Pancreatic β-cell turnover in health and disease

Pancreatic β-cell mass is a principal determinant of glucose homeostasis, and its loss or dysfunction underlies both type 1 and type 2 diabetes. Restoring functional β-cell mass whether through replication of existing β-cells, neogenesis from alternative cellular sources, or protection of stressed cells remains a central therapeutic goal. In this review article, we synthesize evidence from rodent and human studies under normal physiology to highlight how β-cell mass is established, maintained, and adapted. We emphasize the steep decline in proliferative capacity after early life, the long lifespan of adult β-cells, and the limited, context-dependent adaptations observed in obesity, pregnancy, insulin resistance, and impaired glucose tolerance. Beyond apoptosis, β-cell dedifferentiation has emerged as a key mechanism of functional decline, whereby mature β-cells lose identity, revert to a progenitor-like state, and contribute to reduced insulin output. We also examine cell-intrinsic brakes on proliferation, the trophic roles of incretins and growth factors, and the debated contribution of neogenesis and transdifferentiation from ductal, acinar, or non-β endocrine lineages. Advances in β-cell mass quantification, including glucagon-like peptide-1 (GLP-1) receptor-targeted imaging, are discussed alongside methodological challenges in human tissue studies. Finally, we review therapeutic avenues such as GLP-1 receptor agonists (GLP-1RAs) that mitigate ER and oxidative stress, restore autophagy, and preserve functional mass. Together, these insights frame testable strategies to prevent β-cell failure and guide diabetes therapies.