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

Cell Rep. 2015 Jul 21;12(3):495-510. doi: 10.1016/j.celrep.2015.06.034. Epub 2015 Jul 9.

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.

MeSH terms

  • Amino Acids / metabolism*
  • Animals
  • Cell Proliferation
  • Glucagon / metabolism*
  • Liver / cytology*
  • Liver / metabolism*
  • Metabolism
  • Mice
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism*

Substances

  • Amino Acids
  • Glucagon
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse

Associated data

  • GEO/GSE68145