ArticleeLife2023
Leveraging genetic diversity to identify small molecules that reverse mouse skeletal muscle insulin resistance.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Fifteen years of the Diversity Outbred mouse model: a review.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Targeting metabolic inflammation in type 2 diabetes mellitus through exercise: multi-level mechanisms of insulin resistance reversal and precision clinical translation - a review.Frontiers in immunology · 2026Review
- Disulfiram inhibits Gasdermin D pores formation and improves insulin-dependent glucose uptake and glucose homeostasis in skeletal muscle of obesity-induced insulin-resistant mice.Scientific reports · 2025Article
- Genetic variance in the murine defensin locus modulates glucose homeostasis.The EMBO journal · 2025Article
- SEC61B regulates calcium flux and platelet hyperreactivity in diabetes.The Journal of clinical investigation · 2025Article
- Stage-dependent proteomic alterations in aqueous humor of diabetic retinopathy patients based on data-independent acquisition and parallel reaction monitoring.Journal of translational medicine · 2025Article
- Sex-specific skeletal muscle gene expression responses to exercise reveal novel direct mediators of insulin sensitivity change.NAR molecular medicine · 2025Article
- Host-specific effects of Eubacterium species on Rg3-mediated modulation of osteosarcopenia in a genetically diverse mouse population.Microbiome · 2024Article
- Unlocking metabolic insights with mouse genetic diversity.The EMBO journal · 2024Article
- The metabolic consequences of 'yo-yo' dieting are markedly influenced by genetic diversity.International journal of obesity (2005) · 2024Article
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- Systems genetics approaches for understanding complex traits with relevance for human disease.eLife · 2023Review
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Systems genetics has begun to tackle the complexity of insulin resistance by capitalising on computational advances to study high-diversity populations. 'Diversity Outbred in Australia (DOz)' is a population of genetically unique mice with profound metabolic heterogeneity. We leveraged this variance to explore skeletal muscle's contribution to whole-body insulin action through metabolic phenotyping and skeletal muscle proteomics of 215 DOz mice. Linear modelling identified 553 proteins that associated with whole-body insulin sensitivity (Matsuda Index) including regulators of endocytosis and muscle proteostasis. To enrich for causality, we refined this network by focusing on negatively associated, genetically regulated proteins, resulting in a 76-protein fingerprint of insulin resistance. We sought to perturb this network and restore insulin action with small molecules by integrating the Broad Institute Connectivity Map platform and in vitro assays of insulin action using the Prestwick chemical library. These complementary approaches identified the antibiotic thiostrepton as an insulin resistance reversal agent. Subsequent validation in ex vivo insulin-resistant mouse muscle and palmitate-induced insulin-resistant myotubes demonstrated potent insulin action restoration, potentially via upregulation of glycolysis. This work demonstrates the value of a drug-centric framework to validate systems-level analysis by identifying potential therapeutics for insulin resistance.
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