Research Article: ?-cell SLC38A5 supports amino acid-induced ?-cell proliferation and glucagon secretion
Abstract:
Pancreatic ? cells are key regulators of glucose homeostasis, and dysregulated glucagon secretion contributes to hyperglycemia in diabetes. Amino acids strongly stimulate ?-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 ? cells, but its ?-cell–autonomous role in nutrient sensing is unclear.
We generated an ?-cell-specific Slc38a5 knockout mouse model to examine the direct contribution of SLC38A5 to ?-cell proliferation and nutrient-sensitive signaling. Mice were treated with a monoclonal GCGR antibody (GCGR mAb) to induce hyperaminoacidemia. ?-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 ? cells in both mice and humans. Despite comparable increases in circulating amino acids upon GCGR mAb treatment, ?-cell-specific deletion of Slc38a5 markedly attenuated amino acid-induced glucagon secretion and ?-cell proliferation in both sexes demonstrating an ?-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 ?-cell proliferation, highlighting its role in ?-cell nutrient sensing and adaptation.
Introduction:
Pancreatic ? cells are key regulators of glucose homeostasis, and dysregulated glucagon secretion contributes to hyperglycemia in diabetes. Amino acids strongly stimulate ?-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 ? cells, but its ?-cell–autonomous role in nutrient sensing is unclear.
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