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Using mass spectrometry-based phosphoproteomics, we quantified 23,126 phosphosites in skeletal muscle of five genetically distinct mouse strains in two dietary environments, with and without acute in vivo insulin stimulation. Almost half of the insulin-regulated phosphoproteome was modified by genetic background on an ordinary diet, and high-fat high-sugar feeding affected insulin signalling in a strain-dependent manner. Our data revealed coregulated subnetworks within the insulin signalling pathway, expanding our understanding of the pathway\u2019s organisation. Furthermore, associating diverse signalling responses with insulin-stimulated glucose uptake uncovered regulators of muscle insulin responsiveness, including the regulatory phosphosite S469 on Pfkfb2, a key activator of glycolysis. Finally, we confirmed the role of glycolysis in modulating insulin action in insulin resistance. Our results underscore the significance of genetics in shaping global signalling responses and their adaptability to environmental changes, emphasising the utility of studying biological diversity with phosphoproteomics to discover key regulatory mechanisms of complex traits.<\/jats:p>","DOI":"10.7554\/elife.89212","type":"journal-article","created":{"date-parts":[[2023,9,12]],"date-time":"2023-09-12T15:38:14Z","timestamp":1694533094000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.89212","source":"Crossref","is-referenced-by-count":4,"title":["The genetic and dietary landscape of the muscle insulin signalling network"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8093-0704","authenticated-orcid":true,"given":"Julian","family":"van Gerwen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0384j8v12","id-type":"ROR","asserted-by":"publisher"}],"name":"Charles Perkins Centre, School of Life and Environmental Sciences, 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