The other half of the islet story: losing menin also costs the beta cell its identity and raises glucagon
also called Men1 beta cell dedifferentiation · glucagon-expressing tumour Men1 · Men1 heterozygous fasting hyperglycemia
Deleting menin in insulin cells does not only make more of them. Over time the cells lose the markers that make them insulin cells and start making glucagon instead, and mice with one faulty copy end up with high fasting blood sugar driven by too much glucagon.
The same thing, for a scientist
The counterweight to the whole beta-cell benefit argument, and it comes from the same manipulation. Conditional Men1 ablation driven by the insulin promoter produced, in old mutant mice, **glucagon-expressing tumours** as well as insulinomas; the glucagon-expressing tumour cells were menin-deficient and expressed the mature alpha-cell transcription factors Brn4 and MafB, while beta-cell-specific transcription factors were inactivated in mutant beta cells [E1]. Independently, 12-month-old male Men1(+/-) mice show **fasting hyperglycaemia** with raised serum insulin but no insulin resistance; the driver is increased hepatic glucose output secondary to higher basal glucagon from islet-cell proliferation [E2]. So the net glycaemic effect of reduced menin is not monotonically favourable: early and acute it lowers glucose, chronic and heterozygous it can raise it.
Two directions, and what separates them
| Exposure | Duration | Net glycaemic effect | Source |
|---|---|---|---|
| Acute inducible Men1 excision | weeks | Hyperglycaemia reversed in three diabetic models | mechanism-acute-men1-deletion-reverses-established-hyperglycaemia |
| Menin inhibitor MI-463 70 mg/kg/day | 8-12 weeks | Fasting glucose down, GTT improved | mechanism-in-vivo-islet-phenotype-under-pharmacological-menin-inhibition |
| Beta-cell Men1 ablation | to old age | Glucagon-expressing tumours, loss of beta-cell identity 1 | this entry |
| Germline Men1(+/-) | 12 months | Fasting hyperglycaemia via glucagon-driven hepatic glucose output 2 | this entry |
Duration, not direction of the perturbation, determines the sign. That is the same shape as the parathyroid and the bone stories in this beat, and it is the reason the beat's central question is about exposure length rather than about whether menin matters.
Identity loss is a distinct hazard from proliferation
Most of this beat argues about whether menin blockade makes endocrine cells divide too much. 1 raises a different hazard: the cells may stop being what they were. Inactivation of beta-cell transcription factors with gain of Brn4 and MafB is dedifferentiation/transdifferentiation, not hyperplasia, and it would not be detected by any proliferation assay, any hyperplasia call in a toxicology report, or any imaging endpoint. In a child, the readout would be a slow loss of insulin secretory reserve, and nothing in the clinical programme measures insulin secretory reserve.
| kind | essential-function |
|---|---|
| severity | unknown in humans; in mice, loss of beta-cell identity and glucagon-driven fasting hyperglycaemia on chronic or germline exposure |
| mitigation | measure fasting glucose, insulin, C-peptide and glucagon on and after treatment; none is currently collected in any menin-inhibitor trial or on either approved label |
affects
[ "drug-revumenib", "drug-ziftomenib", "drug-bleximenib" ]
- Every proliferation-based safety readout in the nonclinical package would miss dedifferentiation entirely, because the cell count does not change.
- The benefit case for menin inhibition in the islet rests on short exposures; the exposure distribution for menin inhibitors is lengthening into maintenance and front-line settings.
- If glucagon rises, the net glycaemic effect can invert from the reported benefit to fasting hyperglycaemia - the opposite of what the diabetes literature promises.
- At what exposure duration does the islet response cross from compensatory proliferation to identity loss? No study has a time course spanning both.
- Would a treated child show a rise in fasting glucagon? It is a single assay and has never been measured on a menin inhibitor.
- Is beta-cell dedifferentiation reversible after menin restoration? `exp-men1-conditional-restoration-latency-mouse` would answer it if identity markers were added to its readouts.
- E1moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Beta-cell-specific Men1 ablation produces glucagon-expressing tumours with alpha-cell transcription factors and inactivation of beta-cell-specific transcription factors in mutant beta cells.
Conditional deletion of Men1 in the pancreatic beta-cell leads to glucagon-expressing tumor development. · Li F, Su Y, Cheng Y, Jiang X, Peng Y, Li Y, et al. · Endocrinology 2015What this evidence cannot show
RipCre has known extrapancreatic and hypothalamic expression, so strict beta-cell autonomy is not guaranteed; the phenotype appears in old mice; lineage tracing is not reported in the abstract, so transdifferentiation versus alpha-cell expansion is not formally separated.
Evidence that argues against this (1)
- Complete lifelong genetic ablation is a far deeper exposure than months of partial pharmacological occupancy, and the one pharmacological in-vivo experiment at 12 weeks reported preserved beta-cell function with improved GSIS, not identity loss. Ma J et al. 2021
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Male Men1(+/-) mice develop fasting hyperglycaemia at 12 months driven by raised basal glucagon and increased hepatic glucose output, not insulin resistance.
Male Men1 heterozygous mice exhibit fasting hyperglycemia in the early stage of MEN1. · Gao Z, Zhang L, Xie W, Wang S, Bao X, Guo Y, et al. · Journal of Endocrinology 2016What this evidence cannot show
Sex-specific (males only), single time point at 12 months, germline heterozygous model; the mechanism is inferred from pyruvate challenge and gluconeogenic gene expression.
Evidence that argues against this (1)
- Acute Men1 excision improves rather than worsens glucose tolerance in db/db and high-fat-diet mice, so the direction depends on chronicity and on whether the alpha cell has had time to expand. Yang Y et al. 2010
Opposite sign at longer exposure: chronic beta-cell Men1 loss gives glucagon-expressing tumours and identity loss, and germline Men1(+/-) males are fasting hyperglycaemic at 12 months
Bite-back: dedifferentiation is invisible to every proliferation-based safety readout in the nonclinical package and to every endpoint in the clinical programme
The glucagon arm tests the counter-direction: pharmacological reproduction of the germline Men1(+/-) fasting-hyperglycaemia phenotype