Insulin‐stimulated PAK1 activation is required for glucose uptake in skeletal muscle cells (797.1)
Bibliographic record
Abstract
Skeletal muscle accounts for ~80% of postprandial glucose clearance, crucial for maintaining euglycemia and insulin sensitivity. Insulin‐stimulated glucose uptake entails recruitment of glucose transporters (GLUT4) to the plasma membrane (PM) in a process that requires cortical F‐actin remodeling; this process is dysregulated in Type 2 Diabetes. Recent studies have implicated PAK1 as a required element in GLUT4 recruitment in mouse skeletal muscle in vivo, although its underlying mechanism of action and requirement in glucose uptake remains undetermined. Toward this, we have employed the PAK1 inhibitor, IPA3, in studies using L6‐GLUT4‐myc muscle cells, the premiere skeletal muscle cell line for glucose uptake analyses. Confocal microscopy showed IPA3 to fully ablate insulin‐stimulated GLUT4 translocation to the PM, corroborating the observation of ablated insulin‐stimulated GLUT4 accumulation in the PM of skeletal muscle from PAK1 ‐/‐ knockout mice. IPA3‐treatment also abolished insulin‐stimulated glucose uptake into skeletal myotubes. Mechanistically, live‐cell imaging of myoblasts expressing the F‐actin biosensor LifeAct‐GFP treated with IPA3 showed blunting of the normal insulin‐induced cortical actin remodeling. This blunting was underpinned by a loss of normal insulin‐stimulated Cofilin dephosphorylation in IPA3‐treated myoblasts, suggesting a new model: insulin activates PAK1 to signal downstream to Cofilin to trigger actin severing, providing substrate for F‐actin remodeling, which facilitates GLUT4 vesicle translocation toward the PM where GLUT4 promotes glucose uptake into the skeletal muscle cell. Grant Funding Source : DK077614
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.004 |
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".