<i>MIR192</i> Upregulates GLP-1 Receptor and Improves Statin-Induced Impairment of Insulin Secretion
Bibliographic record
Abstract
ABSTRACT Statins are a commonly prescribed cholesterol lowering drug class that can increase the risk of new-onset diabetes (NOD). To investigate the molecular mechanisms underlying this effect, we generated human induced pluripotent stem cells (iPSCs) from individuals identified from electronic health records of Kaiser Permanente of Northern California who were susceptible to developing NOD after statin initiation or controls who maintained stable fasting glucose on statin treatment. RNA-seq analysis of iPSCs incubated with atorvastatin, simvastatin or mock buffer for 24 hours identified the long non-coding RNA MIR194-2HG as a top candidate gene. Statin-induced increases in its expression were observed in NOD resistant controls, while statin-induced reductions occurred in NOD susceptible cases. MIR194-2HG encompasses two microRNA genes: MIR192 and MIR194-2 . The mature microRNA miR-192-5p, derived from the 5’ arm of MIR192 , was predicted to bind the 3’UTR of the glucagon like peptide 1 (GLP-1) receptor ( GLP1R ) transcript. Transfection of a rat insulinoma cell line INS-1 with a miR-192-5p mimic increased Glp1r transcript (1.41-fold) and protein (1.51-fold) levels compared to a scrambled control. Using a luciferase reporter containing the human GLP1R 3’UTR, miR-192-5p overexpression similarly increased luciferase signal (1.44-fold). The miR-192-5p mimic enhanced glucose stimulated insulin secretion (GSIS) in response to GLP1R agonists (1.64-1.81-fold) and rescued simvastatin-induced GSIS impairment in INS-1 cells. Wild-type mice treated with miR-192 AAV8 had improved glucose sensitivity. Islets isolated from these mice exhibited enhanced GLP-1 potentiated GSIS during perifusion ex vivo . These effects were absent in the DIRKO ( Glp1r/Gipr double knockout) mouse islets, consistent with the idea that miR-192 promotes GLP-1 mediated GSIS through GLP1R. These findings implicate MIR192 in statin-induced impairment of GSIS by modulating GLP1R, potentially contributing to the susceptibility to NOD in statin users.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".