Exercise preserves β-cell function in type 2 diabetes by reshaping intra-islet macrophage-β-cell crosstalk

Abstract Type 2 diabetes (T2D) is characterized by pancreatic islet β-cell dysfunction and systemic insulin resistance, with meta-inflammation playing a critical role in disease progression. As the major type of immune cell population in islets, both resident and recruited macrophages are important regulators of the islet immune microenvironment under physiological and T2D conditions. Exercise is an effective strategy for treating T2D, yet its impacts on islet inflammation and β-cell dysfunction remain elusive. Here, we established a mouse model of exercise intervention in obesity-associated T2D by combining high-fat diet (HFD) feeding with treadmill running. Notably, exercise markedly improves glucose tolerance and insulin sensitivity, accompanied by substantial mitigation of HFD-induced β-cell dysfunction, islet hypertrophy, and alterations in β-cell subpopulations. Exercise also reduces intra-islet infiltration of CD45+ immune cells and dampened pro-inflammatory gene expression, indicating robust attenuation of islet inflammation. Using untargeted plasma proteomics, we identified the secreted protein acidic and rich in cysteine (SPARC) as a circulating factor, whose suppression is associated with exercise-linked islet protection under HFD conditions. Mechanistically, our data support a model in which SPARC contributes to β-cell dysfunction, at least in part, through macrophage inflammasome-related signaling. Further analysis of a human cohort demonstrates that circulating SPARC protein levels are markedly elevated in patients with T2D, exhibiting a significant negative correlation with parameters indicative of insulin sensitivity and β-cell function, and a positive correlation with insulin resistance. Together, this work provides a systemic characterization of the effects of exercise intervention on islet homeostasis and β-cell function, and highlights SPARC as a candidate immuno-metabolic node for T2D intervention.