Glucagon Couples Hepatic Amino Acid Catabolism to mTOR-Dependent Regulation of α-Cell Mass

Abstract

Understanding the regulation of islet cell mass has important implications for the discovery of regenerative therapies for diabetes. The liver plays a central role in metabolism and the regulation of endocrine cell number, but liver-derived factors that regulate α-cell and β-cell mass remain unidentified. We propose a nutrient-sensing circuit between liver and pancreas in which glucagon-dependent control of hepatic amino acid metabolism regulates α-cell mass. We found that glucagon receptor inhibition reduced hepatic amino acid catabolism, increased serum amino acids, and induced α-cell proliferation in an mTOR-dependent manner. In addition, mTOR inhibition blocked amino-acid-dependent α-cell replication ex vivo and enabled conversion of α-cells into β-like cells in vivo. Serum amino acids and α-cell proliferation were increased in neonatal mice but fell throughout postnatal development in a glucagon-dependent manner. These data reveal that amino acids act as sensors of glucagon signaling and can function as growth factors that increase α-cell proliferation.

Evidence of Extrapancreatic Glucagon Secretion in Man

“…In line with this, pancreatic a-cell hyperplasia is observed in total disruption of glucagon receptor signaling in mice (46,47) and during partial disruption of glucagon receptor signaling in humans (48). Furthermore, studies in mice with complete disruption of glucagon receptor signaling specifically in the liver have pointed to the existence of a circulating factor, which stimulates a-cell proliferation when glucagon signaling is abolished (49,50). Perhaps this factor is also formed in response to the surgical removal of the pancreas, and thus in the absence of pancreatic a-cells, the enteroendocrine L cells, expressing the GCG gene, might be upregulated instead.…”

Virgin Beta Cells Persist throughout Life at a Neogenic Niche within Pancreatic Islets

“…This represents an important conceptual shift: it suggests that the signal(s) that control plasticity at the neogenic niche are associated with the constellation of cell types and autonomic nerves that converge at the periphery of healthy islets instead of being induced in response to major pancreas remodeling. Of course, this does not rule out a scenario where transdifferentiation is further stimulated under certain (patho)physiological circumstances, as was recently demonstrated when blockade of glucagon-dependent amino acid clearance by the liver promoted alpha cell proliferation, accompanied by increased alpha to beta transdifferentiation (Solloway et al, 2015).…”

Loss of mTORC1 signaling alters pancreatic α cell mass and impairs glucagon secretion

“…The amino acids arginine, alanine, and glutamine potentiate glucagon secretion and this effect is suppressed by high glucose in an insulin-independent manner (13). Recent studies demonstrate that interruption of glucagon receptor signaling by genetic inactivation or treatment with small molecules or glucagon receptor antibodies increases amino acid availability and leads to increased α cell proliferation in an mTORdependent manner (12,(14)(15)(16)(17). These findings support the concept that α cell mass and glucagon secretion are sensitive to extracellular signals including nutrients (amino acids, glucose) and growth factors (insulin) and that the mTORC1 pathway may be involved as a downstream regulator of one or both of these processes.…”

“…Insulin inhibits glucagon gene transcription and secretion and promotes α cell proliferation by activation of IRS2/PI3K/Akt signaling (9,10). α Cell proliferation is reduced by treatment with the mTOR complex 1 (mTORC1) inhibitor rapamycin, suggesting that downstream of the insulin receptor mTORC1 mediates the effects of insulin on α cell mass and glucagon secretion (11,12). The amino acids arginine, alanine, and glutamine potentiate glucagon secretion and this effect is suppressed by high glucose in an insulin-independent manner (13).…”