Pancreatic β-cell remodeling in health and aging: Lessons from rodents and humans

Pancreatic β-cells are essential for maintaining glucose homeostasis throughout life. Although rodent models have been instrumental in elucidating β-cell biology, notable differences exist between rodents and humans across fetal, postnatal and adult stages. This review provides a comparative analysis of β-cell development, proliferation and regenerative capacity between these two species, highlighting critical divergences that must be considered when translating preclinical findings to human therapies. During fetal development, distinct temporal patterns of hormone expression and islet architecture are observed, with human β-cell maturation extending postnatally. Postnatal β-cell expansion in rodents is driven predominantly by replication, whereas in humans, proliferation peaks within the first two years of life and declines sharply thereafter. Adult human β-cells exhibit limited regenerative capacity compared to rodents, attributed to intrinsic constraints such as elevated expression of cell cycle inhibitors and chromatin remodeling associated with aging. Additionally, key signaling pathways that robustly stimulate β-cell proliferation in rodents are less effective in humans. Understanding these species-specific differences is vital for the development of therapeutic strategies aimed at β-cell preservation and regeneration in diabetes. Here, we emphasize the need for human-relevant models, including stem cell-derived β-cells and pancreatic organoids, to bridge the translational gap. Future research should prioritize uncovering mechanisms that can safely and effectively enhance β-cell mass in humans, acknowledging the distinct biological landscape that aging imposes on human pancreatic β-cells.