Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation

E. Danielle Dean, Mingyu Li, Nripesh Prasad, Scott N. Wisniewski, Alison Von Deylen, Jason Spaeth, Lisette Maddison, Anthony Botros, Leslie R. Sedgeman, Nadejda Bozadjieva, Olga Ilkayeva, Anastasia Coldren, Greg Poffenberger, Alena Shostak, Michael C. Semich, Kristie I. Aamodt, Neil Phillips, Hai Yan, Ernesto Bernal-Mizrachi, Jackie D. CorbinKasey C. Vickers, Shawn E. Levy, Chunhua Dai, Christopher Newgard, Wei Gu, Roland Stein, Wenbiao Chen, Alvin C. Powers

Research output: Contribution to journalArticlepeer-review

59 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1362-1373.e5
JournalCell Metabolism
Volume25
Issue number6
DOIs
StatePublished - Jun 6 2017

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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