ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2022
Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- Nutrient and non-nutrient regulators of insulin secretion.Nature reviews. Endocrinology · 2026Review
- Differential Pathophysiological Drivers of Susceptibility to Type 2 Diabetes and Metabolic Dysfunction-Associated Steatotic Liver Disease: Ethnic Differences in Insulin Dynamics, Whole-Body Fat Metabolism, and Organ-Specific Lipid Deposition.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2026Review
- Metabolic and Signaling Dysregulation in a Cellular Model of Hepatic Insulin Resistance.Current issues in molecular biology · 2026Article
- Insulin receptor trafficking and interactions in muscle cells.Journal of the Endocrine Society · 2026Article
- Biomarkers of Insulin Resistance and Their Performance as Predictors of Treatment Response in Overweight Adults.The Journal of clinical endocrinology and metabolism · 2025Article
- Safflower injection against obesity-induced mice podocyte injury by improving insulin resistance through increasing renal INSR and eNOS expression.Renal failure · 2025Article
- Enhanced SLC2A4 expression mitigates insulin resistance in gestational diabetes mellitus via the FoxO signaling pathwayExperimental and therapeutic medicine · 2025Article
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- Fructose induced KHK-C can increase ER stress independent of its effect on lipogenesis to drive liver disease in diet-induced and genetic models of NAFLD.Metabolism: clinical and experimental · 2023Article
- Transcriptomics for Clinical and Experimental Biology Research: Hang on a Seq.Advanced genetics (Hoboken, N.J.) · 2023Review
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- Effects of short-term endurance and strength exercise in the molecular regulation of skeletal muscle in hyperinsulinemic and hyperglycemic Slc2a4Cellular and molecular life sciences : CMLS · 2023Article
- Exercise and inactivity as modifiers of β cell function and type 2 diabetes risk.Journal of applied physiology (Bethesda, Md. : 1985) · 2023Review
- Fructose Induced KHK-C Increases ER Stress and Modulates Hepatic Transcriptome to Drive Liver Disease in Diet-Induced and Genetic Models of NAFLD.bioRxiv : the preprint server for biology · 2023Article
- Circadian Clock Desynchronization and Insulin Resistance.International journal of environmental research and public health · 2022Review
- Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance.Nature communications · 2022Article
- Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance.Molecular metabolism · 2022Article
- Human and mouse muscle transcriptomic analyses identify insulin receptor mRNA downregulation in hyperinsulinemia-associated insulin resistance.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.