CBP/p300 is critical for the expansion and maintenance of functional pancreatic α cell mass.

Pancreatic α cell senses amino acid availability to adjust secretion function and proliferation, yet the underlying molecular mechanisms remain unclear. Here, α cell-specific deletion of CBP/p300 in mice leads to hypoglucagonemia and hyperaminoacidemia, along with decreased functional pancreatic α cell mass due to impaired cell proliferation, dedifferentiation, and cell loss. The knockout of CBP/p300 blocks glucagon receptor antibody-stimulated α cell proliferation and mTORC1 signaling in mice. In CBP/p300-deficient α cells, single-cell RNA sequencing reveals upregulated autophagy-related genes and downregulated α cell identity genes and amino acid transporters, including Slc7a2. Slc7a2 is involved in regulating α cell identity gene expression through lysine-facilitated H3K27 acetylation. In addition, Slc7a2 downregulation compromises arginine-stimulated mTORC1 signaling, thereby suppressing α cell proliferation and triggering autophagy. Collectively, our findings uncover CBP/p300 as central regulators of functional α cell mass partially by orchestrating Slc7a2-mediated amino acid sensing.