The Insulin Resistance Mosaic: Defect, Defense, or Both? A Perspective on What Insulin Resistance Means and Whether...

Insulin resistance is conventionally framed as a pathological defect in insulin action that contributes to type 2 diabetes and related metabolic disease and should therefore be identified and reversed. The comprehensive review by Gastaldelli and colleagues highlights a more complicated reality: insulin resistance is heterogeneous between individuals, tissues, pathways, and physiological states. I argue that this heterogeneity exposes a fundamental issue-insulin resistance is a phenotype, not a mechanism. It can arise through many molecular routes, occur in both disease and normal physiology, originate in different tissues, and long precede overt disease. I propose an "insulin resistance mosaic" in which its clinical significance depends on why and where insulin resistance develops, physiological compensation, environmental exposure, and end-organ vulnerability. Similar degrees of insulin resistance could therefore lead to very different clinical outcomes, remain compensated for decades, or even, in some contexts, be protective. This framework challenges the assumption that insulin resistance represents a single disease process that should invariably be overcome. Instead, we should determine why it has developed, where it resides, what it predicts, and whether modifying it improves clinical outcomes.