Adenylosuccinate Mediates Imeglimin-Induced Proliferative and Antiapoptotic Effects in β-Cells
Bibliographic record
Abstract
Imeglimin, a drug for type 2 diabetes, reportedly promotes β-cell proliferation and increases β-cell survival; however, the detailed underlying molecular mechanism remains unclear. Here, we investigated metabolites in pancreatic islets after imeglimin treatment via liquid chromatography with tandem mass spectrometry. Treatment with imeglimin for 1 h significantly altered the levels of 17 metabolites at 5.6 mmol/L glucose and 11 metabolites at 11.1 mmol/L glucose. After 24 h of treatment, imeglimin changed the levels of 12 metabolites at 5.6 mmol/L glucose and 28 metabolites at 11.1 mmol/L glucose. The metabolites altered by imeglimin under high-glucose conditions were involved in NAD synthesis, amino acid metabolism, and nucleic acid metabolism. Adenylosuccinate (S-AMP), produced by adenylosuccinate synthase (ADSS) from inosine monophosphate (IMP) and aspartate, increased 2.98-fold after treatment with imeglimin. The levels of IMP and aspartate and both the mRNA and protein levels of ADSS were elevated following imeglimin treatment in islets. Alanosine, an inhibitor of ADSS, suppressed imeglimin-induced β-cell proliferation and survival in mouse islets, human islets, human pluripotent stem cell–derived β-cells, and porcine islets. Taken together, these findings suggest that chronic treatment with imeglimin promotes β-cell proliferation and survival partly through an increase in S-AMP production. ARTICLE HIGHLIGHTS Although imeglimin promotes β-cell proliferation and ameliorates β-cell apoptosis, the detailed metabolic changes induced by imeglimin in β-cells are unknown. Imeglimin increases adenylosuccinate (S-AMP), which is produced by adenylosuccinate synthase (ADSS) from inosine monophosphate and aspartate, and imeglimin also increases amino acid content, including aspartate, in mouse islets. Inhibition of S-AMP production by an ADSS inhibitor reduces the ability of imeglimin to increase β-cell proliferation and ameliorate β-cell apoptosis in mouse islets, human islets, porcine islets, and human pluripotent stem cell–derived β-cells. Imeglimin increases S-AMP to promote β-cell proliferation and ameliorate β-cell apoptosis.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".