Glucagon dysfunction in the liver induces hyperplasia of PP cells and the production of glucagon and pancreatic polypeptide double-positive cells

Understanding the mechanisms that regulate cellular identity and proliferation is crucial for elucidating cellular functions. Under normal conditions, pancreatic endocrine cells express only a single hormone, and their numbers are tightly regulated. Contrary to this general principle, our study revealed a significant increase in glucagon (GCG) and pancreatic polypeptide (PP) double-positive cells (GCG ⁺ PP ⁺ double-positive cells), along with hyperplasia of both PP and α cells in proglucagon-deficient mice. Similarly, systemic glucagon receptor-deficient mice exhibited PP-cell hyperplasia and an increase in GCG ⁺ PP ⁺ double-positive cells, with enhanced PP-cell self-replication observed at 4 weeks and the appearance of GCG ⁺ PP ⁺ double-positive cells at 10 weeks. Liver-specific glucagon receptor-deficient mice induced similar effects, which were linked to hyperaminoacidemia. Elevated glutamine levels were found to promote GCG ⁺ PP ⁺ double-positive cell formation via mTOR signaling, suggesting a molecular mechanism driving pancreatic endocrine cell plasticity. Collectively, these findings indicate that increased plasma amino acid levels caused by impaired glucagon action in the liver promotes the proliferation of α cells and PP cells, and disturbs their cellular identity maintenance.