Targeted inhibition of menin promotes β‐catenin‐mediated GLP ‐1 expression and improves glucose tolerance in high‐fat diet‐induced obese mice

Abstract Glucagon‐like peptide‐1 (GLP‐1), derived from enteroendocrine cells, is a pivotal hormone crucial for blood glucose regulation. Menin, encoded by the MEN1 gene and known for its tumor suppressor role, is abundantly expressed in the intestine. Previous research has demonstrated that acute Men1 excision reverses preexisting glucose intolerance in high‐fat diet‐fed mice. However, its impact on GLP‐1 expression in enteroendocrine cells has not been investigated. In the present study, both the knockdown of Men1 and the administration of the MI‐463 menin inhibitor increased GLP‐1 expression in glucose‐stimulated STC‐1 cells. Additionally, administering MI‐463 to obese mice significantly elevated GLP‐1 levels in both ileal epithelial cells and serum. Mechanistically, menin inhibition enhanced the nuclear accumulation of β‐catenin, allowing it to bind TCF7L2, thereby increasing glucagon gene ( Gcg ) transcription. Furthermore, compared with control mice, mice with intestinal epithelial cell‐specific Men1 knockdown exhibited significant improvements in glucose tolerance under fat challenge, which was correlated with elevated GLP‐1 levels. These findings suggest that menin‐mediated regulation of GLP‐1 expression may be an important mechanism through which menin inhibiton alleviates type 2 diabetes.