@article{bedd45ce829045409db261f53d9ec627,
title = "Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation",
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.",
keywords = "Slc38a5, alpha cell, amino acid, amino acid transport, glucagon, glucagon receptor, glutamine, liver, pancreatic islet, proliferation",
author = "Dean, {E. Danielle} and Mingyu Li and Nripesh Prasad and Wisniewski, {Scott N.} and {Von Deylen}, Alison and Jason Spaeth and Lisette Maddison and Anthony Botros and Sedgeman, {Leslie R.} and Nadejda Bozadjieva and Olga Ilkayeva and Anastasia Coldren and Greg Poffenberger and Alena Shostak and Semich, {Michael C.} and Aamodt, {Kristie I.} and Neil Phillips and Hai Yan and Ernesto Bernal-Mizrachi and Corbin, {Jackie D.} and Vickers, {Kasey C.} and Levy, {Shawn E.} and Chunhua Dai and Christopher Newgard and Wei Gu and Roland Stein and Wenbiao Chen and Powers, {Alvin C.}",
note = "Funding Information: We thank Dr. Daniel Drucker (Toronto, ON) for helpful discussion and generously providing GcgrHep?/? mice. We also thank Drs. David Jacobson, Lisa Zimmerman, Daniel Liebler, Pierre Massion, Carlos Arteaga, Graham Carpenter, Volker Haase, Brian Wadzinski, Robert Coffey, Owen McGuinness, Masa Shiota, Alan Cherrington, Richard O'Brien, Maureen Gannon (Vanderbilt), Donald McClain (Wake Forest), Doris Stoffers and Diana Stanescu (U. Pennsylvania), and Cindy Roy (Johns Hopkins) for helpful discussion. The Gcgr?/? mice were generously provided by Dr. Maureen Charron. Special thanks to Mr. Scott Wright (custom media preparation) and to Dr. Derek Yee, Ms. Kayla McCloud, Ms. Aysha Mushtaq, Ms. Ella Baum, and Mr. Gerald Wakefield for technical support. This work was supported by grants from JDRF Research (5-2011-379, 5-2013-111, 2-SRA-2016-149-Q-R), Department of Veterans Affairs (BX000666), NIH (DK66636, DK72473, DK89572, DK89538, DK97829, DK94199, DK104211, and DK106755), and Vanderbilt Diabetes Research and Training Center, including its Islet Procurement and Analysis and Hormone and Analytical Services Cores (DK20593). E.D.D. was supported by a Vanderbilt Molecular Endocrinology Training Program grant (5T32 DK07563) and a JDRF Postdoctoral Fellowship Award (3-PDF-2014-189-A-N). W.G. is an employee of Amgen. H.Y. is an employee of REMD Biotherapeutics. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jun,
day = "6",
doi = "10.1016/j.cmet.2017.05.011",
language = "English (US)",
volume = "25",
pages = "1362--1373.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "6",
}