Modulation of muscle cell insulin receptor signalling, transcription and trafficking by insulin
Bibliographic record
Abstract
Hyperinsulinemia is commonly viewed as a compensatory response to insulin resistance, yet studies have suggested that chronically elevated insulin may also drive insulin resistance. The molecular mechanisms underpinning this potentially cyclic process remain poorly defined. Particularly, the regulation of insulin receptor (INSR) mRNA levels, protein abundance, cell-surface dynamics, and internalization in the presence and absence of insulin are incompletely understood in muscle cells. To study the direct effects of insulin on INSR in muscle cells, we conducted in vitro studies on C2C12 myotubes and myoblasts, and analyzed publicly available human muscle transcriptomic data. Our in vitro studies established that acute AKT and ERK signalling were attenuated by 16 hours of hyperinsulinemia. RNA-sequencing of cells both before and after nutrient withdrawal highlighted genes in the insulin receptor (INSR) signalling, FOXO signalling, and glucose metabolism pathways indicative of ‘hyperinsulinemia’ and ‘starvation’ programs. We observed that hyperinsulinemia led to a substantial reduction in Insr gene expression, and subsequently a reduced surface INSR and total INSR protein, both in vitro and in vivo. Transcriptomic meta-analysis in >450 human samples demonstrated a reliable negative correlation between fasting insulin and INSR mRNA in skeletal muscle. Bioinformatic modelling combined with RNAi identified SIN3A as a negative regulator of Insr mRNA and JUND, MAX, and MXI as positive regulators of Irs2 mRNA. To study INSR internalization, we used surface labelling and live-cell imaging and observed robust basal internalization of INSR and relatively modest effects of insulin in C2C12 myoblasts. We performed a stringent mass spectrophotometry analysis of INSR interactors to provide clues as to the molecular mechanisms associated with internalization, which identified previously unappreciated interactors such as ANXA2. Mapping these interactors into a protein-protein interaction network pointed to a role for caveolin-mediated endocytosis. Interestingly, INSR interacted with both caveolin and clathrin in mouse skeletal muscle and C2C12 myoblasts, with the interactions modulated by insulin. Together, this work identifies novel mechanisms which may explain the cyclic processes underlying hyperinsulinemia-induced insulin resistance in muscle, a process directly relevant to the etiology of type 2 diabetes.
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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 | 0.001 |
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".