Interrupted Glucagon Signaling Reveals Hepatic α Cell Axis and Role for L-Glutamine in α Cell Proliferation.
Journal Article (Journal Article)
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.
Full Text
Duke Authors
Cited Authors
- Dean, ED; Li, M; Prasad, N; Wisniewski, SN; Von Deylen, A; Spaeth, J; Maddison, L; Botros, A; Sedgeman, LR; Bozadjieva, N; Ilkayeva, O; Coldren, A; Poffenberger, G; Shostak, A; Semich, MC; Aamodt, KI; Phillips, N; Yan, H; Bernal-Mizrachi, E; Corbin, JD; Vickers, KC; Levy, SE; Dai, C; Newgard, C; Gu, W; Stein, R; Chen, W; Powers, AC
Published Date
- June 6, 2017
Published In
Volume / Issue
- 25 / 6
Start / End Page
- 1362 - 1373.e5
PubMed ID
- 28591638
Pubmed Central ID
- PMC5572896
Electronic International Standard Serial Number (EISSN)
- 1932-7420
Digital Object Identifier (DOI)
- 10.1016/j.cmet.2017.05.011
Language
- eng
Conference Location
- United States