{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:57:00Z","timestamp":1791284220645,"version":"4.1.0"},"reference-count":65,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Insulin resistance is conventionally described as a single condition, but it is better understood as the point at which several tissue-specific signaling failures, each following its own molecular logic and its own timeline, converge into one measurable phenotype. This review treats insulin resistance as a network rather than a collection of independent organ pathologies. Because the components of this network rest on very different kinds of evidence, each node and edge is graded explicitly by study design and causal status, and the time-staged sequence is presented as a falsifiable proposal rather than an established progression. Put simply, insulin resistance is treated here not as one defect but as the shared endpoint of several tissue-specific failures that develop at different times and communicate with one another. Liver, skeletal muscle, adipose tissue, pancreatic islets, the gut, and the brain are each examined as nodes with characteristic signaling lesions built from a shared architecture of diacylglycerol- and ceramide-activated kinases, inhibitory serine phosphorylation of insulin receptor substrate proteins, and endoplasmic reticulum stress, while inter-organ messengers, incretins, adipokines, bile acids, and autonomic circuits, are treated as the edges that couple these nodes together. The pancreas is included not as a site of resistance but as the network\u2019s compensatory arm, and the brain is treated as an integrated hypothalamic-vagal node rather than a separate neurocognitive topic, closing a loop in which adipose-derived signals impair central insulin and leptin action, weakened central signaling relaxes hepatic glucose control, and reduced satiety sustains the intake that drove adipose dysfunction in the first place. A dedicated section addresses the post-translational and organelle-level machinery, shared serine kinases, ubiquitin-mediated IRS degradation, O-GlcNAcylation, and mitochondria-endoplasmic reticulum contact sites, that allows the same small set of molecular tools to produce different tissue-specific outputs. These mechanisms are then placed on an explicit time axis moving from silent compensation, in which adipose and hypothalamic changes precede any measurable defect elsewhere, through early decompensation in liver and muscle, to established decompensation marked by \u03b2-cell failure and self-sustaining feed-forward loops, a staging distinction that is largely absent from mechanistic studies conducted at a single, typically late, disease stage. This framing helps explain a pattern in current therapeutics: interventions that act on several network nodes at once, most notably incretin-based therapies, have outperformed mechanistically well-motivated single-node strategies, including direct inhibition of shared convergence kinases. The review closes by identifying where the network remains least understood, principally in longitudinal, tissue-resolved human data capable of testing the proposed staging sequence directly.<\/jats:p>","DOI":"10.3389\/fendo.2026.1952238","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T10:43:23Z","timestamp":1791283403000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular signaling networks that connect tissue dysfunction to systemic insulin resistance"],"prefix":"10.3389","volume":"17","author":[{"given":"Rashid","family":"Mir","sequence":"first","affiliation":[{"name":"Prince Fahad Bin Sultan Chair for Biomedical Research, University of Tabuk","place":["Tabuk, Saudi Arabia"]},{"name":"Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk","place":["Tabuk, Saudi 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