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.