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