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 alpha cell proliferation. To identify postulated hepatic-derived circulating factor(s) responsible for alpha cell proliferation, we used transcriptomics/proteomics/metabolomics in three models of interrupted glucagon signaling and found that proliferation of mouse, zebrafish, and human alpha 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 alpha cell proliferation in a newly developed in vitro assay with L-glutamine being a critical AA. alpha cell expression of the AA transporter Slc38a5 was markedly increased in mice with interrupted glucagon signaling and played a role in alpha cell proliferation. These results indicate a hepatic alpha islet cell axis where glucagon regulates serum AA availability and AAs, especially L-glutamine, regulate alpha cell proliferation and mass via mTOR-dependent nutrient sensing.