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

Cell metabolism | Jun 6, 2017

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.

Pubmed ID: 28591638 RIS Download

Mesh terms: Amino Acid Transport Systems, Neutral | Animals | Cell Proliferation | Glucagon | Glutamine | Liver | Mice | Mice, Knockout | Signal Transduction | Zebrafish | Zebrafish Proteins

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Associated grants

  • Agency: NIDDK NIH HHS, Id: T35 DK007383
  • Agency: NIDDK NIH HHS, Id: R01 DK090570
  • Agency: NIDDK NIH HHS, Id: P60 DK020593
  • Agency: NIDDK NIH HHS, Id: UC4 DK104211
  • Agency: NIDDK NIH HHS, Id: P30 DK058404
  • Agency: NIDDK NIH HHS, Id: U01 DK072473
  • Agency: NIGMS NIH HHS, Id: R25 GM062459
  • Agency: NIDDK NIH HHS, Id: U01 DK089572
  • Agency: BLRD VA, Id: I01 BX002728
  • Agency: NIDDK NIH HHS, Id: R33 DK066636
  • Agency: NIGMS NIH HHS, Id: T32 GM007347
  • Agency: BLRD VA, Id: I01 BX000666
  • Agency: NIDDK NIH HHS, Id: R01 DK094199
  • Agency: NIDDK NIH HHS, Id: P30 DK020593
  • Agency: NIDDK NIH HHS, Id: R01 DK069603
  • Agency: NIDDK NIH HHS, Id: R24 DK106755
  • Agency: NIDDK NIH HHS, Id: R01 DK050203
  • Agency: NIDDK NIH HHS, Id: T32 DK007563
  • Agency: NHLBI NIH HHS, Id: P01 HL116263
  • Agency: NIDDK NIH HHS, Id: R01 DK097829
  • Agency: NIDDK NIH HHS, Id: U01 DK089538
  • Agency: NIDDK NIH HHS, Id: R21 DK066636
  • Agency: NIGMS NIH HHS, Id: T32 GM007315

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