-producing tumours have decreased levels of plasma amino acids [11,31], and, conversely, individuals with glucagon receptor mutations [10,32,33] and mice with glucagon receptor deficiency [30,34] exhibit increased levels of plasma amino acids.…”

“…With the use of glucagon receptor antagonists in rodents and in individuals with type 2 diabetes, it has finally been agreed that inappropriate glucagon secretion makes an important contribution to hyperglycaemia in diabetes [2][3][4]. However, in addition to its glucose-regulatory effects, glucagon also regulates amino acid metabolism (ureagenesis) in the liver [5] and, conversely, amino acids stimulate the secretion of glucagon [6], forming a feedback loop between the liver and the pancreatic alpha cells [7,8]-a liver-alpha cell axis. This glucagon-amino acid feedback loop may be as important for metabolism as the glucagon-glucose loop [9].…”

Glucagon receptor signalling – backwards and forwards

“…This concept was initially supported by observations in experimental animals during chronic administration of glucagon, and has now been validated in humans receiving exogenous glucagon 'replacement' during pancreatic clamp studies [13], or patients with a glucagonoma [14]. The opposite effects are evident in the setting of inactivating GCGr mutations, or after administration of GCGr antagonists.…”

“…The opposite effects are evident in the setting of inactivating GCGr mutations, or after administration of GCGr antagonists. There is also recent evidence that hyperaminoacidemia may modulate α-cell activity reciprocally by a feedback loop between the liver and pancreas [14].…”