α-cell SLC38A5 supports amino acid-induced α-cell proliferation and glucagon secretion

Pancreatic α cells are key regulators of glucose homeostasis, and dysregulated glucagon secretion contributes to hyperglycemia in diabetes. Amino acids strongly stimulate α-cell proliferation and glucagon release, yet the transport mechanisms underlying these responses remain incompletely defined. The neutral amino acid transporter SLC38A5 is highly enriched in α cells, but its α-cell-autonomous role in nutrient sensing is unclear.

We generated an α-cell-specific Slc38a5 knockout mouse model to examine the direct contribution of SLC38A5 to α-cell proliferation and nutrient-sensitive signaling. Mice were treated with a monoclonal GCGR antibody (GCGR mAb) to induce hyperaminoacidemia. α-cell proliferation and ribosomal protein S6 phosphorylation were assessed under conditions of elevated circulating amino acids.

Slc38a5/SLC38A5 gene expression was highly enriched in pancreatic α cells in both mice and humans. Despite comparable increases in circulating amino acids upon GCGR mAb treatment, α-cell-specific deletion of Slc38a5 markedly attenuated amino acid-induced glucagon secretion and α-cell proliferation in both sexes demonstrating an α-cell-autonomous requirement for SLC38A5. Phosphorylation of ribosomal protein S6 at Ser235/236 or Ser240/244 was unaffected by SLC38A5 deletion, indicating that global nutrient-responsive signaling at this site is largely SLC38A5-independent.

These data identify SLC38A5 as a mediator linking amino acid availability to α-cell proliferation, highlighting its role in α-cell nutrient sensing and adaptation.