Menin inhibition in the gut, not the islet: MI-463 raises GLP-1 from intestinal L cells
also called menin GLP-1 enteroendocrine · menin beta-catenin Gcg · intestinal Men1 knockdown
Menin is also abundant in the intestine, where it holds down production of the gut hormone GLP-1. Blocking menin there raises GLP-1 in the gut wall and in the blood, and improves how obese mice handle sugar.
The same thing, for a scientist
A second, anatomically separate route by which menin inhibition improves glucose handling. In glucose-stimulated STC-1 enteroendocrine cells, both Men1 knockdown and the menin inhibitor MI-463 increased GLP-1 expression. In obese mice MI-463 raised GLP-1 in ileal epithelial cells and in serum. Mechanistically, menin inhibition increased nuclear beta-catenin, which binds TCF7L2 and raises glucagon-gene (Gcg) transcription. Mice with intestinal-epithelial-cell-specific Men1 knockdown had improved glucose tolerance under fat challenge, correlated with elevated GLP-1 [E1]. This matters for granularity: the islet phenotype and the gut phenotype are different tissues, different cell types and different transcriptional mechanisms, and they compound.
Why a separate entry from the islet
The islet effect runs menin-JunD-HDAC3 to Pbk [see mechanism-menin-jund-hdac3-pbk-axis-in-beta-cells]; the gut effect runs menin to nuclear beta-catenin to TCF7L2 to Gcg 1. Different cell (intestinal L cell versus beta cell), different partner, different target gene, different anatomical compartment. They are also additive in principle: more GLP-1 from the gut arriving at a beta cell whose GLP1R menin has stopped repressing [see mechanism-menin-prmt5-represses-glp1r-transcription].
The consequence for the safety argument
Menin's normal-tissue distribution is wider than the three MEN1 target organs the endocrine beat is built around. Menin is abundantly expressed in intestine 1, in osteoblasts and osteocytes, in cranial neural crest, in liver and in decidua. A systemic menin inhibitor engages all of them. The endocrine beat's organ list - parathyroid, pituitary, enteropancreatic - is the MEN1 tumour spectrum, not the menin expression spectrum, and using the first as a proxy for the second systematically underestimates the number of tissues with an on-target pharmacology.
| tissue | intestinal epithelium / enteroendocrine L cell |
|---|---|
| axis | menin -| nuclear beta-catenin -> TCF7L2 -> Gcg -> GLP-1 |
| compound | MI-463 |
| human evidence | none |
models
[ "STC-1 cells", "diet-induced obese mice", "intestinal epithelial Men1 knockdown mice" ]
- The mechanism of benefit here is nuclear beta-catenin gain in gut epithelium, which is the canonical initiating lesion of colorectal neoplasia; a benefit in glucose is bought with an unmeasured oncogenic signal in a second tissue.
- Menin is expressed far beyond the MEN1 tumour organs, so the beat's organ list understates the on-target surface of a systemic inhibitor.
- None of the gut work uses a clinical menin inhibitor, so the effect size at human exposures is unknown in either direction.
- Is serum GLP-1 altered in patients on revumenib? It is a single cheap assay on banked samples and has never been run.
- Does chronic menin inhibition raise intestinal beta-catenin activity enough to matter for adenoma risk over a childhood?
- Which other menin-expressing normal tissues have an unexamined on-target pharmacology - liver, decidua, mammary, neural crest?
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Menin inhibition with MI-463 and intestinal Men1 knockdown raise GLP-1 in enteroendocrine cells and serum via nuclear beta-catenin/TCF7L2-driven Gcg transcription, improving glucose tolerance in obese mice.
Targeted inhibition of menin promotes beta-catenin-mediated GLP-1 expression and improves glucose tolerance in high-fat diet-induced obese mice. · Cao X, Yu L, Zhang Q, Cheng Z, Meng H, Wang C, et al. · FASEB Journal 2025What this evidence cannot show
STC-1 is a transformed murine enteroendocrine line; the in-vivo arms are diet-induced obese mice and an intestinal-epithelium Men1 knockdown, with no human tissue; MI-463 is a tool compound, not a clinical menin inhibitor; no dose or duration is stated in the abstract and the full text was not read for this entry.
Evidence that argues against this (1)
- Raising beta-catenin activity is not a neutral pharmacology in the intestine: beta-catenin/TCF7L2 signalling is the central driver of colorectal adenoma, so a chronic intestinal beta-catenin gain in a child is a risk the paper's therapeutic framing does not weigh. Chamberlain CE et al. 2014
- co-occurs with →Menin represses GLP1R - the receptor a whole class of diabetes drugs exists to switch on
Two anatomically separate arms of the same pharmacology: more GLP-1 released from gut L cells, arriving at a beta cell whose GLP1R menin has stopped repressing
Menin restrains beta-catenin/TCF7L2-driven Gcg transcription in intestinal enteroendocrine cells; a tissue outside the MEN1 tumour spectrum entirely
- ← depends onWhy endocrine tumours do not carry KRAS mutations: menin blocks the proliferative arm of RAS
and the ligand arm: menin inhibition raises circulating GLP-1 from gut L cells, completing the synergistic pair in a single-agent exposure