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.
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•Interrupted glucagon signaling (IGS) stimulates mouse and human α cell proliferation•IGS alters hepatic gene expression and increases serum amino acid levels•L-glutamine is required for high amino acid stimulation of α cell proliferation•IGS leads to α cell expression of SLC38A5, which enhances α cell proliferation
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.
