Immune activation induced by dysregulated lipid metabolism in the pathogenesis of type 2 diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is characterized by two core pathological features: Insulin resistance and β-cell dysfunction, with dyslipidemia and immune dysregulation playing critical roles in its pathogenesis. Ectopic lipid deposition and lipotoxicity, resulting from dysregulated lipid metabolism, drive T2DM progression by reshaping immune microenvironments across multiple organs. Over the past two decades, the concept of “immune-metabolic coupling” has gained widespread recognition: Lipotoxicity activates immune cells through pattern recognition receptors, eliciting chronic low-grade inflammation and systematically disrupting insulin signaling pathways. This process involves key metabolic tissues including adipose tissue, liver, skeletal muscle, pancreatic islets, and the intestine. Free fatty acids, inflammatory mediators, extracellular vesicles, and immune cell trafficking collectively form a cross-organ communication network that perpetuates the progression of T2DM. This review systematically summarizes organ-specific immune alterations and their interactive mechanisms, and emphasizes that future research should focus on elucidating the mediators and pathways of inter-organ crosstalk, as well as the origins and migration routes of immune cells. These insights will provide a theoretical foundation for advancing from mere management of T2DM toward the restoration of immunometabolic homeostasis.

Keywords: Type 2 diabetes mellitus; Insulin resistance; Lipid metabolism disorders; Cross-organ communication; Immunity

Core Tip: Type 2 diabetes mellitus (T2DM) is driven by insulin resistance and β-cell dysfunction. This review highlights the innovative concept of “immune-metabolic coupling”, where dysregulated lipid metabolism (dyslipidemia) causes lipotoxicity, activating immune cells and triggering chronic inflammation that disrupts insulin signaling across multiple organs. We focus on the cross-organ communication network that perpetuates T2DM and argue that future research must target this immunometabolic crosstalk to move beyond managing the disease and toward restoring long-term immunological and metabolic homeostasis.