Switching menin off reverses diabetes that is already there - in three different diabetic mouse models
also called acute Men1 excision diabetes · Men1 deletion ameliorates diabetes · inducible Men1 beta cell mass
In mice that already had diabetes, deleting the menin gene did not just prevent the disease - it reversed the high blood sugar that was already established, by making more insulin-making cells. It worked in three different kinds of diabetic mouse.
The same thing, for a scientist
This is the primary source behind the widely repeated statement that inducible Men1 deletion increases beta-cell mass and ameliorates diabetes. Acute, tamoxifen-inducible, temporally controlled Men1 excision ameliorated **pre-existing** hyperglycaemia in streptozotocin-treated mice, improved pre-existing hyperglycaemia and glucose intolerance in genetic db/db mice, and reversed pre-existing glucose intolerance in high-fat-diet-fed mice; the mechanism was at least partly increased proliferation of endogenous beta cells and increased islet size, with up-regulation of pro-proliferative genes in islets [E1]. A companion paper shows Men1 excision also **prevents** streptozotocin-induced hyperglycaemia, with increased BrdU incorporation, islet size and circulating insulin, and preserved membrane localisation of GLUT2 [E2]. The design point the authors make is the one that matters here: most gene-deletion diabetes models only show prevention, and this one shows reversal of established disease.
Three models, one direction
| Model | Diabetes type | Intervention | Result [E1] |
|---|---|---|---|
| Streptozotocin | Beta-cell ablation | Acute inducible Men1 excision after disease established | Pre-existing hyperglycaemia ameliorated |
| db/db | Genetic, leptin-receptor | Acute inducible Men1 excision | Pre-existing hyperglycaemia and glucose intolerance improved |
| High-fat diet | Diet-induced | Acute inducible Men1 excision | Pre-existing glucose intolerance reversed |
And separately, in a prevention design, Men1 excision made mice resistant to streptozotocin-induced hyperglycaemia, with increased beta-cell BrdU incorporation, islet size and circulating insulin, and preserved GLUT2 membrane localisation 2.
What this does to the beat's central framing
The endocrine beat reads Men1 deletion in the beta cell through one lens: concept-men1-loss-to-endocrine-tumour-latency records hyperplastic islets by 2 months and insulinoma by 6 with full penetrance. Both statements are true of the same manipulation, and they are true at different times. The early consequence of beta-cell menin loss is functional compensation that corrects diabetes; the late consequence is neoplasia. What the graph has been missing is the early half, and with it the recognition that the latency curve has a beneficial phase before it has a malignant one. A menin inhibitor given for a median 2.5 months sits, on this timeline, in the beneficial phase - which is an argument about where on the curve the exposure lands, not an argument that the curve has no bad end.
Limits that must be stated with it
These are genetic excisions, not drug exposures, and they are complete within the targeted cells rather than partial. The animals are adult mice with induced diabetes. None of them is followed long enough to report tumour incidence after reversal, and none has a restoration arm - exp-men1-conditional-restoration-latency-mouse is still the missing experiment. Importantly, deletion is more complete than pharmacological occupancy, so if anything these models overstate the exposure and still produce benefit at the timescales studied.
| manipulation | tamoxifen-inducible, temporally controlled Men1 excision |
|---|---|
| design | reversal of established disease (plus a separate prevention design) |
| mechanism | increased endogenous beta-cell proliferation and islet size; up-regulated pro-proliferative islet genes |
models
[ "streptozotocin", "db/db", "high-fat diet" ]
not measured
[ "tumour incidence after reversal", "restoration of menin", "human tissue" ]
- The same excision that reverses diabetes at weeks produces insulinoma at months in the same tissue; the benefit and the harm are the same intervention read at different times.
- Genetic excision is a deeper exposure than pocket occupancy, so a null result from a menin inhibitor would not refute this - but a positive one would mean a child's islets are being pushed along the early part of a curve whose late part is neoplasia.
- If a treated child's beta-cell mass rises and then the drug stops, the excess mass has to go somewhere; nobody has looked for post-treatment hypoglycaemia.
- How long after Men1 excision does the beta-cell phenotype remain reversible - the interval between the benefit and the insulinoma is entirely unmeasured.
- Does partial pharmacological occupancy reproduce any fraction of the reversal, or is there a threshold below which nothing happens?
- Would the reversal hold in a juvenile animal, whose beta cells are already replicating faster?
- E1strong confidence 4 of 5: Replicated in peer-reviewed work by more than one group.paper
Acute inducible Men1 excision reverses pre-existing hyperglycaemia and glucose intolerance in streptozotocin, db/db and high-fat-diet diabetic mice, partly by increasing endogenous beta-cell proliferation and islet size.
Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene. · Yang Y, Gurung B, Wu T, Wang H, Stoffers DA, Hua X · Proceedings of the National Academy of Sciences USA 2010What this evidence cannot show
Mouse only; genetic excision, not a drug; short follow-up with no tumour incidence reported; the excision is whole-body tamoxifen-inducible in the primary design, so extrapancreatic contributions are not fully excluded.
Evidence that argues against this (2)
- Longer follow-up of beta-cell Men1 deletion produces glucagon-expressing tumours and loss of beta-cell transcription-factor identity, so the same manipulation that reverses diabetes early produces neoplasia late. Li F et al. 2015
- Men1(+/-) mice, followed to 21 months, develop parathyroid hyperplasia by 9 months, insulinomas, prolactinomas and adrenocortical tumours with hypercalcaemia and hypophosphataemia - the long-run cost of even monoallelic loss. Harding B et al. 2009
- E2moderate confidence 3 of 5: One strong study, or several smaller consistent ones.paper
Men1 excision prevents streptozotocin-induced hyperglycaemia, with increased beta-cell BrdU incorporation, islet size, circulating insulin and preserved GLUT2 membrane localisation.
Deletion of the Men1 gene prevents streptozotocin-induced hyperglycemia in mice. · Yang Y, Wang H, Hua X · Experimental Diabetes Research 2010What this evidence cannot show
Prevention rather than reversal design; small journal, tamoxifen-inducible and tissue-specific models both used but numbers are modest; no long-term tumour follow-up.
Evidence that argues against this (1)
- Preserved GLUT2 and raised insulin are functional improvements measured over weeks; the beta-cell dedifferentiation seen in older Men1-deleted mice is the opposing long-run finding. Li F et al. 2015
The latency entry records only the neoplastic end of beta-cell Men1 loss; the same manipulation reverses established diabetes in three models before that, so the curve has a beneficial early phase the entry omits
- co-occurs with →Pancreatic neuroendocrine tumours in MEN1: the manifestation that kills, and the one the animal data points at
Same tissue, same gene, opposite sign at different exposure durations: reversal of hyperglycaemia at weeks, insulinoma at months
Genetic counterpart of the pharmacological phenotype; deletion is the deeper exposure and still produces benefit at the durations studied
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