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

Publication date: 6 June 2017
Source:Cell Metabolism, Volume 25, Issue 6
Author(s): 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. Corbin, Kasey C. Vickers, Shawn E. Levy, Chunhua Dai, Christopher Newgard, Wei Gu, Roland Stein, Wenbiao Chen, Alvin C. Powers
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.

Graphical abstract

Teaser

Blocking glucagon action lowers blood glucose, but also results in hyperplasia of glucagon-secreting α cells in pancreatic islets. Dean et al. demonstrate that loss of hepatic glucagon signaling elevates circulating amino acids and leads to α cell proliferation, thus revealing a hepatic α cell axis.


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