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

Summary

Using α cell–specific knockout mice, the authors show that CBP/p300 maintains functional α-cell mass by integrating amino acid sensing with mTORC1 signaling, in part via regulation of the amino acid transporter Slc7a2 and H3K27 acetylation. Loss of CBP/p300 causes hypoglucagonemia, hyperaminoacidemia, α-cell dedifferentiation and cell loss, and blocks glucagon receptor antibody-induced α-cell proliferation.

Key Findings

• α cell–specific CBP/p300 deletion in mice caused hypoglucagonemia, hyperaminoacidemia, and reduced functional α-cell mass via impaired proliferation, dedifferentiation, and cell loss.
• CBP/p300 knockout blocked glucagon receptor antibody–stimulated α-cell proliferation and mTORC1 signaling.
• Single-cell RNA-seq showed upregulated autophagy genes and downregulated α-cell identity genes and amino acid transporters, including Slc7a2.
• Slc7a2 downregulation impaired lysine-facilitated H3K27 acetylation and arginine-stimulated mTORC1, suppressing α-cell proliferation and triggering autophagy.

Clinical Implications

While preclinical, these findings suggest that preserving CBP/p300 activity or rescuing Slc7a2-dependent amino acid sensing could modulate α-cell mass and influence responses to glucagon receptor–targeted therapies. They also caution that α-cell proliferative responses to hyperaminoacidemia may depend on intact CBP/p300 signaling.

Limitations

• Findings are from murine models; human islet validation is needed.
• The upstream signals triggering Slc7a2 regulation and broader metabolic consequences were not fully delineated.

Future Directions

Validate the CBP/p300–Slc7a2–mTORC1 axis in human α cells, test pharmacologic modulation of CBP/p300 or Slc7a2, and assess how this pathway shapes responses to glucagon receptor–directed therapies and diabetes phenotypes.