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

作者：Mark J. Solloway, Azadeh Madjidi, Chunyan Gu, Jeff Eastham-Anderson, Holly J. Clarke, Noelyn M. Kljavin, Jose Zavala‐Solorio, Lance Kates, Brad A. Friedman, Matt Brauer, Jianyong Wang, Oliver Fiehn, Ganesh Kolumam, Howard M. Stern, John B. Lowe, Andrew S. Peterson, Bernard B. Allan · 发表于：Cell Reports · 年份：2015 · DOI：10.1016/j.celrep.2015.06.034 · 被引用次数：196 · 研究领域：Pancreatic function and diabetes、Metabolism, Diabetes, and Cancer、Diabetes and associated disorders

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.