Abstract
Hyperinsulinemia is commonly viewed as a compensatory response to insulin resistance, yet studies have demonstrated that chronically elevated insulin may also drive insulin resistance. The molecular mechanisms underpinning this potentially cyclic process remain poorly defined, especially on a transcriptome‐wide level. Transcriptomic meta‐analysis in >450 human samples demonstrated that fasting insulin reliably and negatively correlated with INSR mRNA in skeletal muscle. To establish causality and study the direct effects of prolonged exposure to excess insulin in muscle cells, we incubated C2C12 myotubes with elevated insulin for 16 h, followed by 6 h of serum starvation, and established that acute AKT and ERK signaling were attenuated in this model of in vitro hyperinsulinemia. Global RNA‐sequencing of cells both before and after nutrient withdrawal highlighted genes in the insulin receptor (INSR) signaling, FOXO signaling, and glucose metabolism pathways indicative of ‘hyperinsulinemia’ and ‘starvation’ programs. Consistently, 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. Bioinformatic modeling combined with RNAi identified SIN3A as a negative regulator of Insr mRNA (and JUND, MAX, and MXI as positive regulators of Irs2 mRNA). Together, our analysis identifies mechanisms which may explain the cyclic processes underlying hyperinsulinemia‐induced insulin resistance in muscle, a process directly relevant to the etiology and disease progression of type 2 diabetes.
Highlights
Hyperinsulinemia and insulin resistance are cardinal features of type 2 diabetes (T2D), yet their co-association makes it challenging to establish their precise physiological and molecular relationships
The goal of this study was to explore the mechanisms of hyperinsulinemia-induced insulin resistance in skeletal muscle cells with a focus on transcriptomic changes
We demonstrated that prolonged physiological and supraphysiological hyperinsulinemia induced a reduction of AKT serine/threonine kinase (AKT) and extracellular signal-r egulated kinase (ERK) signaling and insulin-stimulated glucose uptake (Figure 7E)
Summary
Hyperinsulinemia and insulin resistance are cardinal features of type 2 diabetes (T2D), yet their co-association makes it challenging to establish their precise physiological and molecular relationships. An early study by Di Camillo et al.[23] of the time-dependent transcriptomic responses in muscle cells to physiological insulin (20 nM) identified strong feedback to gene expression in the canonical insulin signaling pathways, yet no impact on the expression of the insulin receptor was reported. It remains unclear how hyperinsulinemia-induced insulin resistance in a cell model impacts the transcriptome, and whether such changes mimic in vivo observations. We further identify transcriptional regulators that play important roles in mediating the effects of hyperinsulinemia, illuminating how hyperinsulinemia contributes to insulin resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
