Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance.
Level 5 - mechanism / opinion, no new human data
Bench and in vitro cell culture experiments combined with animal studies and cross-sectional human transcriptomic meta-analysis
PubMed 34921686 · doi:10.1096/fj.202100497RR
What was done
Authors performed a transcriptomic meta-analysis across >450 human skeletal muscle samples examining the correlation between fasting insulin and INSR mRNA. To establish causality, C2C12 mouse myotubes were exposed to elevated insulin for 16 hours followed by 6 hours of serum starvation to assess acute AKT and ERK signaling. Global RNA-sequencing was conducted to evaluate pathway alterations, followed by in vitro and in vivo assessments of Insr gene expression, surface INSR, and total INSR protein, alongside RNAi knockdown to identify transcriptional regulators.
What was found
Fasting insulin negatively correlated with INSR mRNA in human muscle (exact correlation values not stated in the abstract). In C2C12 myotubes, hyperinsulinemia attenuated acute AKT and ERK signaling and altered INSR, FOXO, and glucose metabolism pathways. Hyperinsulinemia substantially reduced Insr gene expression, surface INSR, and total INSR protein both in vitro and in vivo. Bioinformatic modeling and RNAi identified SIN3A as a negative regulator of Insr mRNA, and JUND, MAX, and MXI as positive regulators of Irs2 mRNA.
Why it matters
This study shows that hyperinsulinemia is not merely a passive compensatory response to insulin resistance but can actively drive receptor downregulation in muscle. Elucidating this regulatory pathway identifies potential mechanistic targets to break the cycle of type 2 diabetes progression.
Limits
The abstract provides no exact numerical values, effect sizes, or confidence intervals. Causality and mechanistic pathways were defined in mouse cells and in vivo animal models rather than human interventional trials, limiting direct clinical translation.
Cited by
- supports An excess of insulin in the human body eventually creates a resistance to itself.