Targeting metabolic inflammation in type 2 diabetes mellitus through exercise: multi-level mechanisms of insulin resistance reversal and precision clinical translation — a review

Insulin resistance (IR) remains the central pathophysiological driver of type 2 diabetes mellitus (T2DM) and is inadequately targeted by current pharmacotherapies. Emerging evidence in immunometabolism identifies metabolic inflammation (meta-inflammation) as a critical mechanistic bridge between chronic nutrient excess and IR progression, primarily through IKKβ/NF-κB and JNK signaling cascades, NLRP3 inflammasome activation, mitochondrial dysfunction, and lipotoxicity. Exercise intervention counteracts these processes via coordinated multi-tiered mechanisms, including AMPK-mediated insulin sensitization, myokine-driven anti-inflammatory modulation, mitophagy-based mitochondrial quality control, liver-muscle-adipose metabolic crosstalk, and epigenetic reprogramming of inflammatory transcriptional responses. However, clinically significant interindividual variability in exercise responsiveness-termed exercise non-response-limits the effectiveness of population-averaged prescription guidelines. This heterogeneity is attributable to genetic polymorphisms, baseline inflammatory burden, gut microbiota composition, and suboptimal exercise protocol design. This review synthesizes mechanistic evidence linking meta-inflammation, exercise, and IR, and proposes a precision exercise medicine framework integrating multi-omics phenotyping (genomics, metabolomics, and microbiome profiling) with data-driven clinical decision-support tools. This approach aims to translate mechanistic insights into individualized therapeutic strategies for the long-term management of T2DM.