Potential role of exercise-associated glucose metabolic reprogramming of immune cells in ameliorating chronic low-grade inflammation in type 2 diabetes mellitus: mechanisms and evidence

Type 2 diabetes mellitus (T2DM) is often accompanied by chronic low-grade inflammation, an important driver of the development and progression of insulin resistance. The functional phenotypes of monocytes/macrophages and T cells involved in inflammatory responses are highly dependent on their intracellular glucose metabolic patterns. Immunometabolic research indicates that, in specific cell types and under particular activation conditions, some pro-inflammatory immune cells exhibit enhanced aerobic glycolysis, whereas some immune cells with anti-inflammatory or regulatory functions rely relatively more on mitochondrial oxidative phosphorylation. However, these metabolic–functional relationships are context-dependent and cannot serve as a universal basis for classifying all immune cells. This gives rise to an integrative hypothesis: beyond glucose-lowering and fat-loss effects, exercise may ameliorate chronic inflammation in T2DM by reshaping the functional profile of immune cells via reprogramming their glucose metabolic programmes. Whether such metabolic shifts serve as a direct mediator of the anti-inflammatory effects of exercise remains to be verified by metabolic flux measurements and mechanism-focused investigations. Centered on the cascade “exercise stimulation → altered immune-cell metabolic flux → remodelled inflammatory signalling → improved glycaemic control”, this review summarises the features of disrupted glucose metabolism in immune cells and their proinflammatory mechanisms in T2DM. This review summarises the plausible molecular bases through which acute exercise and chronic training regulate immune cell metabolism via lactate signalling, the AMPK–mTOR–HIF-1α axis, epigenetic modifications and myokines. It distinguishes evidence obtained from human studies, animal experiments and in vitro cellular investigations, and discusses the effects of aerobic exercise, resistance training and high-intensity interval training, alongside limitations in head-to-head comparative evidence. Acute exercise triggers transient metabolic and signalling perturbations. Whether repeated bouts of exercise induce sustained immunometabolic adaptations through epigenetic regulation and mitochondrial remodelling constitutes the working model advanced herein; its stability and mediating role in patients with T2DM remain unconfirmed. We further perform an evidence-level appraisal of available data and identify critical gaps supporting this hypothesis, including the scarcity of direct metabolic flux measurements, limited accessibility of tissue-resident immune cell samples, and a lack of formal mediation analyses. Future work integrating stable-isotope tracing, single-cell multi-omics and mechanism-driven randomised controlled trials may help clarify whether glucose metabolic reprogramming mediates the anti-inflammatory effects of exercise. Such findings could lay a theoretical foundation for developing personalised exercise prescriptions for T2DM based on immunometabolic subtyping.