Type 2 diabetes (T2D) is marked by insulin resistance together with the progressive failure of pancreatic β-cells. Increasing evidence suggests that this failure is shaped not only by β-cells themselves, but also by the local islet immune microenvironment, where resident and recruited macrophages can influence inflammation, islet architecture, and insulin secretion. Exercise is a cornerstone of diabetes management, yet how it acts within this islet microenvironment has remained unclear.
Recently, a study published in Life Metabolism, led by Prof. Zhuo-Xian Meng and colleagues from Zhejiang University and collaborating institutions, provides a mechanistic view of this question. Using a high-fat diet (HFD)-induced mouse model of T2D combined with treadmill running, the researchers found that exercise improved glucose tolerance and insulin sensitivity, and mitigated HFD-induced islet hypertrophy, β-cell dysfunction, and shifts in β-cell subpopulations. These findings indicate that exercise helps restore not only systemic metabolic control, but also the architecture and functional state of pancreatic islets under metabolic stress.
The immune component of this response was central. Exercise reduced the infiltration of CD45+ immune cells into islets and dampened pro-inflammatory gene expression, suggesting that physical activity can rebalance the islet immune microenvironment. Through untargeted plasma proteomic profiling, the team identified SPARC (secreted protein acidic and rich in cysteine), a circulating protein suppressed by exercise under HFD conditions. Mechanistically, SPARC did not appear to act primarily by directly targeting β-cells. Instead, the data support a model in which SPARC promotes a pro-inflammatory state in islet macrophages, at least in part through inflammasome-related signaling, thereby creating an immune microenvironment that can compromise β-cell function.
Further human evidence strengthens the translational relevance of this mechanism. In functional assays, SPARC impaired glucose-stimulated insulin secretion in human islets as well as mouse islets. In a human cohort, circulating SPARC protein levels were markedly elevated in patients with T2D and were negatively associated with parameters of insulin sensitivity and β-cell function, while positively associated with insulin resistance. Although the cohort analysis remains correlative, these findings connect the mouse mechanistic work to human islet function and clinical metabolic phenotypes.
Together, the study links exercise-induced systemic changes to local immune remodeling within pancreatic islets. By identifying SPARC as a candidate immunometabolic node connecting exercise, macrophage activation, islet inflammation, and β-cell function, the work offers a framework for understanding how exercise may preserve pancreatic endocrine function in T2D. Further studies will be needed to determine whether this pathway can be therapeutically targeted in patients.
DOI
10.1093/lifemeta/loag014