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

Abstract 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. Competing Interest Statement The authors have declared no competing interest. Footnotes In this revision, there are no major content changes. The only modification is to the legend of S6 Fig B.