Insulin resistance and inflammation as drivers of multiorgan damage

Abstract

Insulin resistance (IR)—characterized by a diminished response to insulin action in skeletal muscle, liver, and adipose tissue—plays a central role in the pathophysiology of type 2 diabetes mellitus (T2DM) and other cardiometabolic diseases. IR is currently recognized as a systemic disorder closely associated with chronic low-grade inflammation; these processes reinforce one another and promote progressive multiorgan damage. Visceral obesity plays a fundamental role in this interaction through adipocyte hypertrophy, macrophage infiltration, and the release of proinflammatory cytokines. These alterations activate intracellular inflammatory pathways that interfere with insulin signaling, perpetuating a vicious cycle between inflammation and IR. The persistence of these mechanisms promotes oxidative stress, endothelial dysfunction, and tissue fibrosis, contributing to the development of cardiovascular events, metabolic dysfunction-associated steatotic liver disease (MASLD), chronic kidney disease, and cognitive decline. Furthermore, it reduces glucose uptake in skeletal muscle and accelerates the functional loss of pancreatic β-cells, thereby promoting progression toward T2DM. In summary, available evidence demonstrates that insulin resistance and inflammation constitute interdependent pathophysiological mechanisms driving the onset and progression of chronic metabolic diseases.