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

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

Author information

1
Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
2
Department of Pathology, Genentech Inc., South San Francisco, CA 94080, USA.
3
Department of Biomedical Imaging, Genentech Inc., South San Francisco, CA 94080, USA.
4
Department of Bioinformatics, Genentech Inc., South San Francisco, CA 94080, USA.
5
Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA.
6
The West Coast Metabolomics Center, University of California, Davis, CA 95616, USA.
7
Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: peterson.andrew@gene.com.
8
Department of Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA. Electronic address: ballan@ngmbio.com.

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.

PMID:
26166562
DOI:
10.1016/j.celrep.2015.06.034
[Indexed for MEDLINE]
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