Cell Metabolism
Volume 25, Issue 6, 6 June 2017, Pages 1362-1373.e5
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Article
Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation

https://doi.org/10.1016/j.cmet.2017.05.011Get rights and content
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Highlights

  • Interrupted glucagon signaling (IGS) stimulates mouse and human α cell proliferation

  • IGS alters hepatic gene expression and increases serum amino acid levels

  • L-glutamine is required for high amino acid stimulation of α cell proliferation

  • IGS leads to α cell expression of SLC38A5, which enhances α cell proliferation

Summary

Decreasing glucagon action lowers the blood glucose and may be useful therapeutically for diabetes. However, interrupted glucagon signaling leads to α cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for α cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human α cells was mTOR and FoxP transcription factor dependent. Changes in hepatic amino acid (AA) catabolism gene expression predicted the observed increase in circulating AAs. Mimicking these AA levels stimulated α cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. α cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in α cell proliferation. These results indicate a hepatic α islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate α cell proliferation and mass via mTOR-dependent nutrient sensing.

Keywords

pancreatic islet
glucagon
glucagon receptor
alpha cell
amino acid
glutamine
proliferation
Slc38a5
amino acid transport
liver

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