Revisiting Insulin Resistance in the Pathophysiology of Type 2 Diabetes Mellitus: A Multi-Organ Perspective

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a heterogeneous, multisystem disease that extends beyond chronic hyperglycemia to encompass cardiovascular disease, chronic kidney disease, and metabolic dysfunction-associated steatotic liver disease. Central to this expanded disease spectrum is insulin resistance arising from coordinated metabolic, inflammatory, neuroendocrine, and immune disturbances across multiple organs. Rather than a uniform defect in insulin signaling, insulin resistance represents a dynamic, tissue-specific, and stage-dependent process involving multiorgans, with substantial interorgan crosstalk. This review synthesizes contemporary mechanistic insights into the pathogenesis of insulin resistance in T2DM, integrating molecular pathways, organ-specific dysfunction, and systemic metabolic networks. Ectopic lipid accumulation, mitochondrial dysfunction, chronic low-grade inflammation, immune dysregulation, and gut dysbiosis are highlighted as convergent processes that impair insulin action and drive clinical heterogeneity. Insulin resistance is further contextualized within the cardiovascular–kidney–metabolic syndrome framework, which unifies metabolic, renal, and cardiovascular disease through shared upstream mechanisms. In addition, how contemporary glucose-lowering therapies exert benefits beyond glycemic control by targeting insulin resistance, metabolic reprogramming, and interorgan crosstalk is discussed. Collectively, insulin resistance is positioned as a central pathophysiological driver of T2DM and its complications, supporting a shift toward mechanism-based, organ-protective, and precision-oriented therapeutic strategies.